KDM2B- and SETD1B-Related Disorders and 12q24.31 Microdeletion

Class of neurodevelopmental disorders of the 12q24.31 region caused by epigenetic chromatin regulators: KDM2B-related disorder (CxxC, JmjC and loss-of-function groups), 12q24.31 microdeletion syndrome and SETD1B-related disorder, with the paralogue KDM2A (11q13.2) in subsections of its own.

Literature and regulatory information updated: 1 November 2026.

0. Initial Reference Table

1. Introduction

1.1. Historical overview and molecular discovery

The 12q24.31 region entered the clinical literature before any of its genes had been associated with a monogenic disorder. In 2010, Baple, Palmer and Hennekam described the first de novo interstitial microdeletion of 12q24.31, detected by array comparative genomic hybridisation (aCGH) and confirmed by fluorescence in situ hybridisation (FISH), in a child whose neonatal presentation (recurrent hypoglycaemia, macroglossia and overgrowth) led to suspicion of Beckwith-Wiedemann syndrome, with a normal study of the 11p15 region; the course included persistent overgrowth, altered glucose homeostasis, marked developmental delay and anxiety, and the authors interpreted the picture as a contiguous gene syndrome, with HNF1A, ACADS and P2RX7 included in the deletion [31]. Isolated reports followed: a deletion of about 1 Mb inherited from a father with insulin-dependent diabetes since the age of 14 [17], a 12q24.31 deletion in a Canadian cohort with autism and intellectual disability studied with a 2.7-million-probe array [36] and an 11-year-old girl with intellectual disability, stereotypies, seizures and dysmorphism, in whom Palumbo and colleagues first proposed SETD1B as a candidate gene [37].

In 2016, Labonne and colleagues narrowed the putative critical region to 445 kb, with seven genes, one microRNA and one non-coding RNA, by comparative mapping of the smallest deletion then known; they proposed KDM2B, which encodes a histone demethylase, and SETD1B, which encodes a histone methyltransferase, about 224 kb apart, as the two most plausible candidates for the intellectual disability, autism, epilepsy and craniofacial anomalies, and observed two patients with deletion of only one of the two genes [38]. In 2018, Hiraide and colleagues described two de novo variants in the SET domain of SETD1B in patients with epilepsy, intellectual disability and autistic behaviour, and suggested that SETD1B dysfunction would be the core defect of the deletion [39]. In 2019, Krzyzewska and colleagues defined a DNA methylation signature specific to SETD1B loss-of-function variants, which allowed two variants of uncertain significance to be reclassified [40]. SETD1B-related disorder was then delineated in series from 2021 and 2022 and brought together in GeneReviews in 2022, with 38 individuals [7].

The direct involvement of KDM2B began with a Japanese family with dominant inheritance of minor marfanoid-type anomalies, intellectual disability and schizophrenia, in which positional cloning and exome sequencing identified the variant NM_032590.5:c.2173G>A p.(Ala725Thr) (described in NM_032590.4, with the same numbering) in the PHD domain, with KDM2B expression in lymphoblastoid lines reduced to about half, no change in H3K4 methylation, and an allele frequency of 0.0004 in a Japanese population database [19, 41]; this variant was later considered of uncertain significance, because it lies outside the JmjC and CxxC domains [3]. The founding article on KDM2B-related disorder is that of van Jaarsveld and colleagues, published electronically on 1 November 2022 and included in the 2023 volume of Genetics in Medicine: starting from an index case with the de novo variant c.1912G>A p.(Gly638Ser), detected by trio exome sequencing in a child with speech delay, autism and congenital heart disease, the authors gathered through GeneMatcher, the literature and internal databases 27 individuals from 22 families, of whom 21 had a pathogenic or likely pathogenic variant, and defined a DNA methylation episignature specific to the gene and a sub-episignature for CxxC domain variants [12]. Before this work, two sporadic patients and one family with missense variants of uncertain significance had been described, without a delineated monogenic disorder [12].

In 2025, van Oirsouw and colleagues showed that CxxC domain variants reduce the binding of the protein to DNA and cause a distinct syndrome, more extensive and more penetrant than haploinsufficiency, with congenital heart disease in 14 of 18 patients [3]. In 2026, the same group compiled 68 individuals with KDM2B variants or 12q24.31 microdeletions of up to 2 Mb, organised them into four genotypic groups and concluded that KDM2B contributes strongly to the microdeletion syndrome, which remains a contiguous gene syndrome [13]. In the same year, Ceroni and colleagues extended the spectrum to structural ocular anomalies (anophthalmia, microphthalmia, coloboma and congenital glaucoma) [30] and Gomes and colleagues described three children with CxxC variants and recurrent ocular and dermatological manifestations [42]. OMIM entry #621474 for the CxxC form (NEDCRO) was created on 21 January 2026, based on the 2023 and 2025 series, and last edited on 3 February 2026; the gene entry (*609078) has existed since December 2004 and was updated in January 2026 with the gene–phenotype relationship [18, 19]. Entry #619000 (IDDSELD) dates from August 2020 [20].

1.2. Nomenclature, classifications and reclassifications

The nomenclature of this class is not consistent across databases. OMIM uses Neurodevelopmental disorder with congenital cardiac defects and variable renal and ocular abnormalities (NEDCRO, #621474) and describes global delay with hypotonia, walking and language acquired with mild delay, intellectual disability ranging from learning difficulties to severe, behavioural problems or autistic traits, congenital heart disease in most (septal defects, patent ductus arteriosus, patent foramen ovale) and, variably, single kidney, ocular anomalies, dysmorphism and distal limb defects [1, 18]. OMIM also records the Japanese family with p.(Ala725Thr) only as a "provisional association" in the gene entry, without a phenotype of its own [19]. For SETD1B, OMIM uses Intellectual developmental disorder with seizures and language delay (IDDSELD, #619000) and describes global delay with speech and language disorder, seizures starting in the first years, tending to be myoclonic, behavioural problems (mainly autism and anxiety) and, inconsistently, dysmorphism, tapering fingers and skin pigmentary changes [20]. Orphanet designates the same entity Global developmental delay-facial dysmorphism-atrial septal defect syndrome (ORPHA:717841), with the synonym Neurodevelopmental disorder due to KDM2B-CxxC domain mutation, exact mapping to OMIM 621474, malformation syndrome typology and autosomal dominant inheritance [2]. MONDO maintains a broader concept, KDM2B-related neurodevelopmental disorder (MONDO:0700363), which covers all genotypic groups [1], and GenCC and PanelApp Australia classify the KDM2B–neurodevelopmental disorder relationship (MONDO:0700092) as strong [24, 26]. Patients with loss-of-function or JmjC domain variants have no phenotype entry of their own in OMIM or Orphanet, where KDM2B is also listed in the ORPHA:528084 grouping (non-specific syndromic intellectual disability) [21].

12q24.31 microdeletion syndrome has its own Orphanet code (ORPHA:717812; ICD-10 Q93.5) and Orphanet assigns SETD1B and KDM2B a role in the phenotype [6]. Orphanet links this code to OMIM 619000 with the relation "ORPHAcode narrower than the target code", that is, the microdeletion is represented by the SETD1B phenotype entry (IDDSELD), without the two entities being equivalent [6, 7]. SETD1B-related disorder has no Orphanet code of its own and SETD1B appears in the ORPHA:178469 grouping (autosomal dominant non-syndromic intellectual disability) [22].

1.3. Definition of the entities within scope

KDM2B-related disorder is defined by the presence of a pathogenic or likely pathogenic heterozygous variant in KDM2B, or of a deletion that includes the gene, in an individual with developmental delay, intellectual disability or behavioural problems, with or without congenital anomalies. The 2026 cohort distinguishes four genotypic groups with different clinical implications [13]: the CxxC group, made up of missense variants or small in-frame deletions in the DNA-binding domain, which corresponds to NEDCRO and has a consistent, extensive and penetrant phenotype; the JmjC group, made up of missense variants in the catalytic domain, with incomplete penetrance; the pLOF group, made up of predicted loss-of-function variants (nonsense, frameshift, canonical splicing), also with incomplete penetrance and variable expressivity; and the group of 12q24.31 microdeletions of up to 2 Mb, which include KDM2B and, as a rule, other genes.

12q24.31 microdeletion syndrome is a contiguous gene syndrome, with deletions of 356 kb to 1.66 Mb with no smallest region of overlap, in which KDM2B contributes to the neurodevelopmental core, SETD1B to the epilepsy and other genes, such as HNF1A, to additional manifestations (macroglossia, diabetes) [13]. Larger 12q24 deletions (of several megabases, terminal or interstitial) share part of the picture but include dozens of additional genes and are not attributed to KDM2B alone [43, 44].

SETD1B-related disorder is defined by the presence of a pathogenic or likely pathogenic heterozygous variant in SETD1B in an individual with developmental delay or intellectual disability; the picture is dominated by language delay, often refractory epilepsy and autism, with organ anomalies rare [7]. It belongs to this class because the gene is located at 12q24.31, about 224 kb from KDM2B, because both genes regulate trimethylation of lysine 4 of histone H3 in opposite directions, and because the two disorders have their own episignatures that coexist in deletions including both genes [7, 12, 38].

KDM2A-related disorder does not belong to the 12q24.31 region but is included in this article because it is caused by the paralogue of KDM2B, with the same domain architecture (JmjC, CxxC, PHD, F-box and leucine-rich repeats), the same H3K36me1/2 demethylation activity and an overlapping phenotype that requires molecular differential diagnosis [8, 16]. It is defined by the presence of a pathogenic or likely pathogenic de novo heterozygous variant in KDM2A in an individual with developmental delay or intellectual disability, usually accompanied by prenatal or postnatal growth deficiency, microcephaly, feeding difficulties or mild facial dysmorphism; the delineation series of Anderson and colleagues, published online on 29 December 2025 and in the January 2026 volume of the American Journal of Human Genetics, brought together 18 individuals and established the gene–disease association with studies in human cells, in Drosophila melanogaster and of DNA methylation [8]. Before this work, two de novo missense variants and one de novo frameshift variant had appeared only in large cohorts of autism and neurodevelopmental disorders, without delineation of the phenotype [8], and in 2024 Ren and colleagues described two de novo variants in individuals with intellectual disability, with studies in neural stem cells and brain organoids [45].

The KDM2B gene is also affected by somatic alterations with no described relationship to the germline disease: fusions of KDM2B with EPC1, EPC2, EP400, CITED1 or CREBBP define uterine sarcomas of the BCOR-altered group [46]. These alterations fall outside the clinical scope of this article.

2. Molecular Genetics and Pathophysiology

2.1. The KDM2B gene and protein

The KDM2B gene (lysine demethylase 2B; HGNC:13610; OMIM *609078) is located at 12q24.31, at GRCh38 coordinates 12:121,408,461–121,582,279, and its MANE Select reference transcript is NM_032590.5 (ENST00000377071.9), which encodes the protein NP_115979.3 [1, 11, 19]. The historical symbols and aliases include FBXL10 (F-box and leucine-rich repeat protein 10), NDY1, CXXC2 (CXXC finger protein 2), JHDM1B (JmjC domain-containing histone demethylase 1B), PCCX2 and Fbl10, which appear in the cell biology and oncology literature [11, 12, 19]. As an F-box protein, KDM2B can form part of SCF complexes (with SKP1 and a cullin) with ubiquitin ligase activity, binding to SKP1 through the F-box and to substrates through the other interaction domains [19]. The canonical long isoform (KDM2B-LF) has 1336 amino acids and is organised, from the amino to the carboxyl terminus, into a JmjC (catalytic) domain, a CxxC zinc finger domain, a PHD domain, an F-box domain and a leucine-rich region (LRR) [3]. There is a short isoform (KDM2B-SF), lacking the JmjC domain, expressed in early murine development; in the mouse, the long isoform has 1309 amino acids and the short one, with 776 amino acids, is translated from an internal promoter, begins at the CxxC and is the predominant form in the embryo and in most adult tissues [19]; the two main isoforms contain the CxxC, PHD, F-box and LRR domains, and only the long one contains the JmjC [3, 30].

The JmjC domain removes methyl groups from lysines 4, 36 and 79 of histone H3, with a preference for trimethylated lysine 4 (H3K4me3) and dimethylated lysine 36 (H3K36me2) [5, 12]. The CxxC domain binds unmethylated CpG dinucleotides and directs the protein to CpG islands, which are associated with about 70% of mammalian promoters; in mouse embryonic stem cells, KDM2B occupies about 84% of CpG islands [3]. Through the LRR region, KDM2B interacts with the nuclear components of Polycomb repressive complex 1 (PRC1) and forms the non-canonical PRC1.1 complex, which is recruited to developmental genes [3, 12]. The protein also binds transcribed regions of ribosomal DNA, where it represses ribosomal RNA transcription, and takes part in the cell cycle, metabolic regulation and DNA damage repair [5, 12]. In cell studies summarised in OMIM, JHDM1B localises to the nucleolus and represses ribosomal RNA genes through JmjC-dependent H3K4me3 demethylation, with a negative effect on cell size and proliferation; FBL10 binds through the CxxC to unmethylated CpGs of the JUN promoter and represses JUN-dependent transcription, the loss of which disturbs the cell cycle and increases cell death after ultraviolet radiation; and, in Blm-deficient mice, Fbxl10 behaved as a possible tumour suppressor, with an increased mutation rate after silencing, through a repair process distinct from mismatch repair [19].

The structure of the CxxC domain (PDB entry 4O64) comprises two cysteine-rich clusters (CxxCxxCx4CGxCxxC and CxxRxC) in which eight cysteines tetrahedrally coordinate two zinc ions, a linker segment with the KFGG motif, which confers rigidity, and the KQ motif, which directly contacts the CpG dinucleotide in the major groove; residues Arg610 and Arg649 form hydrogen bonds with the minor groove, and cytosine methylation prevents binding [3, 30].

