SETD2-Related Neurodevelopmental Disorders (including MRD70) and MRT70 (RSRC1)

Luscan-Lumish syndrome, Rabin-Pappas syndrome, autosomal dominant intellectual developmental disorder 70 and autosomal recessive intellectual developmental disorder 70

Literature and regulatory information updated: 28 October 2026.

0. Initial Reference Table

The name «intellectual developmental disorder type 70» corresponds to two entries in the OMIM catalogue (Online Mendelian Inheritance in Man) with different genes, inheritance and mechanisms: autosomal dominant intellectual developmental disorder 70 (MRD70), caused by heterozygous variants of SETD2, and autosomal recessive intellectual developmental disorder 70 (MRT70), caused by biallelic variants of RSRC1 [1, 2]. MRD70 belongs to the allelic class of SETD2-related neurodevelopmental disorders (SETD2-NDD, neurodevelopmental disorders), which also includes Luscan-Lumish syndrome (LLS) and Rabin-Pappas syndrome (RAPAS) [3, 