2.2. Role in development and animal models

Mouse models explain the sensitivity of development to dosage and to the integrity of the CxxC domain. Complete loss of Kdm2b is embryonic lethal, with small body size, failure of neural tube closure, limb and craniofacial malformations and absence of the heart and aorta; homozygosity for an allele lacking the CxxC is also lethal [3]. About 40% of embryos lacking the long isoform have neural tube defects, retinal coloboma and expansion of the neural retina [30]. In the heterozygous state, null animals appear healthy, whereas heterozygous deletion of the CxxC causes partial lethality and skeletal malformations with homeotic transformations, and heterozygous conditional loss of the CxxC in neurons produces deficits in spatial and motor learning, fear conditioning and social behaviour, of autistic type [3, 12]. Similar phenotypes occur in mice lacking RING1A or RING1B, components of PRC1 [3]. In the model of Boulard and colleagues (2015), an allele truncated just after the CxxC, affecting both isoforms, caused complete embryonic lethality in the homozygous state before embryonic day 10.5, whereas heterozygotes were normal and fertile [19]. There is also a bovine model: in the Romagnola breed, in Italy, "paunch calf syndrome" (paunch calf syndrome), with craniofacial deformities, an abdomen distended by fluid, hepatic fibrosis and stillbirth in most cases, results from the substitution Kdm2b p.(Asp835Asn) in a conserved region between the CxxC and the F-box [19].

The protective function of KDM2B over CpG islands has been demonstrated in embryonic stem cells: loss of Kdm2b causes genome-wide hypermethylation of Polycomb-associated promoters (promoters bound only by KDM2B, without PRC, are spared, which suggests that, in the absence of KDM2B, PRC recruits DNA methyltransferases), and re-expression of the short isoform lacking the JmjC restores CpG island methylation and rescues embryonic lethality, whereas CxxC mutants do not rescue differentiation [12, 19]. The protective function against methylation therefore does not depend on demethylase activity [19]. This observation links the disease mechanism to the hypermethylation episignature observed in patients' blood (section 2.6).

2.3. Disease mechanisms: haploinsufficiency and CxxC domain variants

Two mechanisms explain the clinical spectrum. pLOF variants and microdeletions act through haploinsufficiency; KDM2B is intolerant to loss of function in gnomAD (observed/expected ratio 0.09, interval 0.05–0.18, in the version analysed in 2022; 0.19, interval 0.14–0.27, with a probability of loss-of-function intolerance, pLI, of 1 in version 4.1.0) and to missense variants (z of 3.44 in the version analysed in 2022; 4.63 in version 4.1.0) [12, 13, 30]. Missense variants in the JmjC domain cluster clinically with the pLOF variants; in the paralogue KDM2A, JmjC variants reduce protein stability, which also suggests loss of function [13].

CxxC domain variants follow another mechanism. In HEK293T cells, the short and long isoforms with nine CxxC variants are expressed at levels similar to the wild type, which rules out protein degradation; in electrophoretic mobility shift assays (EMSA) with the recombinant CxxC-PHD protein (amino acids 600–750), all the CxxC variants tested reduced binding to unmethylated CpG DNA to less than 30% bound protein (p < 0.0001), and at higher protein concentrations all, except p.(Cys616Arg), maintained a reduction of at least 25% relative to the wild type [3]. The authors propose that loss of binding compromises the recruitment of PRC1.1 and the protection of CpG islands against de novo methylation, in keeping with the more marked hypermethylation of the CxxC sub-episignature, and interpret the effect as dominant negative or, at least, distinct from haploinsufficiency; the assay is in vitro and simplified [3]. The in-frame intragenic deletion p.(Asn579_Ala653del), which removes the entire CxxC, produces in HEK293T a protein about 8.3 kDa smaller, with expression comparable to the wild type with or without a proteasome inhibitor, and the carrier has a CxxC group phenotype [13].

CxxC variants affect zinc coordination (seven of the 15 variants in the 2025 cohort eliminate a cysteine), the KFGG motif (positions 635 and 638) or DNA-contacting residues (Arg610, Arg649); none affects the KQ motif [3]. Seven of the 15 variants occur at positions conserved in the homologous CxxC of KMT2A that carry pathogenic variants in Wiedemann-Steiner syndrome [3]. Rosetta stability prediction classified eight variants as destabilising (ΔΔG > 1) (p.Arg610Gln, p.Cys616Arg, p.Cys630Ser, p.Asp632Tyr, p.Gly638Ser, p.Gly638Asp, p.Cys646Tyr and p.Arg649Pro) [3].

2.4. Population constraint and regions requiring cautious interpretation

The distribution of variants in the population defines regions with different significance. In gnomAD v4.1.0, only 464 of 57,655 missense variants (0.80%) fall in the JmjC, which occupies 12.57% of the protein, and 34 (0.06%) in the CxxC, which occupies 3.44%; class 4–5 pathogenic variants cluster in or near these two domains, where intolerance measured by MetaDome and AlphaMissense is greatest [13]. No missense variant outside these domains has evidence of pathogenicity, and the seven variants of uncertain significance (VUS) outside them that were tested were negative for the episignature [13].

As regards pLOF variants, 5511 of 5657 (97.4%) of those observed in the population lie in exon 1, where nonsense-mediated decay (NMD) is inefficient and there is an alternative initiation codon between exons 1 and 2; there are smaller clusters in the last exon (13; 0.2%), in the penultimate exon (31; 0.5%) and near codon 500 of exon 11 of the canonical transcript (34; 0.6%), upstream of the start of the short isoform and downstream of short isoforms that retain the JmjC [13]. A pLOF variant in these regions should not be interpreted as causing haploinsufficiency without additional evidence [13].

2.5. KDM2B variant spectrum

The following table brings together the variants from the 2023, 2025 and 2026 cohorts and the 2026 cases, normalised in VariantValidator; the c. numbering is identical in transcripts NM_032590.4 (used in 2023) and NM_032590.5 (MANE), as confirmed for c.1912G>A and c.3370C>T [3, 12, 14, 30]. The classification shown is that assigned by the authors according to the 2015 criteria of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP), which may differ from that of clinical laboratories [13].

Other variants illustrate the spectrum: an in-frame intragenic deletion p.(Asn579_Ala653del) that removes the entire CxxC [13]; the de novo VUS c.1627G>A p.(Ala543Thr), c.2297G>A p.(Arg766Gln) and c.3637C>T p.(Arg1213Trp), the last two negative for the episignature [12]; and, in ClinVar, 46 pathogenic or likely pathogenic records involving KDM2B (including large 12q CNVs), among them c.1838dup p.(Cys613fs), c.1913G>T p.(Gly638Val), c.1913G>C p.(Gly638Ala), c.758A>G p.(His253Arg), c.1936dup p.(Cys646fs), c.2913del p.(Gln971fs), c.1945C>T p.(Arg649Trp), c.1946G>A p.(Arg649Gln), c.1847G>T p.(Cys616Phe), c.3325del p.(His1109fs), c.778-2A>G and c.500G>A p.(Arg167Gln), almost all with review by a single submitter [47]. Recent submitters use the designation NEDCRO, including for pLOF variants [47]. No founder variants have been described, nor any divergent historical nomenclature for KDM2B.

2.6. KDM2B DNA methylation episignature

The KDM2B episignature was defined on DNA methylation arrays from peripheral blood: of the samples from 21 individuals, two were excluded for technical error and three did not cluster (5.1, 14 and 19); the remaining 15, with 13 variants, defined a signature of 156 differentially methylated probes, predominantly hypermethylated [12]. The support vector machine classifier gave the training samples a methylation variant pathogenicity (MVP) score above 0.8 and the controls values close to zero; in a specificity test against the EpiSign database, the cases scored above 0.85 and the other disorders below 0.5, with the exception of three disorders that are also hypermethylated: autosomal dominant cerebellar ataxia, deafness and narcolepsy (ADCADN; DNMT1, OMIM 604121), Hunter-McAlpine syndrome (5q35 duplication with NSD1, OMIM 601379) and DYT28 dystonia (KMT2B, OMIM 617284) [12]. A sample with a diagnosis of IDDSELD and a high score corresponded to a microdeletion that included SETD1B but not KDM2B, interpreted as disruption of KDM2B regulatory regions [12, 13].

Within the general signature there is a CxxC sub-episignature: a classifier trained on five CxxC missense samples (107 significant probes, 106 hypermethylated) separates KDM2B cases from controls and the CxxC group from the loss-of-function group, with a mean methylation difference at the hypermethylated probes of 16.56% ± 4.21% in the CxxC group, against 10.38% ± 3.68% in the general signature [12]. The nine CxxC samples tested by EpiSign version 4 in 2025 were all positive for the general signature [3]. In 2026, the cumulative total was 23 positive variants and nine negative (eight missense and one putative splicing variant), with the high-confidence criterion defined by concordance between MVP score, hierarchical clustering and multidimensional scaling [13].

The episignature detected two diagnoses in the same individual: samples 29 and 30, with 12q24.31 deletions that included KDM2B and SETD1B, had both episignatures, and sample 3.1, with Phelan-McDermid syndrome due to a 22q13 deletion and the variant p.(Arg1124Ter), also showed two signatures [12]. The signature served as functional evidence (criterion PS3) for the classification of 15 variants [5, 12].

2.7. Genotype–phenotype correlation, penetrance and expressivity

Genotype–phenotype correlation is the central clinical finding of the class. CxxC variants are associated with a consistent and penetrant phenotype, with congenital heart disease in 14/18, single kidney in 5/18 and ophthalmological anomalies in 10/18, whereas none of the six individuals with pathogenic missense variants outside the CxxC or pLOF variants in the 2023 cohort had heart disease, an ophthalmological anomaly or renal agenesis, and none of the four individuals with a microdeletion including KDM2B and a positive episignature had cardiovascular, ophthalmological or urogenital anomalies [3]. In the founding cohort, heart disease occurred in 6/9 CxxC patients and in 2/8 with pLOF variants, and these two also had Noonan or Phelan-McDermid syndrome; epilepsy was absent with the CxxC variants of this series and present with one JmjC variant, one frameshift and two microdeletions [12]. In the 2026 cohort, the JmjC and pLOF groups show incomplete penetrance and variable expressivity, with developmental delay or intellectual disability in about half, and the four known inherited variants were pLOF or JmjC, all rare, predicted to be deleterious and with a positive episignature [13].

Facial analysis by GestaltMatcher of photographs of 17 individuals showed a consistent gestalt in the CxxC group (97.5% of pairwise distances below the threshold of 0.915), moderate in the microdeletions (70.2%) and low in the JmjC group (36.4%), with 90% of the distances between CxxC and microdeletion above the threshold; the method is based on similarity and the subgroups are small [13].

Sex appears to modulate expression. All the inherited variants but one were transmitted by mildly affected or unaffected men to more severely affected daughters; the published 12q24.31 microdeletions predominate in females (11 against 3), the mouse model shows a correlation between sex and severity, and Kdm2b takes part in X chromosome silencing in the mouse; in the SETD1B cohort there is, by contrast, male over-representation [12, 13]. The same variant may be associated with different pictures: p.(Arg614Pro) caused severe structural ocular anomalies in one boy and single kidney, heart disease and myopic astigmatism in another, without structural anomalies of the eye, and p.(Cys627Tyr) was associated with heart disease and renal agenesis with normal eyes, which points to genetic, environmental or stochastic modifiers [30]. There are no numerical estimates of penetrance.

2.8. The SETD1B gene and the related disorder

The SETD1B gene (OMIM *611055; HGNC:29187), at 12q24.31, encodes SET domain-containing protein 1B, a lysine methyltransferase which, with four additional subunits, forms the catalytic component of a histone H3 lysine 4 methylation complex [7]. The protein translated from the transcript used in the first descriptions (NM_015048.1) has 1923 amino acids, shares about 39% identity with the paralogue SETD1A and 37% with yeast Set1, has the SET and post-SET domains at the C-terminal end and an RNA recognition domain at the N-terminal end, and lacks the HCF1-binding motif present in SETD1A [15]. In immunoprecipitation assays, SETD1B forms part of a complex of about 450 kDa that trimethylates histone H3 lysine 4 in vitro; GeneReviews refers to four additional subunits, whereas OMIM, based on the same 2007 study, lists five non-catalytic components shared with the SETD1A complex (CXXC1, RBBP5, ASH2L, WDR5 and WDR82), and activation of all MLL/SET1 family methyltransferases depends on an RBBP5-ASH2L heterodimer [7, 15]. SETD1A and SETD1B occupy almost non-overlapping sets of euchromatic nuclear speckles, which suggests distinct targets and non-redundant functions; expression is broad, highest in the ovary and testis, and in tumour cell lines SETD1B is recruited to chromatin by the hypoxia-inducible factor (HIF) heterodimer, where it activates a subset of its target genes [15]. The MANE Select transcript is NM_001353345.2 (protein NP_001340274.1) [14]. Loss of SETD1B function is associated with insufficient production of H3K4me3 and DNA hypermethylation at specific loci, which constitutes an episignature of its own [7, 40]. The accepted mechanism is total or partial loss of function, not yet fully confirmed functionally, and GeneReviews allows that variants with other mechanisms might produce distinct episignatures [7]. One example is the de novo frameshift variant in the last exon described by Den and colleagues (2019), NM_015048.1:c.5644_5647del p.(Ile1882SerfsTer118), which in the MANE transcript corresponds to NM_001353345.2:c.5773_5776del p.(Ile1925SerfsTer118), escapes nonsense-mediated decay and predicts a truncated protein, consistent with a gain-of-function effect not yet demonstrated [14, 15, 20].

The pathogenic variants described are missense, nonsense and frameshift variants in the coding region, detectable by sequencing; no multi-exon intragenic deletions or duplications have been described, and no clinically relevant genotype–phenotype correlations have been identified [7]. The first published variants, c.5524C>T p.(Arg1842Trp) and c.5575C>T p.(Arg1859Cys), in the SET domain, were numbered in transcript NM_015048.1 (NP_055863.1), whose coding region has 43 fewer codons than that of MANE from a point lying between codons 978 and 1322 [14, 15, 39]. In NM_001353345.2 they correspond to c.5653C>T p.(Arg1885Trp) (NC_000012.12:g.121827996C>T) and c.5704C>T p.(Arg1902Cys) (NC_000012.12:g.121828047C>T); the original numbering applied directly to MANE gives wrong results (position c.5524 has T in the reference and c.5575C>T would correspond to p.(Gln1859Ter)) [14]. OMIM records them as alleles 611055.0001 (p.Arg1842Trp) and 611055.0002 (p.Arg1859Cys); they were identified by trio exome sequencing in a cohort of 337 individuals with childhood-onset epilepsy, and the most severely affected patient also had variants in KCNH7 (de novo), CNKSR2 (hemizygous), TBX22 and PCDH19, which may have contributed to the phenotype [20]. Krzyzewska and colleagues (2019), who used the numbering of the long transcript, described p.(Arg1885Trp) in a 7-year-old boy, p.(Arg1902Cys) de novo in a 16-year-old boy and p.(Arg1301Ter) de novo in a 13-year-old boy [15, 40]. As the 2018 patients were a 12-year-old girl and a 34-year-old man, these are different individuals, and the two SET domain variants recur in independent patients, despite shared co-authorship between the two studies [15, 39]. In the largest molecular series (Weerts and colleagues, 2021; 36 patients), 32 had heterozygous variants, of which 28 were de novo, one inherited from an affected parent and one inherited from an unaffected parent, with 14 classified as pathogenic and 10 as likely pathogenic; four patients from three families had biallelic variants of uncertain significance inherited from unaffected carrier parents, without proof of a recessive form [20]. Among the alleles selected by OMIM, all de novo, are, in the MANE transcript, the variants of Roston and colleagues (2021) c.2932C>T p.(Gln978Ter), c.3964C>T p.(Gln1322Ter) and c.5833T>C p.(Phe1945Leu), and those of Weerts and colleagues c.284_286delinsA p.(Phe95Ter), the 27-nucleotide inversion c.337_363inv p.(Asn113_Asp121delins9), c.3386C>T p.(Ala1129Val), c.5702C>A p.(Ala1901Glu) and c.5842G>A p.(Glu1948Lys) [14, 15]. In the functional studies of the 2021 series, the protein with p.(Glu1948Lys) colocalised less with the ASH2L subunit than the normal protein, the protein with p.(Ala1901Glu) had abnormal thermal stability and the product of the inversion did not localise correctly to the nucleus; in patients with these variants, the DNA methylation pattern matched the SETD1B episignature [15]. Predicted penetrance is high, and GeneReviews records no confirmed cases inherited from an unaffected parent; the transmission from an unaffected parent described in the 2021 series does not have, in the sources read, the classification of the variant stated [7, 20]. Somatic SETD1B variants appear in haematological neoplasms and in endometrial carcinoma; in the germline disorder a single tubular adenocarcinoma of the sigmoid colon at 30 years has been described, in the 2018 patient with profound intellectual disability and additional variants in other genes, with no paediatric neoplasms reported [7, 20].

2.9. 12q24.31 microdeletion as a contiguous gene syndrome

The 15 microdeletions compiled in 2026 measure 356 kb to 1.66 Mb and have no smallest region of overlap; they encompass 72 coding and non-coding genes, 16 with a LOEUF (upper bound of the confidence interval of the observed/expected loss-of-function ratio) below 0.6 [13]. All affect KDM2B except one, which does not include it but has a positive KDM2B episignature, consistent with disruption of regulatory regions [13]. Individuals with deletions that include neither SETD1B nor other shared haploinsufficient genes have developmental delay or intellectual disability, behavioural problems, dysmorphism and epilepsy, which supports the role of KDM2B at the core of the picture; macroglossia, absent in the KDM2B and SETD1B cohorts, implicates other genes [13]. Epilepsy occurred in 5/11 deletions including SETD1B, and four of the six patients with SETD1B deleted and without epilepsy also had deletion of RNF34, whose silencing increases GABAergic innervation, which the authors propose as a protective effect [13].

Larger 12q24 deletions add genes and manifestations: a 12q24.23q24.31 deletion of about 6.6 Mb, with 122 genes including KDM2B, SETD1B, HNF1A, RNF34, VPS33A, CLIP1, DENR, ACADS and NCOR2, caused complex heart disease, growth restriction and refractory epilepsy [43]; a 12q24.31–32 deletion of 8.6 Mb with HNF1A, DHX37 and SETD1B caused syndromic diabetes and hypergonadotrophic hypogonadism attributed to DHX37 [48]; and terminal 12q24.31-q24.33 deletions of about 9 Mb have been associated with hydrocephalus, polydactyly and severe autism [44]. These pictures are not attributed to KDM2B alone.

2.10. Allelic forms and related entities

For KDM2B, the allelic forms are the four genotypic groups described, which share autosomal dominant inheritance and differ in mechanism and phenotype [13]. The psychiatric phenotype of the Japanese family with p.(Ala725Thr) (schizophrenia) has not been replicated in the cohorts, and the variant is considered of uncertain significance; OMIM keeps this association in the category of provisional associations [3, 19, 41]. The paralogues KDM2A and KDM5A cause neurodevelopmental disorders of their own, whose phenotype does not transfer to KDM2B [5, 8]. For SETD1B, no other intragenic germline phenotypes besides IDDSELD are known [7].

2.11. The paralogue KDM2A: gene, mechanism and variant spectrum

The KDM2A gene (OMIM *605657) is located at 11q13.2 and encodes lysine demethylase 2A, also called FBXL11 or JHDM1A, a nuclear protein with a catalytic JmjN-JmjC domain at the amino terminus, a central CxxC zinc finger and PHD domain, and an F-box and eight leucine-rich repeats at the carboxyl terminus [16]. KDM2A was the first JmjC domain demethylase to be identified: in the presence of iron(II) and alpha-ketoglutarate it removes mono- and dimethylation from lysine 36 of histone H3 (H3K36), producing formaldehyde and succinate [16]. Through the F-box it forms part of SCF E3 ubiquitin ligase complexes (SKP1-cullin-F-box protein) [16]. The CxxC domain binds unmethylated CpG DNA, which keeps the protein in the nucleus; KDM2A represses transcription of centromeric satellite repeats, contributes to the maintenance of heterochromatin and regulates the stability of unphosphorylated nuclear beta-catenin [8]. Expression is ubiquitous, with the highest levels in the brain (mainly the cerebellum and subthalamic nuclei), testis and ovary [16].

Animal models show that the gene is essential. Mice with constitutive inactivation of Fbxl11/Kdm2a die between embryonic days 10.5 and 12.5, with severe growth retardation, reduced cell proliferation, increased apoptosis, reduced Ezh2 and Polycomb-mediated H2A ubiquitination, and increased levels of the cyclin-dependent kinase inhibitor p21Cip1 [49]. Conditional inactivation in the adult causes testicular atrophy and male infertility, through derepression of more than 750 genes during spermatogonial differentiation, increased H3K36me2 and reduced H3K27me3 at CpG-rich promoters and failure of meiotic synapsis [50]. In human neural stem cells and brain organoids, reduction of KDM2A decreases progenitor proliferation, increases apoptosis, brings forward neuronal differentiation and alters synaptic maturation, with modulation of the MAPK pathway through H3K36me2 [45]. Drosophila has a single orthologue (Kdm2) for KDM2A and KDM2B, and its inactivation in the adult causes no evident phenotype under the conditions tested [8].

The mechanism of the human variants has been studied in three missense variants. In the 2026 series, p.(Pro235Leu), in the JmjC domain, shifted the protein from the nucleus to the cytoplasm, carried endogenous KDM2A with it, reduced the levels of both forms and shortened the protein half-life from 7.04 h to 4.35 h in HEK293T cells; p.(Tyr141Cys), in the JmjN subdomain, and p.(His811Asn), in the F-box region, retained predominantly nuclear localisation, with occasional cytoplasmic aggregates [8]. Expressed in Drosophila, the three variants caused eye degeneration, motor deficit and reduced survival greater than those caused by the normal protein, most marked with p.(Pro235Leu), and worsened the phenotype on a background with Kdm2 silenced or inactivated, in which the normal human protein had no effect [8]. The authors concluded that there is a dual mechanism: loss of nuclear function for some variants and additional toxicity through cytoplasmic gain of function for p.(Pro235Leu) [8]. Truncating variants have not been studied functionally; except for those located in the last exon, they are predicted to lead to nonsense-mediated mRNA decay and loss of function [8]. In gnomAD v4, KDM2A is the most constrained gene of the lysine demethylase family for loss-of-function and missense variants (LOEUF 0.06; pLI 1; missense observed/expected ratio 0.49; z 6.9) [8]. The two de novo variants described by Ren and colleagues reduced protein expression [45].

The delineation series included 11 distinct missense variants and seven predicted loss-of-function variants, all absent from gnomAD v4; none was recurrent and only two affected the same residue (Lys776) [8]. The missense variants lie in or near the JmjC domain and around the CxxC domain, the same distribution as the de novo missense variants of KDM2B; seven were predicted to be damaging by several algorithms and four had mixed or benign predictions [8]. The following table presents the variants with nomenclature confirmed in VariantValidator.

Source: Anderson and colleagues (age at last assessment) [8]; nomenclature confirmed in VariantValidator on 1 November 2026 [14]. F, female; M, male; ADHD, attention deficit hyperactivity disorder; IQ, intelligence quotient; IUGR, intrauterine growth restriction.

Some patients appear in more than one publication. The de novo variant c.1676dup p.(Ile560AspfsTer71) was also described in a 13-year-old boy from a French cohort with severe learning and language disorders, with global delay without intellectual disability, ADHD and dysmorphism, with a recruitment centre and authors in common with the 2026 series, which suggests that this is individual 14 [8, 51]. In an autism cohort from Qatar, a de novo variant described as NM_001256405.2:c.1010A>G p.(Lys337Arg), classified as likely pathogenic, corresponds in the MANE transcript to NM_012308.3:c.2327A>G p.(Lys776Arg) (same genomic position, NC_000011.10:g.67250357A>G), the variant of individual 9, with authors in common [8, 14, 52]. ClinVar records, as of 1 November 2026, the variants of the series with the condition "KDM2A-related neurodevelopmental disorder" and additional pathogenic or likely pathogenic submissions without an associated publication, among them NM_012308.3:c.1147C>T p.(Arg383Ter), c.974_984del p.(Arg325LeufsTer3), c.1924_1926delinsACTCA p.(Cys642ThrfsTer96), c.1777_1779del p.(Lys593del) and c.1702C>G p.(Arg568Gly), the latter with the condition "neurodevelopmental disorder" [9, 14]. Multi-megabase 11q13 duplications and deletions that include KDM2A encompass dozens of genes and are not attributed to this gene [9].

DNA methylation in peripheral blood was studied by enzymatic methylation sequencing with a capture panel of about 5.5 million CpG sites, and not by arrays [8]. In the 13 individuals analysed (pLOF and missense variants), comparison with age- and sex-matched controls identified 817 differentially methylated regions; with more stringent filters, the first KDM2A episignature comprised 598 regions (585 hypermethylated and 13 hypomethylated), with a median methylation difference of 16.2% [8]. Four individuals with frameshift variants (14, 15, 16 and 18) and four with missense variants (2, 4, 7 and 8) clustered with the KDM2A profile; four individuals with missense variants (1, 5, 9 and 11) clustered with the controls, despite de novo variants and a compatible phenotype, and in the case of p.(His811Asn) despite toxicity demonstrated in Drosophila [8]. A 19th individual, adopted at 2 months, with a missense variant of undeterminable origin and methylation similar to that of controls, was excluded from the series [8]. As in the KDM2B disorder, the predominance of hypermethylation is the direction of the profile, but the two signatures have not been compared with each other [8, 12].

As of 2026, no genotype–phenotype correlation has been established. Feeding difficulties occurred only in carriers of missense variants, as did microcephaly, except for the fetus with a nonsense variant; the other manifestations appeared with both variant types [8]. There are no penetrance data, because all variants of known origin were de novo in affected individuals [8].

3. Clinical Spectrum and Manifestations by System

3.1. Origin and limits of the data

All the clinical data for this class come from case series recruited through genotype-sharing platforms (GeneMatcher), the literature, diagnostic laboratories, ERN ITHACA and the UK 100,000 Genomes programme [3, 12, 13]. They are cohorts of patients referred for genetic testing because of developmental delay or congenital anomalies, assessed at different ages, mainly in childhood, with denominators that vary between manifestations because not all patients were assessed for each one. These frequencies describe diagnosed patients and not the natural history of all carriers, and tend to overestimate severity in the groups with incomplete penetrance. The documented natural history is that of patients who received usual care (cardiac surgery, shunting for hydrocephalus, developmental therapies), with no untreated cohorts for comparison. The main series are the 2023 founding cohort (27 individuals, 21 with a pathogenic or likely pathogenic variant) [12], the 2025 CxxC cohort (19 individuals, 18 with a pathogenic variant) [3], the 2026 compilation (68 individuals; 47 with a pathogenic or likely pathogenic variant, divided into microdeletion n = 15, pLOF n = 5, JmjC n = 8 and CxxC n = 18) [13], the 2026 synthesis of 21 CxxC cases [30] and, for SETD1B, the 38 individuals in GeneReviews [7] and the 28 used in the 2026 comparison [13], whose frequencies of seizures (20/28), intellectual disability (21/25) and autism (18/28) coincide with those of the clinical series of Weerts and colleagues (2021) [20].

3.2. Comparison by genotypic group

ᵃ Includes two individuals with a second genetic diagnosis (SHOC2-related Noonan syndrome and Phelan-McDermid syndrome), which explains part of the heart disease in this group. ND, not determined. Source: van Oirsouw et al. 2026, table 2, with the SETD1B cohort taken from the literature [12, 13].

The 2026 cohort described for the first time bilateral iridocorneal adhesions, tibial bowing, craniosynostosis and splenic cysts; the sources read do not assign each of these findings to a genotypic group, and the tibial bowing belongs to a patient from an already published family [13].

The core shared by all groups is developmental delay or intellectual disability with mild, non-specific dysmorphism. What distinguishes the groups is heart disease, single kidney, nasolacrimal duct stenosis and planovalgus foot in the CxxC group; macroglossia and anxiety in the microdeletions; and epilepsy in the microdeletions and in SETD1B disorder [13].

3.3. CxxC form (NEDCRO)

Development and cognition. All 18 patients in the 2025 CxxC cohort had developmental delay in one or more domains, mainly early speech delay (18/18) and motor delay (15/18), with cognitive function ranging from below-average intelligence quotient to severe intellectual disability without language; intellectual disability or learning difficulties in 10/13 assessed [3]. The 2026 synthesis of 21 CxxC cases gives speech delay in 21/21, motor delay in 18/21 and intellectual disability or learning difficulties in 10/13 [30]. Motor delay tends to improve with age, whereas speech delay persists in childhood; a boy with gross motor delay at 4 years had at 12 years only mild fine motor difficulties [3]. There are patients with severe structural anomalies and normal cognition, such as a 19-year-old young woman with anophthalmia and microphthalmia without cognitive impairment or speech delay [30].

Behaviour. Behavioural problems occur in 8/18, autism or autistic traits in 6/18 and attention deficit hyperactivity disorder (ADHD) in 3/16; tantrums, anxiety and self-injury by skin picking have been described [3]. The frequency of autism is lower than in the microdeletions and in SETD1B disorder [13].

Cardiovascular system. Congenital heart disease occurs in 14/18 (78%) in the 2025 cohort and in 17/21 in the 2026 synthesis, mainly atrial septal defect (ASD; 11/18), patent foramen ovale (PFO; 5/18), ventricular septal defect (VSD; 4/18), pulmonary stenosis (4/18) and patent ductus arteriosus (PDA; 4/18) [3, 30]. Atrial septal aneurysm, bicuspid aortic valve, ventricular dilatation, mild mitral regurgitation, fetal atrial flutter and double outlet right ventricle (the latter in a patient with a pLOF variant and a 22q13 deletion) have been described [3, 12]. Several patients required surgical closure of an ASD or VSD, and in one family the sister of a patient had an ASD that closed spontaneously [3].

Urinary and genital system. Urogenital anomalies occur in 8/18, with single kidney in 5/18 (unilateral renal agenesis), renal cysts with asymmetric kidneys, vesicoureteric reflux and cryptorchidism [3, 12]. The 2026 synthesis gives renal agenesis in 6/21 [30]. In the founding cohort, unilateral renal agenesis and ocular anomalies occurred only in CxxC patients [12].

Eye and adnexa. Ophthalmological anomalies occur in 10/18 in the 2025 cohort and in 13/21 in the 2026 synthesis [3, 30]. The most frequent are myopia (4/18), stenosis or absence of the nasolacrimal duct (3/18), strabismus and astigmatism, with cases of megalocornea, Duane anomaly and intermittent exotropia [3]. Severe structural ocular anomalies occurred in 3/21 CxxC cases and were not observed outside this group: unilateral anophthalmia with sensorineural hearing loss (p.Cys616Arg), coloboma (p.Cys616Tyr), bilateral congenital glaucoma with iris hypoplasia, corectopia, posterior embryotoxon and chorioretinal coloboma (p.Arg614Pro), and left anophthalmia with right microphthalmia (p.Cys627Ser) [12, 30]. The three children in the 2026 series of Gomes and colleagues had myopic astigmatism [42].

Central nervous system. Brain imaging was abnormal in 5/10, with intracranial cysts (arachnoid cysts, posterior fossa cyst) in 3/10 and ventriculomegaly in 3/10; one patient required shunting for hydrocephalus and another surgical removal of a 25 mm arachnoid cyst [3]. Seizures are infrequent in the CxxC group (2/18); one infant had focal epilepsy from the first month of life, treated with sodium valproate [3]. Hypotonia occurs in 7/16, with spasticity in one patient [3].

Growth. There is a tendency towards below-average postnatal growth: height ≤ −1 standard deviation (SD) in 6/18 and weight ≤ −1 SD in 6/16; microcephaly in 4/15 and macrocephaly in 2/15 [3]. One patient had faltering growth with temporary gastric tube feeding [3].

Feeding. Feeding difficulties occur in 6/11, including food selectivity and neonatal difficulties [3].

Skeleton and limbs. Skeletal or limb anomalies occur in 12/18 (14/21 in the 2026 synthesis), with planovalgus foot (5/18), sandal gap, postaxial polydactyly of the feet, clinodactyly, joint stiffness, hip dysplasia, Perthes disease, pectus carinatum, genu valgum, kyphosis, talipes calcaneus and leg length discrepancy [3, 12, 30]. A patient with p.(Asp632Tyr) had hypertonia with progressive contractures and an inguinal hernia [12].

Dysmorphism. Dysmorphism is present in 17/18 [3]. The recurrent features are long arched eyebrows, downslanting palpebral fissures, a bulbous nasal tip, a prominent Cupid's bow, full cheeks, asymmetric or dysplastic ears and prominent ear lobes [3, 13]. In the 2023 cohort, CxxC patients had a broad nasal tip, large lobes and a pronounced Cupid's bow, without a consistent facial gestalt being recognised at the time [12].

Teeth, skin and other systems. Delayed tooth eruption and persistence of deciduous teeth requiring extraction, oligodontia and crowded teeth have been described [3, 30]. Gomes and colleagues highlighted haemangiomas, hypertrichosis and atopic dermatitis [42]. Hypoglycaemia occurred in 2/18 [13]. Laryngomalacia, umbilical hernia and bifid uvula appear in isolated reports [3].

3.4. Loss-of-function (pLOF) and JmjC variant forms

In these groups the picture is less consistent: intellectual disability or learning difficulties in 4/5 (pLOF) and 4/8 (JmjC), speech delay in 2/4 and 4/7, behavioural problems in 4/5 and 4/7, autism or autistic traits in 3/5 and 2/7 and seizures in 1/5 and 2/8 [13]. In the founding cohort, the 15 patients without a microdeletion or a second diagnosis all had speech delay, developmental delay, learning difficulties or intellectual disability, with autism or ADHD in 9/15 and normal growth in most [12]. Organ anomalies are rare and do not include single kidney: the heart disease in the pLOF group (3/5) is concentrated in patients with a second diagnosis, and the JmjC group has no heart disease (0/8) [13]. Congenital ptosis, cryptorchidism and malformation of cortical development have been described [12].

The family with the JmjC variant p.(Val316Ile) illustrates variable expressivity: a 15-year-old boy with mild intellectual disability, autism, ADHD and epilepsy, his 21-year-old sister with moderate intellectual disability, autism and anxiety, and their 65-year-old father with learning difficulties, mild intellectual disability, reduced renal function and osteoporosis in adulthood [12]. In the family with p.(Arg1124Ter), the daughter had severe intellectual disability and a concomitant 22q13 deletion, and the 42-year-old father had learning difficulties and attention deficit disorder [12].

3.5. 12q24.31 microdeletion syndrome

Microdeletions are associated with intellectual disability (12/14), behavioural problems (13/14), mainly autism (10/14) and anxiety (6/14), and with epilepsy in 7/14 [13]. Macroglossia or protruding tongue (8/13) is the feature that most distinguishes this group [13]. In the neonatal period, the combination of macroglossia, overgrowth and hypoglycaemia can mimic Beckwith-Wiedemann syndrome [31]. Heart disease is less frequent than in the CxxC group (3/13), with ASD, PDA and PFO [13]. Other findings described are bilateral hip dislocation, cutis marmorata, Hashimoto's thyroiditis, scoliosis, hyperlordosis, cryptorchidism, polycystic kidney disease, delayed bone age, cutaneous T-cell lymphoma, café-au-lait spots, eczema and pigmentary changes [7, 13, 36]. The case described by Chouery and colleagues (a girl aged 2.3 years) had infantile spasms, hypotonia, microcephaly, a flat face, full cheeks, macroglossia, a high-arched palate, retrognathia, narrow ear canals and café-au-lait spots [17]; the 11-year-old girl described by Palumbo and colleagues had seizures, spastic tetraparesis, stereotypies, anxiety, macroglossia, neonatal hypoglycaemia and hypocalcaemia, and PFO [37, 43].

Glucose metabolism depends on whether HNF1A is included. The five individuals with a deletion that included HNF1A had obesity or diabetes at some point, and one had neonatal hypoglycaemia due to hyperinsulinism [13]. The father in the Chouery case, cognitively normal, had insulin-dependent diabetes at 14 years [12, 17]. In the published deletions with HNF1A and diabetes, the diabetes began in early adolescence [48]. Larger deletions add other phenotypes, such as growth restriction, complex heart disease (tricuspid atresia with single ventricle), hypergonadotrophic hypogonadism, conductive hearing loss, hydrocephalus and polydactyly [43, 44, 48].

3.6. SETD1B-related disorder (IDDSELD)

Development and cognition. Global developmental delay occurs in 36/38 and speech delay or disorder in 34/37; of the individuals whose age at first word is known, 14/30 spoke after 2 years, three were non-verbal at 2.5, 3 and 3.5 years, and independent walking appeared between 12 months and 4.5 years [7]. Developmental regression, mainly of language, occurred in 6/38 and did not always coincide with the onset of seizures [7]. Intellectual disability (25/38) is usually mild (13) or moderate (10), with one severe and one profound case [7].

Epilepsy. Seizures (30/38) usually begin before 5 years, with six cases of later onset and two before 6 months; the types are heterogeneous and often multiple or evolving (absences 18, myoclonic 13, generalised tonic-clonic 12, focal 4, atonic 2), with eyelid myoclonia in at least four [7]. Seizures are daily in most, worsen with age and were intractable in at least four; no antiseizure medicine has shown consistent efficacy [7].

Behaviour. Autism was diagnosed in 22/37 and autistic traits in four more; about half have other behavioural problems (hyperactivity 10, aggressiveness 9, anxiety 6, sleep disturbance 6, obsessive-compulsive behaviour 3), more frequent in males [7].

Published cases. The individual reports summarised in OMIM show the breadth of the picture [20]. A Japanese girl had, at 2 years and 9 months, refractory myoclonic seizures with neck anteflexion and upward eye deviation, which evolved into myoclonic absences, with diffuse 2–3 Hz spike-and-wave discharges on the electroencephalogram (EEG); she became seizure-free at 6 years on polytherapy, walked at 20 months and, at 10 years and 9 months, had an intelligence quotient (IQ) of 64, normal language and autism. A 34-year-old Japanese man, with myoclonic seizures from 4 years and generalised tonic seizures from 6, partially controlled, had an IQ of 10, anxiety, autism and dysmorphism (square face, thick eyebrows, downslanting palpebral fissures, flat occiput, full cheeks and lower lip, slightly tapering fingers), with a normal brain MRI. Another Japanese girl began at 2 years to have fever-associated myoclonus, followed by daily myoclonic seizures, with language delay and autistic behaviour, without dysmorphism. In the series of Roston and colleagues (2021; four patients aged 3.5 to 19 years), seizures began between 2 and 3 years in three and at 12 years in one, with myoclonus, eyelid myoclonia, facial jerks, absences and tonic-clonic seizures, difficult to control in some; joint hyperlaxity, lumbar hyperlordosis, inguinal hernia, eczema or pigmentary changes, periodic hand tremor and persistent fetal finger pads have been described. Krzyzewska and colleagues also described cleft lip and palate and oligodontia, and in the series of Weerts and colleagues (28 patients) there was sleep disturbance in 6/25, with a high anterior hairline, thick arched or straight eyebrows, deep-set eyes, thin lips and a prominent nose [20].

Other systems. Hypotonia occurs in 15/34; brain magnetic resonance imaging (MRI) is abnormal in 8/34, with non-specific findings (white matter hyperintensities, corpus callosum abnormalities, delayed myelination, heterotopia) [7]. Facial dysmorphism (35/38) is non-specific, with ear anomalies, a high anterior hairline, frontal bossing and coarse features; it is not known whether the coarse features result from antiseizure medication [7]. There is strabismus (4/38), astigmatism, amblyopia, myopia and feeding difficulties (3/32); organ anomalies are single cases (dysplastic kidneys with transplantation, cryptorchidism, hearing loss, hypoplastic left heart syndrome, PDA) [7]. The male to female ratio is about 1.7:1 (24/38 male) [7].

3.7. Course in adulthood

Data on adults are scarce and come from family studies. The following have been described: a 42-year-old man with a pLOF variant, learning difficulties, attention deficit disorder and chronic obstructive pulmonary disease; a 65-year-old man with a JmjC variant, mild intellectual disability, reduced renal function and osteoporosis; a 21-year-old woman with moderate intellectual disability, autism and anxiety; a 21-year-old man with a CxxC variant and mild intellectual disability; and an adult man with a microdeletion that included HNF1A, cognitively normal, with diabetes from 14 years [3, 12]. In SETD1B disorder, one adult had microcephaly and another, a man with profound intellectual disability and partially controlled epilepsy, had colon adenocarcinoma at 30 years [7, 20]. There are no data on life expectancy.

3.8. KDM2A-related disorder

The clinical data come from a single international series of 18 individuals (17 born, aged between 3 and 25 years at last assessment, and one fetus), gathered through collaboration and GeneMatcher with a standardised questionnaire, all identified by exome or genome sequencing after negative analysis of the known disease genes [8]. Selection by neurodevelopmental phenotype and the size of the series preclude estimation of population frequencies, and the data describe natural history without targeted treatment.

Source: Anderson and colleagues [8]. ADHD, attention deficit hyperactivity disorder; IUGR, intrauterine growth restriction.

Development is the axis of the picture. Most have mild delay, with acquisition of language, and four individuals have severe disability, two without language at 8 and 25 years; none lost acquired skills [8]. Growth is the second axis: growth restriction often begins before birth, short stature persists in childhood and one patient had delayed bone age [8]. Feeding difficulties are concentrated in the neonatal period, with tube feeding needed in two patients, and two continue to have poor weight gain later [8]. Epilepsy is not constant and has a heterogeneous course: two patients still had seizures at the last assessment (focal seizures from 10 years and generalised seizures from 9 years), and three became seizure-free, including an infant with epileptic spasms at 5 months [8]. Behaviour includes autism, ADHD, aggressiveness and anxiety [8]. The facial gestalt is subtle and was recorded in two thirds of patients; the authors suggest that facial phenotyping assisted by facial recognition tools may come to help with recognition, without published validation [8].

Manifestations outside the nervous system and growth were isolated: cryptorchidism, supernumerary nipple, inverted nipples, bilateral club foot, umbilical hernia and delayed tooth eruption [8]. Unlike the KDM2B CxxC group, there is no recurrent heart disease, renal anomaly or structural ocular anomaly; the cardiac, gallbladder and pancreatic malformations and the diabetes of individual 15 were attributed to a coexisting GATA6 variant [8]. The polymicrogyria of individual 4 has no alternative genetic explanation on trio exome sequencing, but it is not a known manifestation of disorders of the epigenetic machinery, and its inclusion in the spectrum remains open [8]. Data on adults are limited to two 25-year-old individuals, one with severe disability and active epilepsy and the other with mild disability and the malformations associated with GATA6; there is no information on fertility, despite the male infertility of the conditional mouse model [8, 50].

4. Clinical Recognition and Warning Signs

4.1. When to suspect, by age and context

Prenatal period. Ultrasound may show septal heart disease, unilateral renal agenesis, anophthalmia or microphthalmia, ventriculomegaly and intracranial cysts, or polydactyly; ClinVar records a CxxC variant submitted in the context of fetal anomalies with a probable genetic cause [3, 44, 47]. The combination of septal heart disease with single kidney or a structural ocular anomaly in a fetus without aneuploidy suggests the CxxC form, which can be confirmed only by sequencing.

Neonatal period. The warning signs are the association of ASD, VSD, PDA or pulmonary stenosis with single kidney, nasolacrimal duct stenosis, a structural ocular anomaly (anophthalmia, microphthalmia, coloboma, congenital glaucoma) or planovalgus foot, which points to the CxxC form [3, 30]. Macroglossia with hypoglycaemia and overgrowth, with a normal study of the 11p15 region, points to a 12q24.31 microdeletion [13, 31]. Neonatal hypoglycaemia due to hyperinsulinism occurs in deletions that include HNF1A [13].

Infancy and preschool age. The most frequent reason for referral is speech delay, with or without motor delay and hypotonia, in a child with operated heart disease or with a single kidney [3]. In SETD1B disorder, the warning sign is language delay accompanied by absence, myoclonic (including eyelid myoclonia) or tonic-clonic seizures before 5 years, refractory to several antiseizure medicines, or by language regression [7].

School age and adolescence. Learning difficulties, autism, ADHD and anxiety without organ anomalies may be the only expression of the pLOF and JmjC forms [13]. In adolescents with a microdeletion that includes HNF1A, glycosuria on school screening, polydipsia or hyperglycaemia indicate syndromic diabetes [48].

Adults. Diagnosis in adults arises almost only through study of the parents of an affected child, who may have mild learning difficulties or no signs at all [12, 13]. The schizophrenia described in one family with a variant of uncertain significance is not enough to suggest KDM2B in adult psychiatry [41].

4.2. Warning and emergency signs

The signs requiring immediate assessment are: recurrent neonatal hypoglycaemia (microdeletion, especially with HNF1A; also recorded in 2/18 CxxC patients) [13]; signs of raised intracranial pressure or rapid increase in head circumference in a child with ventriculomegaly or an intracranial cyst, given that shunting for hydrocephalus and removal of an arachnoid cyst have been described [3]; raised intraocular pressure or buphthalmos, because of the congenital glaucoma described [30]; status epilepticus or daily refractory seizures, especially in SETD1B disorder and in the microdeletions [7, 13]; signs of heart failure or cyanosis in uncorrected heart disease [43]; and, in deletions with HNF1A, symptomatic hyperglycaemia with weight loss [48].

4.3. Newborn screening

There is no newborn screening for these entities. No biochemical biomarker identifies the disorder; the diagnosis is molecular.

4.4. When to suspect KDM2A-related disorder

Clinical suspicion is non-specific and the diagnosis is almost always made by exome or genome sequencing requested for developmental delay [8]. The combination that should prompt consideration of the gene is intrauterine growth restriction or short stature with developmental delay, microcephaly, neonatal feeding difficulties and mild dysmorphism (epicanthic folds, upslanting palpebral fissures, thin lips), without visceral malformations [8]. In the prenatal period, growth restriction with primary microcephaly was the presentation of the only fetus in the series [8]. The emergency signs are those common to neurodevelopmental disorders: epileptic spasms in infancy, faltering growth requiring nutritional support and regression, the latter not described in the series [7, 8].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Diagnostic criteria

There are no formal clinical criteria. The diagnosis is established by identifying a pathogenic or likely pathogenic heterozygous variant in KDM2B or SETD1B, or a 12q24.31 deletion classified as pathogenic, in an individual with developmental delay, intellectual disability or behavioural problems [7, 13]. Under the ACMG/AMP standards, the terms "pathogenic" and "likely pathogenic" are synonymous for clinical decisions; a variant of uncertain significance (VUS) neither establishes nor excludes the diagnosis [7].

5.2. Diagnostic algorithm

5.3. Exome and genome sequencing

Trio exome sequencing identified the index case of the founding cohort and most subsequent cases [12]. For SETD1B disorder, GeneReviews indicates an exome, genome or multigene panel, given that the phenotype is indistinguishable from many other forms of intellectual disability and epilepsy, and considers single-gene testing rarely useful; sequencing detects 100% of the published pathogenic variants, with no multi-exon deletions described [7]. The 2021 ACMG guideline recommends considering exome or genome sequencing as a first- or second-line test in paediatric patients with congenital anomalies with onset before 1 year or developmental delay/intellectual disability with onset before 18 years, because of the higher diagnostic yield and possibly better cost-effectiveness when requested early [32].

5.4. Chromosomal microarray and CNV analysis

12q24.31 microdeletions are detected by chromosomal microarray; ClinVar records pathogenic deletions ranging from about 316 kb (chr12:121970346–122287290, hg19) to several megabases [47]. The smallest deletion known in 2016 (445 kb) and the 356 kb deletions imply that the array resolution must allow CNVs of this order to be detected [13, 38]. After detection, the laboratory should list the genes included, because inclusion of HNF1A changes surveillance [13]. The in-frame intragenic deletion that removes the CxxC (about 225 coding bp) is not detectable by microarray and requires sequencing with small deletion calling or high-resolution CNV analysis [13].

5.5. DNA methylation episignature

Episignature analysis assesses methylation at about a thousand loci in leucocytes and compares the profile with references from controls and from each known disorder [4]. KDM2B and SETD1B have episignatures of their own [4, 12, 40]. GeneReviews considers the analysis useful as a second-line test when first-line molecular testing has not established the diagnosis and unsuitable as a first-line test; its indications are the presence of a VUS, suspicion of a variant missed because of methodological limitations (large deletions or duplications, non-coding variants, mosaicism) and a phenotype suggestive of more than one disorder with a signature [4]. A positive signature is suggestive, but the diagnosis, confirmation and family studies require identification of the causal variant [4].

The overall performance of EpiSign in clinical practice has been described in a network of laboratories in Europe, the USA and Canada: of the first 207 patients, 57 (27.6%) were positive for a diagnostic episignature, 48/136 (35.3%) in the targeted cohort (prior ambiguous genetic findings or VUS) and 8/71 (11.3%) in the screening cohort (syndromic phenotype without a prior genetic finding), with 4/207 (1.9%) inconclusive [53]. These values refer to the full panel and not to the KDM2B signature. The KDM2B signature was published in 2023 and is not included in the 2022 study that described 19 new episignatures [12, 54].

In practice, the KDM2B episignature is positive with pathogenic pLOF, JmjC and CxxC variants and with microdeletions, and negative with missense variants outside these domains and with the splice variant c.777+5G>A [12, 13]. Results are graded by confidence ("moderate", "strong"); the p.(Arg614Pro) variant had moderate confidence, interpreted as a possible hypomorphic effect, and p.(Cys627Ser) strong confidence with EpiSign version 5 [30]. The CxxC sub-episignature allows the CxxC group to be distinguished from the loss-of-function group [12].

5.6. Variant interpretation

The authors of the cohorts applied the 2015 ACMG/AMP criteria with adaptations: PM1 for variants in the CxxC domain (mutational clustering), PS3 based on the EpiSign result and PP2 because of the constraint on missense variants [12, 30]. The classifications of p.(Arg614Pro) (PS1, PM1_supporting, PM2, PM5, PP2, PP3, PP4) and of p.(Cys627Ser) (PS2, PM1_moderate, PM2, PM5, PP2, PP3, PP4) exemplify the application [30]. The regions associated with pathogenicity (JmjC and CxxC) were defined with MetaDome, AlphaMissense, gnomAD and cohort data; as of 2026, a missense variant outside these domains has no evidence of pathogenicity [13]. pLOF variants in exon 1, in the last two exons or near codon 500 require cautious interpretation [13]. The authors' classification may differ from that of clinical laboratories, and most ClinVar submissions have a single submitter [13, 47].

A variant inherited from a mildly affected or unaffected parent should not be discarded for that reason in the pLOF and JmjC groups, because penetrance is incomplete; trio exome filtering restricted to de novo variants may miss these cases, and the episignature helps to recover them [12, 13]. In the CxxC group, 13/14 pathogenic variants were de novo; the only inherited one, p.(His628Leu), from an unaffected father, remained a VUS, without exclusion of paternal post-zygotic mosaicism [3]. Functional DNA-binding assays are available only in research (UMC Utrecht) [34].

5.7. Limits of testing

A negative result does not exclude the diagnosis. Exome sequencing does not detect deep intronic variants nor, as a rule, deletions of one or a few exons, and its CNV calling has variable sensitivity; microarray does not detect point variants or small intragenic deletions [4, 7]. The episignature exists only for disorders with a known signature, depends on the tissue (patterns validated in blood may not be valid in amniocytes, chorionic villi or fibroblasts), may fail in mosaics with the variant absent or at a very low level in leucocytes and may be negative with variants that have a functional effect (four negative variants in the founding cohort remained VUS) [4, 12]. There is score overlap with disorders that are also hypermethylated (ADCADN, Hunter-McAlpine, DYT28) [12]. There may be a second molecular diagnosis: 2/21 patients in the founding cohort had another genetic disease (Noonan syndrome, Phelan-McDermid syndrome), so an atypical phenotype justifies looking for another cause [12].

5.8. Content of the laboratory report

The report should state the gene, the reference transcript with its version (NM_032590.5 for KDM2B; NM_001353345.2 for SETD1B), the HGVS c. and p. nomenclature, the genomic coordinates with the genome build, the zygosity, the origin when known (de novo confirmed by trio or inherited), the ACMG/AMP class with the criteria applied, the domain affected (CxxC, JmjC or other), the episignature result with the degree of confidence when performed and, for deletions, the coordinates, the size and the list of genes included, with HNF1A and SETD1B indicated [13, 14, 30]. Stating the domain has a direct clinical consequence, because the CxxC group justifies systematic cardiac, renal and ophthalmological assessment [3].

5.9. Prenatal and preimplantation diagnosis

After identification of the variant or deletion in a relative, prenatal diagnosis by chorionic villus sampling or amniocentesis and preimplantation genetic testing are possible [7]. The episignature characterised in blood may not be applicable to fetal DNA from amniocytes or villi and should not replace testing for the variant [4]. In a fetus with ultrasound anomalies without a diagnosis, microarray and trio exome sequencing allow the variant to be identified; the interpretation of an inherited pLOF or JmjC variant in the prenatal setting is limited by incomplete penetrance [13].

5.10. Diagnosis of KDM2A-related disorder

There are no formal clinical criteria; the diagnosis requires the identification of a pathogenic or likely pathogenic heterozygous variant in KDM2A [8]. Trio exome or genome sequencing is the appropriate test, in line with the 2021 ACMG guideline for developmental delay and intellectual disability, and confirmed de novo origin was, in the 2026 series, one of the two inclusion criteria, with the methylation profile as the alternative [8, 32]. As the gene was not associated with disease before 2026, many laboratories evaluated it only in research analyses of candidate genes; reanalysis of previous negative exomes is therefore a route to diagnosis [8]. The report should use the MANE transcript NM_012308.3, state the origin and type of variant and apply the ACMG/AMP criteria, which the authors applied retrospectively with knowledge of the whole cohort [8, 14].

The KDM2A episignature was defined with enzymatic methylation sequencing on a research platform and, as of 2026, is not included in clinical episignature panels; four of 12 carriers of de novo missense variants with a compatible phenotype had a profile similar to that of controls, which shows that a normal profile does not exclude the diagnosis [8]. This interpretation follows the 2024 recommendations on the diagnostic utility of episignatures, according to which the absence of an abnormal profile does not exclude a specific diagnosis [55]. As of 2026, KDM2A disorder also has no OMIM phenotype entry or Orphanet code, which requires the report to describe the condition by the gene name [16, 23].

The limits of testing are those of section 5.7. Missense variants outside the regions already described and inherited variants have, as of 2026, no evidence of pathogenicity, because there are no published inherited cases; a variant inherited from a healthy parent should be interpreted with caution, and its classification depends on additional data [8]. An isolated variant without parental testing and without an abnormal methylation profile does not support the diagnosis, as in the individual excluded from the series [8]. In the prenatal diagnosis of a fetus with growth restriction and microcephaly, trio exome sequencing may identify the variant, but individual prognosis cannot be predicted from 18 cases [8].

6. Differential Diagnosis

6.1. Comparative table

6.2. Differential within the 12q24.31 region

The three entities of the region are distinguished by genetic testing, but the phenotype guides interpretation. Epilepsy is the dominant manifestation of SETD1B disorder (71% in the 2026 comparison, 30/38 in GeneReviews) and is rare in the CxxC group (11%), whereas heart disease, single kidney and nasolacrimal duct stenosis were not described in the 28 SETD1B patients of the same comparison [7, 13]. Macroglossia is almost exclusive to the microdeletions (62%) [13]. In deletions that include both genes, the two episignatures coexist [12]. Sex may weakly guide suspicion: female predominance in the microdeletions and male predominance in SETD1B disorder [7, 13].

6.3. The paralogue KDM2A

De novo variants in KDM2A cause a neurodevelopmental disorder described in 18 individuals, with developmental delay or intellectual disability ranging from learning difficulties to severe, feeding difficulties, intrauterine growth restriction, short stature and microcephaly, with epicanthic folds, upslanting palpebral fissures, thin vermilion of the lip and low-set ears (see 2.11 and 3.8) [8]. The mechanism is dual (loss of nuclear function and, for p.(Pro235Leu), cytoplasmic toxicity), and KDM2A pLOF and missense variants are associated with an episignature of their own [8]. The growth deficiency and upslanting fissures distinguish it from the KDM2B CxxC group, with heart disease and renal and ocular anomalies; confirmation is molecular, and the phenotypes of the two paralogues do not transfer [5, 8].

Sources: Anderson and colleagues, van Oirsouw and colleagues (2025 and 2026) and van Jaarsveld and colleagues [3, 8, 12, 13]. IUGR, intrauterine growth restriction.

The authors of the KDM2A series place it among the Mendelian disorders of the epigenetic machinery, with which it shares developmental delay and growth abnormalities, and cite as examples of a recognisable gestalt Kabuki syndrome (KMT2D, OMIM 147920) and Rubinstein-Taybi syndrome (CREBBP, OMIM 180849) [8, 66]. The distinction is made by sequencing, because the facial picture of KDM2A is subtle [8].

6.4. Disorders of CxxC domain proteins and of the Polycomb complex

Other regulators with a CxxC domain cause disorders with partial overlap: KMT2A (Wiedemann-Steiner syndrome, in which CxxC variants may be associated with a more severe neurodevelopmental picture), KMT2B (intellectual disability and DYT28 dystonia), DNMT1 (ADCADN and hereditary sensory neuropathy IE) and TET3 (Beck-Fahrner syndrome); in these genes, except KMT2A, no CxxC-specific pathogenic variants have been described [3]. Among the PRC1 components, haploinsufficiency of BCOR causes oculofaciocardiodental syndrome and that of RNF2 Luo-Schoch-Yamamoto syndrome [3]. Oculofaciocardiodental syndrome is the closest differential of the CxxC forms with structural ocular, dental and cardiac anomalies, because BCOR forms part of PRC1.1 and interacts with KDM2B [30]. In a series of 34 women from 20 families with heterozygous BCOR variants, all had congenital cataract, 28 (82%) microphthalmia or microcornea, 25 of 26 assessed septate nasal cartilage, 20 of 27 assessed heart disease (septal in 17) and 20 of 22 with dental radiographs radiculomegaly, the cardinal dental sign of this syndrome; skeletal anomalies, mainly syndactyly of the 2nd and 3rd toes and hammer toes, occurred in 28 of 29 [56]. The distinguishing features of the other differentials are also well delimited. Wiedemann-Steiner syndrome combines hypertrichosis of the elbows and back, short stature and a face with long eyelashes and thick laterally extended eyebrows [58]. In KMT2B, DYT28 dystonia begins in the first decade, usually focally in the lower limbs, with later generalisation; in a series of 133 patients, onset was slightly earlier with truncating variants or microdeletions (median 5.0 years) than with missense variants (6.0 years), the penetrance of missense variants was estimated at 85.3%, and deep brain stimulation of the globus pallidus produced significant improvement in the motor subscale of the Burke-Fahn-Marsden scale after one year in 8 of 15 patients assessed [60]. The MRD68 form of the same gene presents with intellectual disability, microcephaly, growth deficiency and feeding difficulties without dystonia, and in one family the mother had MRD68 and her son DYT28, which documents variable expressivity [59]. The two DNMT1 disorders are adult-onset neurodegenerative diseases (cerebellar ataxia, narcolepsy-cataplexy, sensorineural deafness and dementia in ADCADN; sensory neuropathy with hearing loss between 20 and 35 years and cognitive and behavioural decline from the fourth decade in HSN1E), so the overlap with KDM2B is limited to the methylation signature score [12, 61, 62]. Beck-Fahrner syndrome has dominant or recessive transmission, and many heterozygous parents in recessive families have milder behavioural problems, anxiety or learning difficulties [64]. Luo-Schoch-Yamamoto syndrome has been described in two girls with de novo variants in RNF2, with intrauterine growth restriction, early-onset seizures, stereotypies, white matter abnormalities and, in one of them, regression of language and hand use at around 9 years [57]. Hunter-McAlpine syndrome, whose OMIM entry has no assigned gene, resulted in the families studied from a 5q35-qter duplication due to a cryptic unbalanced translocation (with obligate carriers of the balanced translocation) and combines craniosynostosis, microcephaly, almond-shaped palpebral fissures, small mouth and short stature [63].

6.5. Structural ocular anomalies

Anophthalmia, microphthalmia and coloboma are genetically heterogeneous and syndromic in 20–45% of cases, with more than 140 genes on diagnostic panels (for example, panel 509 Structural Eye Disease of the UK PanelApp) [30]. In a screen of 706 families with developmental ocular anomalies, 456 of them without a prior genetic diagnosis, two had KDM2B CxxC variants [30]. CHARGE (CHD7) and Kabuki 1 (KMT2D) are other disorders with an epigenetic mechanism and ocular anomalies [30]. In CHARGE syndrome, the clinical criteria are based on coloboma, choanal atresia, ear anomalies (including the semicircular canals) and cranial nerve involvement; the birth incidence has been estimated at 1 in 12,000, and a national surveillance study in Canada found 3.5 per 100,000 live births, with up to 1 in 8500 in the Atlantic provinces [65]. In Kabuki syndrome, the 2019 international consensus allows a definitive diagnosis at any age when there is infantile hypotonia, developmental delay or intellectual disability and at least one of two major criteria: a pathogenic or likely pathogenic variant in KMT2D or KDM6A, or typical dysmorphism (long palpebral fissures with eversion of the lateral third of the lower eyelid and at least two of: arched eyebrows with a sparse or notched lateral third, short columella with a depressed nasal tip, large or prominent ears, persistent fetal finger pads) [66]. The authors recommend testing KDM2B and its episignature in patients with structural ocular anomalies, especially with congenital heart disease or renal anomaly [30].

6.6. Neonatal overgrowth and hypoglycaemia

12q24.31 microdeletion can mimic Beckwith-Wiedemann syndrome in the newborn, with macroglossia, overgrowth and hypoglycaemia; a normal study of the 11p15 region and a microarray showing a 12q24.31 deletion resolve the differential [31]. Over time, marked developmental delay and anxiety rule out Beckwith-Wiedemann syndrome [31].

7. Treatments and Risk Management Strategies

7.1. Principles and absence of specific guidelines

There is no mechanism-directed treatment, nor any clinical guideline or consensus for KDM2B-related disorder or for 12q24.31 microdeletion; GeneReviews records the same absence for SETD1B disorder [3, 7]. Management is symptomatic and multidisciplinary and rests on three sources of different kinds: the recommendations of the authors of the KDM2B cohorts, which are expert opinion without grading or follow-up intervals [3, 30]; the GeneReviews management model for SETD1B disorder, which applies by extrapolation to the other entities of the class, with the phenotypic differences noted [7]; and, for comorbidities with pharmacological treatment, the ISPAD 2022 guideline for HNF1A-MODY diabetes and the official labels of the medicines, with the extrapolation declared [33, 67–72].

7.2. Evaluation after diagnosis

7.3. Development, communication and behaviour

Early support for speech, behaviour and motor function is the intervention recommended by the authors of the KDM2B series, given the constancy of the speech delay [3]. The GeneReviews model, described for the USA and with variations between countries, provides for referral to early intervention from 0 to 3 years (occupational therapy, physiotherapy, speech and feeding therapy), preschool education with developmental support from 3 to 5 years and, at all ages, an individualised education plan reviewed annually, with a transition plan in adolescence [7]. SETD1B disorder may involve regression even without seizures, so a normal initial assessment does not remove the need for developmental follow-up in early childhood [7]. For expressive language difficulties, assessment by a speech and language therapist experienced in augmentative and alternative communication is recommended [7]. Children with autism may benefit from behavioural interventions, including applied behaviour analysis (ABA, applied behavior analysis), used in patients from the KDM2B series [3, 7]. Severe aggressiveness justifies assessment by child psychiatry, and medication for ADHD may be prescribed when needed [7].

Physiotherapy targets mobility and the prevention of contractures, scoliosis and hip dislocation, with orthoses and positioning devices when needed; several CxxC patients used ankle-foot orthoses [3, 7]. Hypertonia or dystonia may require specialists to manage baclofen, tizanidine, botulinum toxin or orthopaedic surgery [7]. Occupational therapy addresses fine motor skills with an impact on feeding, hygiene, dressing and writing [7].

7.4. Malformations and organ complications

Heart disease. Management follows usual paediatric cardiology practice; in the published CxxC patients there was surgical closure of ostium secundum ASD (for example, at 2 years and 4 months and at 3 years and 4 months) and of VSD, and in one case of complex heart disease (tricuspid atresia, single ventricle) ligation of the ductus arteriosus and a Glenn procedure [3, 30, 43]. There are no data on the postoperative course specific to this class.

Kidney and urinary tract. A single kidney discovered at molecular diagnosis justifies nephrology follow-up according to usual practice for a solitary kidney; in Ceroni's case 1, renal ultrasound performed after the molecular diagnosis revealed left renal agenesis [30]. An adult with a JmjC variant had reduced renal function [12]. Orchidopexy was performed in patients with cryptorchidism [3].

Eye. Congenital glaucoma required trabeculotomy and trabeculectomy at 14 days and implantation of Ahmed valves at 1 and 2 months; anophthalmia required sequential orbital expansion with hydrophilic expanders; absence or stenosis of the nasolacrimal duct was operated on; refractive errors and strabismus are treated in the usual way, with low vision services when needed [3, 7, 30].

Central nervous system. Hydrocephalus was treated with shunting and a 25 mm arachnoid cyst was surgically removed [3]. In a larger terminal deletion, a ventriculoperitoneal shunt was placed at 8 months [44].

Feeding. Feeding therapy is the first measure; gastrostomy may be needed for persistent difficulties, with a low threshold for a videofluoroscopic swallowing study if there are signs of dysphagia [7]. One CxxC patient required temporary gastric tube feeding [3].

Teeth. Persistence of deciduous teeth and delayed eruption led to surgical extraction of deciduous teeth and unerupted canines [3, 30].

Hearing. Hearing aids may be useful, according to the otorhinolaryngological assessment [7].

7.5. Epilepsy

Treatment of epilepsy follows the usual standards by seizure type, led by an experienced neurologist, with caregiver education on the presentations of seizures [7]. In SETD1B disorder, many antiseizure medicines may be effective, but none has shown specific efficacy, seizures are often refractory to several medicines and require frequent follow-up, and there are no published data on the ketogenic diet [7]. For the KDM2B forms there are no response data; a CxxC infant with focal epilepsy from the first month was treated with sodium valproate [3]. In a 7-year-old Saudi child weighing 13 kg with a 6.6 Mb 12q24.23q24.31 deletion, refractory epilepsy was partially controlled with clobazam 14 mg twice daily, levetiracetam 450 mg twice daily and valproic acid 250 mg twice daily; these doses are an individual report and not a recommendation [43]. The sources consulted do not describe antiseizure medicines to be avoided specifically in this class.

7.6. Diabetes in deletions that include HNF1A

Haploinsufficiency of HNF1A in 12q24.31 deletions brings these patients close to HNF1A-MODY diabetes, and the ISPAD 2022 guideline applies by extrapolation, without studies in patients with a deletion [13, 33]. According to ISPAD, diet may suffice initially, but most need medication because of progressive deterioration; these patients are very sensitive to sulfonylureas, which usually give better control than insulin in children and young adults (grade B) [33]. The starting dose of sulfonylurea should be low, about one quarter of the usual adult starting dose, to avoid hypoglycaemia, and, in the absence of hypoglycaemia, maintenance on a low dose (for example, gliclazide 20–40 mg per day) can last for decades [33]. If there is hypoglycaemia despite adjustment of a once- or twice-daily preparation, a modified-release preparation or a short-acting secretagogue with meals, such as a meglitinide, may be considered; in a randomised trial, a GLP-1 receptor agonist (GLP1RA) gave lower fasting blood glucose than a sulfonylurea [33].

The presence of intellectual disability or autism modifies the choice. In the 12-year-old Japanese boy with a 12q24.31–32 deletion and diabetes (HbA1c 10.8%, fasting blood glucose 261 mg/dL, negative autoantibodies, peak C-peptide 3.35 ng/mL on the glucagon test), the team avoided sulfonylurea because of the risk of hypoglycaemia that the patient would be unable to recognise or manage, and started nateglinide with basal insulin glargine; the doses appear only in a figure of the article [48]. This individual approach diverges from the ISPAD first line and is based on safety given the inability to self-manage [33, 48]. The summary of product characteristics (SmPC) and the label of gliclazide were not consulted; the reference dose is that of the guideline.

7.7. Symptomatic pharmacotherapy: ADHD, irritability and aggressiveness

There are no studies of psychotropic medicines in patients with KDM2B or SETD1B disorders. When ADHD, irritability associated with autism or aggressiveness persist despite non-pharmacological interventions, the medicines approved for these indications in the general population are used; the following doses come from the official labels and are applied by extrapolation, because there is no guideline dose for these comorbidities in this class [7, 67–72].

Precautions before starting. Before methylphenidate, the US label requires assessment for heart disease (clinical history, family history of sudden death or ventricular arrhythmia and physical examination) and screening for tics or Tourette syndrome [67]. The Portuguese SmPC requires cardiovascular assessment (blood pressure, heart rate, family history of sudden death), recording of height and weight on a growth chart and psychiatric assessment, and does not recommend stimulants in children or adolescents with known structural cardiac anomalies, cardiomyopathy, serious rhythm disturbances or other serious cardiac problems; certain cardiovascular disorders are a contraindication, unless paediatric cardiology advises otherwise [68]. This precaution applies directly to the CxxC group, in which congenital heart disease occurs in 78%, and requires an echocardiogram and a cardiology opinion before a stimulant [3, 68]. For aripiprazole, the dose should be halved in CYP2D6 poor metabolisers [71].

Adverse effects and management. With methylphenidate, the most frequent effects are insomnia, nervousness, decreased appetite and moderate reduction in weight and height gain with prolonged use in children; the Portuguese SmPC requires monitoring of blood pressure and pulse at each dose adjustment and at least every 6 months, of height, weight and appetite at least every 6 months and of psychiatric status, reassessment of treatment after 12 months and, according to the US label, discontinuation if there is no improvement after one month of adjustment [67, 68]. With risperidone, the effects recorded in children with a frequency ≥ 5% and at least double that in adults include somnolence or sedation, fatigue, headache, increased appetite, vomiting, upper respiratory infections, abdominal pain, dizziness, tremor and enuresis; in children with conduct disorder, weight increased by a mean of 7.3 kg after 12 months (the expected gain at 5–12 years is 3 to 5 kg per year), and there is a risk of hyperprolactinaemia and of extrapyramidal symptoms, a risk factor for tardive dyskinesia [70]. Persistent somnolence is managed by dosing at bedtime, splitting the dose or reducing it [69]. With aripiprazole, the paediatric trials recorded akathisia and parkinsonism, and there is somnolence, fatigue and weight gain, which should be monitored [72].

7.8. Regulatory status

There is no medicine approved, under regulatory review or with an orphan medicinal product designation for the entities of this class, according to the searches of October 2026; a negative search does not prove absence [73]. The status of medicines in Brazil (registration and package insert of the Brazilian Health Regulatory Agency, ANVISA) and the Portuguese SmPC for risperidone were not consulted; the European information used for risperidone is that harmonised in 2008, which may have been updated in national authorisations [70].

7.9. Clinical trials and supporting evidence

None of these studies included patients with KDM2B or SETD1B disorders or with 12q24.31 microdeletion, and the results cannot be transferred without reservation: the population of the risperidone trials had conduct disorder with intellectual disability, and not behavioural problems of monogenic cause, and the diabetes trial included patients with HNF1A variants, not contiguous deletions with intellectual disability [33, 70]. Indirect comparison between these studies is not possible. No negative trials, suspensions or withdrawals were found for these entities.

7.10. Developments in the last 12 months

Between November 2025 and October 2026, all developments were publications of clinical and molecular characterisation, without therapeutic trials or regulatory applications [73]. In December 2025 (electronic publication), a series of three children with CxxC variants highlighted ocular and dermatological manifestations (observational study) [42], and a study of 18 individuals with de novo KDM2A variants with a Drosophila model delineated the paralogue (human study and animal model) [8]. In April 2026, the study of structural ocular anomalies associated with CxxC variants (observational study with screening of 706 families) [30] and the cohort of 68 individuals with the redefinition of 12q24.31 microdeletion (observational study with in vitro functional studies) [13] were published. In June 2026, a 12q24.31–32 deletion with syndromic diabetes due to HNF1A and hypogonadism due to DHX37 was described (case report) [48]. In the same period, OMIM entry #621474 (created on 21 January 2026) and ClinVar submissions with the NEDCRO designation appeared [18, 47]. ERN ITHACA maintains a collaboration call for clinical and genetic characterisation, with a functional DNA-binding assay and induced pluripotent stem cells derived from patients' fibroblasts (translational research, no clinical phase) [34].

7.11. Special populations and particular situations

Pregnancy. In women with epilepsy, mortality in pregnancy is higher and antiseizure medicines reduce that risk; fetal exposure may increase the risk of adverse outcome depending on the medicine, the dose and the period, but this risk is often lower than that of untreated maternal epilepsy [7]. Methylphenidate is not recommended in pregnancy, unless postponing treatment poses a greater risk [68]. Newborns exposed to antipsychotics, including aripiprazole, in the third trimester may have extrapyramidal or withdrawal symptoms (agitation, hypertonia, hypotonia, tremor, somnolence, respiratory or feeding difficulty) and should be monitored [72].

Lactation. Methylphenidate passes into breast milk; one infant with weight loss during exposure, recovered after discontinuation, has been reported, and a risk cannot be excluded [68].

Perioperative care. The sources do not describe specific anaesthetic care. CxxC patients frequently undergo cardiac, ophthalmological, urological or neurosurgical operations in childhood, so prior cardiac assessment and the record of known malformations should accompany the patient [3]. In patients with a deletion that includes HNF1A treated with sulfonylurea, the sensitivity to these medicines and the risk of hypoglycaemia described by ISPAD require attention during periods of fasting [33].

Agents to be used with caution. Stimulants in patients with structural heart disease (Portuguese SmPC) [68]; sulfonylureas at usual adult doses in deletions with HNF1A, because of the sensitivity described, and sulfonylureas in patients who neither recognise nor manage hypoglycaemia [33, 48]; aripiprazole in CYP2D6 poor metabolisers [71].

Transition to adulthood. The transition plan should be included in the education plan in adolescence, and affected young adults should receive genetic counselling on the risks to offspring and the reproductive options [7]. In carriers of a deletion with HNF1A, the age of risk for diabetes extends into adulthood [33].

7.12. Available recommendations and divergences

The available recommendations do not diverge from one another, because they cover different aspects: the authors of the KDM2B series recommend baseline echocardiography and renal ultrasound in all CxxC patients, early developmental support and consideration of ophthalmological examination and brain imaging [3]; Ceroni and colleagues recommend including KDM2B and its episignature in the investigation of structural ocular anomalies [30]; GeneReviews defines the evaluation and surveillance model for SETD1B disorder [7]; and ISPAD defines the treatment of HNF1A diabetes [33]. The relevant divergence is regulatory and concerns the antipsychotics (indication in autism in the USA, absent in the EU) [69–72], and the documented clinical divergence is that of the Japanese case, which preferred nateglinide and insulin to the sulfonylurea recommended by ISPAD for safety reasons [33, 48].

7.13. Management of KDM2A-related disorder

There is no targeted treatment, guideline, consensus, clinical trial or regulatory application for KDM2A-related disorder; the 2026 series makes no management recommendations [8]. Management is symptomatic and follows the multidisciplinary model applied to the other entities of the article, with three priorities defined by the phenotype: growth and feeding, development and behaviour, and epilepsy [7, 8].

Growth and feeding require attention from birth. Neonatal feeding difficulties led to tube feeding in two patients, and poor weight gain persisted in two; assessment by the feeding team and a swallowing study follow the general indications for faltering growth or dysphagia in neurodevelopmental disorders, applied by extrapolation [7, 8]. Short stature justifies assessment by paediatric endocrinology according to usual practice; there are no data on growth hormone secretion or on treatment with somatropin in this disorder, and the delayed bone age of one patient was not followed by a published study [8]. Development and behaviour benefit from the interventions of section 7.3 (early intervention, speech and language therapy, occupational therapy, educational support and behavioural intervention) [7].

For epilepsy, antiseizure medicines are chosen by seizure type, as in section 7.5; three of the five patients with seizures became seizure-free and later stopped medication without relapse, and two still had seizures at the last assessment, with no identification of the medicines used [7, 8]. For ADHD, irritability associated with autism and aggressiveness, the medicines and doses from the official labels in the table of section 7.7 apply by extrapolation (methylphenidate from 6 years, up to 60 mg/day; risperidone and aripiprazole with the indications and the age and weight limits of each jurisdiction), with the same monitoring [67–72]. The reduction in appetite and in weight and height gain with methylphenidate has a particular consequence in a disorder with short stature and feeding difficulties: recording of height, weight and appetite at least every 6 months, required by the Portuguese SmPC, should begin before treatment, with a baseline growth curve [8, 68].

The experimental models do not yet suggest a therapeutic strategy. The cytoplasmic toxicity of p.(Pro235Leu) and the loss of function of the truncating variants indicate different mechanisms between variants, and the approaches the authors point to (functional study of truncating variants, clarification of the cytoplasmic toxicity) are basic research, without a defined preclinical therapy phase [8]. There are no gene therapies or genome editing therapies in development for this disorder in the sources consulted.

8. Reproductive Options and Family Counselling

8.1. Inheritance and origin of variants

All the entities of the class have autosomal dominant inheritance [2, 6, 7]. The proportion of de novo cases differs between groups and shapes counselling. In the CxxC group, 13 of the 14 pathogenic variants in the 2025 cohort were de novo, and the only inherited one (p.His628Leu, from an unaffected father) remained a VUS [3]. In the pLOF and JmjC groups, variants may be inherited from mildly affected or unaffected parents: in the founding cohort, 17 variants were confirmed de novo and 4 inherited, all of paternal origin [12]. In the microdeletions, 10/15 were de novo and one was inherited from a father without a neurodevelopmental phenotype [13, 17]. In SETD1B disorder, most cases are de novo, with one transmission from an affected mother to an affected son, and predicted penetrance is high [7]; in the 2021 series, 28 of 32 heterozygous variants were de novo, one inherited from an affected parent and one from an unaffected parent, and the biallelic variants of uncertain significance found in three families do not establish recessive inheritance [20].

8.2. Incomplete penetrance and effect of sex

The incomplete penetrance of the pLOF and JmjC groups and of the microdeletions has practical consequences: an inherited variant should not be discarded for that reason, and a carrier parent may have only learning difficulties or no manifestation at all [12, 13]. All the inherited variants but one were transmitted by mildly affected or unaffected men to more severely affected daughters, and the published microdeletions predominate in females (11 against 3) [13]. The authors of the founding cohort considered three explanations for the adult man with a microdeletion, a positive episignature and no neurodevelopmental phenotype: variable expressivity, mosaicism (the grandparents were not tested) or lower severity in males [12]. There are no numerical estimates of penetrance by sex; counselling should present the possibility that a female offspring may be more severely affected than the transmitting parent, as an observation from small series [13].

8.3. Recurrence risks by scenario

8.4. Cascade testing and relatives

Testing of the parents is recommended in all cases, to distinguish a de novo variant from an inherited one and to support classification [7, 13]. If a parent is a carrier, the risk extends to relatives on that side [7]. In microdeletions with HNF1A, identification of carrier relatives has its own medical consequence, because of the age-dependent penetrance of diabetes (63% before 25 years, 79% before 35 and 96% before 55 in carriers of HNF1A variants) [33]. The episignature does not replace identification of the variant in family studies [4].

8.5. Prenatal diagnosis and preimplantation genetic testing

Once the variant or deletion has been identified in the family, prenatal diagnosis and preimplantation genetic testing are possible; the appropriate time to discuss the risk and these options is before pregnancy [7]. GeneReviews recognises differences in perspective between professionals and families regarding the use of these tests and considers them a personal decision, with benefit from discussion [7]. In the groups with incomplete penetrance, a positive prenatal result does not allow severity to be predicted, which should be explained before testing [13]. The episignature validated in blood may not be applicable to DNA from amniocytes or chorionic villi [4].

8.6. Counselling of minors and affected adults

Testing asymptomatic minor siblings of a carrier of a pLOF or JmjC variant has no immediate medical benefit demonstrated in the sources, except in deletions that include HNF1A, in which the result guides glycaemic surveillance [13, 33]. Affected young adults should receive counselling on the 50% risk to offspring and the reproductive options [7].

8.7. Counselling in KDM2A-related disorder

KDM2A-related disorder has autosomal dominant inheritance, with all variants of known origin de novo (17/17); the only patient without parental testing was identified by singleton exome sequencing [8]. No inherited cases or cases of parental mosaicism have been published, so penetrance and intrafamilial variability are unknown [8]. After a de novo variant confirmed in the leucocytes of both parents, the risk to siblings has not been quantified for KDM2A; the figure of about 1% used for SETD1B because of the possibility of germline mosaicism applies by extrapolation [7, 8]. The risk to the offspring of an affected person is 50% per pregnancy, with no data on fertility in humans; the mouse model with conditional inactivation in the testis has male infertility, a finding with no demonstrated human counterpart [8, 50]. Prenatal diagnosis and preimplantation genetic testing are possible after identification of the variant in the family, as for the other entities of the article [7]. In the fetus with intrauterine growth restriction and primary microcephaly, trio exome sequencing identified a de novo nonsense variant and the pregnancy was terminated [8].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Frequency

There are no prevalence or incidence estimates for any of the entities; Orphadata has no epidemiological data for ORPHA:717841 or ORPHA:717812 [2, 6]. The available figures are counts of published patients and yields in selected cohorts. Up to April 2026, 68 individuals with KDM2B variants or 12q24.31 microdeletions of up to 2 Mb had been compiled, 47 of them with a pathogenic or likely pathogenic variant [13]. In the 100,000 Genomes programme (aggV2 release), among 78,195 participants in rare disease and cancer cohorts of the UK National Health Service, five had a CxxC variant; this figure measures the frequency in a clinical cohort, not in the general population [3]. In an international cohort of 706 families with developmental ocular anomalies, two had a pathogenic CxxC variant (2/706; 2/456 among families without a prior diagnosis), which measures the diagnostic yield in that context [30]. For SETD1B, GeneReviews counted 38 individuals in 2022 [7]. SFARI Gene assigns KDM2B a score of 1 (high confidence) for autism, with 16 reports, 8 of them of autism, and 51 rare variants [27].

9.2. Geographical distribution and populations

The published KDM2B cases come mainly from the Netherlands, France, the United Kingdom, Italy, Israel and the USA, with cases in Japan (family with p.Ala725Thr and a 12q24.31–32 deletion), Lebanon (inherited deletion), Saudi Arabia (6.6 Mb deletion) and Brazil [13, 17, 41, 43, 44, 48]. The Brazilian case, assessed in São Paulo, has a terminal 12q24.31-q24.33 deletion of about 9 Mb detected by array CGH in 2011, much larger than the typical microdeletions, in a child of first-cousin parents [44]. The sources consulted include no cases from Portugal. No founder variants or differences in frequency between populations have been described, and the concentration of cases in Europe may reflect the origin of the research groups and recruitment through ERN ITHACA more than the distribution of the disease. One of the cases in the ocular anomalies study is a Black boy, which shows that the severe ocular phenotype is not confined to patients of European ancestry [30]. The absence of data from other regions in the sources consulted does not demonstrate the absence of patients.

The KDM2A series was assembled by centres in Germany, the United Kingdom (including Northern Ireland), France, the Netherlands, Switzerland, the USA, Australia and Qatar, according to the authors' affiliations; the article does not state the ancestry of the patients, there are no published cases from Portugal or Brazil and there are no prevalence estimates [8]. The p.(Lys776Arg) variant was recorded in an autism cohort from Qatar and c.1676dup in a French cohort of learning and language disorders [51, 52]. Orphadata has no entity or association for KDM2A, which prevents Orphanet coding of this disorder in registries [23].

9.3. Epidemiological gaps

The available data do not allow estimation of prevalence, of the proportion of de novo cases in the population, of penetrance by sex or of the true frequency of the CxxC form among patients with congenital heart disease and developmental delay. Selection by clinical presentation in the cohorts overestimates severity, especially in the groups with incomplete penetrance, and underdiagnosis of mildly affected adults is likely, given that they are identified almost only through family studies [12, 13].

9.4. European reference networks, registries and patient associations

ERN ITHACA (European reference network for intellectual disability, telehealth, autism and congenital anomalies) is the relevant network and maintains a collaboration call for the clinical and genetic characterisation of KDM2B-related disorder, coordinated by Dr R. Oegema at the Department of Genetics of UMC Utrecht (KDM2B@umcutrecht.nl), which collects clinical and genetic data and DNA samples to refine the episignature and offers optional reanalysis [34]. One of the participating centres of the 2026 cohort belongs to ERN EpiCARE, dedicated to rare and complex epilepsies, which is the relevant network for the refractory epilepsy of SETD1B disorder and the microdeletions [13]. The Dutch foundation Stichting 12q, created in 2015 by families with chromosome 12q alterations, funds research at Erasmus MC [35]. GeneReviews lists the Simons Searchlight registry and North American and Canadian epilepsy associations for SETD1B disorder [7]. No patient association specific to KDM2B was found, which does not exclude its existence.

10. Illustrative Clinical Case

10.1. CxxC variant with congenital glaucoma, renal agenesis and developmental delay

Ceroni and colleagues described in 2026 a 9-year-old Black boy, born at term weighing 3.15 kg [30]. In the neonatal period, bilateral congenital glaucoma with buphthalmos was diagnosed, treated with trabeculotomy and trabeculectomy in the right eye at 14 days of life and with Ahmed valves in the right eye at the first month and in the left at the second month [30]. At 9 years he had right exotropia, asymmetric bilateral myopia (−8.25 dioptres on the right and −0.50 on the left) with buphthalmos, bilateral iris hypoplasia with corectopia, left posterior embryotoxon, a small left anterior capsular cataract present since 8 months (possibly related to the valve), a small left chorioretinal coloboma and optic disc cupping of 0.80 on the right and 0.65 on the left [30]. He had facial asymmetry, a high forehead, bitemporal narrowing, malar hypoplasia, small ears and short stature (117.2 cm at 8 years, below the 3rd centile), generalised delay of dentition with extraction of two persistent deciduous teeth at 8 years and developmental delay with possible autism, without formal assessment [30].

Microarray showed a 1q21.3 deletion (chr1:152,028,001–152,250,046, hg38) considered non-contributory [30]. Exome sequencing identified the variant NM_032590.5:c.1841G>C p.(Arg614Pro) in KDM2B (NC_000012.12:g.121453238C>G), absent from gnomAD v4.1.0 and from the mother, with the father unavailable for testing [14, 30]. The KDM2B episignature was positive with moderate confidence, interpreted as a possible hypomorphic effect, and the variant was classified as pathogenic with criteria PS1, PM1_supporting, PM2, PM5, PP2, PP3 and PP4 [30]. After the molecular diagnosis, renal ultrasound showed a single right kidney, with agenesis of the left, and the echocardiogram was normal [30]. The patient's photographs appear in figure 1A–B of the original article; the description is based on the text and on table 1 [30].

This case shows three points with clinical consequences. The molecular diagnosis led to the discovery of a previously unknown renal agenesis, which supports the authors' recommendation of baseline renal ultrasound in all CxxC patients [3, 30]. The same variant, p.(Arg614Pro), described in another 2-year-old boy with single kidney, heart disease and myopic astigmatism without a structural eye anomaly, illustrates the variability between carriers of the same variant that prevents the phenotype being predicted from the variant [30]. And congenital glaucoma, absent from the 2023 and 2025 cohorts, extends the ocular spectrum beyond refractive errors [30]. The ophthalmological management described is that of congenital glaucoma and does not constitute a recommendation specific to the disorder.

10.2. Microdeletion with HNF1A: syndromic diabetes in adolescence

Nakagawa and colleagues described in 2026 a 12-year-old Japanese boy with an 8.6 Mb 12q24.31–32 deletion that included HNF1A, DHX37, SETD1B, ORAI1 and VPS33A, among other genes; the figure in the article does not mention KDM2B [48]. He had been born small for gestational age (42 cm, −3.81 SD; 2007 g, −3.75 SD) and had autism, conductive hearing loss, short stature, afebrile seizures and severe intellectual disability (developmental quotient of 28 at 5 years) [48]. At 11 years glycosuria was detected on school screening and at 12 polydipsia appeared; HbA1c was 10.8% and fasting blood glucose 261 mg/dL, with negative autoantibodies, a peak C-peptide of 3.35 ng/mL on the glucagon test and a HOMA-IR insulin resistance index of 2.67, and the diabetes was attributed to HNF1A [48]. Follicle-stimulating hormone was raised and testosterone rose from 85 to 498 ng/dL after human chorionic gonadotrophin (3000 IU/m² per day for 3 days), a picture interpreted as hypergonadotrophic hypogonadism due to DHX37 haploinsufficiency [48]. The team avoided sulfonylurea because the patient could neither recognise nor manage hypoglycaemia and started nateglinide, to which basal insulin glargine was added [48]. This choice diverges from the ISPAD 2022 first line, which recommends low-dose sulfonylurea in HNF1A-MODY diabetes, and is justified in the report on safety grounds [33, 48]. The case illustrates the need to check the gene list of a 12q24 deletion and to monitor blood glucose in adolescence when HNF1A is included.

10.3. KDM2A missense variant: severe disability, late-onset focal epilepsy and polymicrogyria

Anderson and colleagues described, among the 18 individuals of the 2026 series, a woman last assessed at 25 years, the first case identified and the starting point of the cohort [8]. She had severe intellectual disability without language, dysarthria, short stature and dysmorphism with upslanting palpebral fissures, a narrow mouth with a thin vermilion of the upper and lower lips and tapering conical fingers [8]. At 10 years she began to have focal seizures, which were not controlled at the last assessment; brain magnetic resonance imaging showed a malformation of cortical development of the polymicrogyria spectrum [8]. Trio exome sequencing identified the de novo variant NM_012308.3:c.956G>A p.(Arg319Gln) (NC_000011.10:g.67219402G>A), absent from gnomAD v4, with no other candidate variant in genes for malformations of cortical development [8, 14]. The methylation profile in blood clustered with the KDM2A profile [8]. ClinVar classifies the variant as likely pathogenic for KDM2A-related disorder [9]. The description does not mention the antiseizure medicines used or rehabilitation interventions [8].

The case shows three points. Identification came from a research analysis of candidate genes after a negative diagnostic exome, which justifies reanalysis of older exomes [8]. Epilepsy may appear late, in later childhood, which keeps seizure surveillance in place throughout childhood [8]. Polymicrogyria, with no other cause identified, cannot yet be attributed to the disorder, and magnetic resonance imaging showed no cortical malformations in the other 12 patients studied [8]. The facial figures of the series were not reproduced.

11. Prognosis and Long-term Follow-up

11.1. Prognosis

Prognostic data are limited to series of mainly paediatric patients and a few adults identified through family studies, with no data on life expectancy [12, 13]. In the CxxC group, morbidity depends on the malformations (cardiac surgery, hydrocephalus with shunting, blindness due to structural ocular anomalies) and on the degree of intellectual disability, which ranges from below-average intelligence quotient to severe disability without language; motor delay tends to improve, and speech delay persists in childhood [3, 30]. There are CxxC patients with severe structural anomalies and normal cognition [30]. In the pLOF and JmjC groups, the course ranges from no manifestations to moderate intellectual disability with autism, and adults aged 42 and 65 years still had mild learning difficulties, with chronic obstructive pulmonary disease in one and reduced renal function and osteoporosis in the other [12]. In the microdeletions, epilepsy (50%) and anxiety (43%) weigh on quality of life, and HNF1A diabetes adds morbidity from adolescence [13, 48]. In SETD1B disorder, seizures are daily in most, worsen with age and are refractory in some patients, and intellectual disability is usually mild to moderate [7].

In KDM2A-related disorder, the prognosis is based on 17 individuals born with follow-up up to 3–25 years: most have mild disability with language, without regression, four have severe disability, short stature persists in childhood and epilepsy, present in five, was controlled in three, with withdrawal of antiseizure medicines; there are no data on life expectancy or on the course in adulthood beyond two 25-year-old patients [8].

11.2. Surveillance table

There are no published surveillance intervals for KDM2B, for 12q24.31 microdeletion or for KDM2A; the "every visit" intervals come from the GeneReviews model for SETD1B, applied by extrapolation, and those for methylphenidate from the Portuguese SmPC [7, 68].

12. Summary and Final Considerations

The disorders of the 12q24.31 region form a class of neurodevelopmental disorders caused by two neighbouring epigenetic regulators with opposite actions on histone H3 methylation: the demethylase KDM2B, which through its CxxC domain binds unmethylated CpG islands and recruits the Polycomb complex PRC1.1, and the methyltransferase SETD1B. KDM2B-related disorder, delineated in 2022–2023, is divided into four genotypic groups. CxxC domain variants (NEDCRO, OMIM 621474, ORPHA:717841) are almost always de novo, reduce DNA binding without degrading the protein and cause a penetrant picture with speech delay in all patients, congenital heart disease in 78% (mainly atrial septal defect), ophthalmological anomalies in 56%, single kidney in 28% and skeletal anomalies in 67%, with a recognisable facial gestalt. Loss-of-function and JmjC domain variants act through haploinsufficiency, have incomplete penetrance and variable expressivity, with intellectual disability in about half, and may be inherited from mildly affected or unaffected parents, especially by daughters. 12q24.31 microdeletion syndrome (ORPHA:717812) is a contiguous gene syndrome: KDM2B explains the neurodevelopmental core, SETD1B the epilepsy and other genes the macroglossia and, when HNF1A is included, adolescent-onset diabetes. SETD1B-related disorder (IDDSELD, OMIM 619000) is characterised by language delay, often refractory epilepsy and autism, without the malformations of the CxxC group.

Diagnosis rests on exome or genome sequencing and microarray, with the DNA methylation episignature as a second-line test to classify variants of uncertain significance, to interpret loss-of-function variants in regions of translation reinitiation and to detect dual diagnoses. Stating the affected domain in the report has a direct consequence, because the CxxC group justifies echocardiography, renal ultrasound and ophthalmological examination at diagnosis. There is no targeted treatment or specific guideline; management combines the recommendations of the authors of the series, the GeneReviews model for SETD1B, the ISPAD 2022 guideline for HNF1A diabetes and the labels of symptomatic medicines, with attention to heart disease before stimulants and to the divergence between the USA and the European Union in the indication of antipsychotics in autism. Counselling should integrate incomplete penetrance, the possible effect of sex, the 50% risk to offspring and the limits of the episignature in prenatal samples. ERN ITHACA coordinates the data collection that will make it possible to define the natural history, the penetrance and the surveillance intervals that do not yet exist.

The paralogue KDM2A, at 11q13.2, causes an autosomal dominant de novo neurodevelopmental disorder, delineated in 2026 in 18 individuals, without an OMIM phenotype entry or an Orphanet code. The picture combines developmental delay, usually mild, with intrauterine growth restriction or short stature, microcephaly, feeding difficulties, inconstant epilepsy and subtle dysmorphism, without the cardiac, renal and ocular malformations of the KDM2B CxxC group. The mechanism combines loss of function and, for at least one missense variant, cytoplasmic toxicity; its own methylation profile is still a research tool and may be normal in carriers of missense variants. Management is symptomatic, with surveillance of growth and feeding from birth.

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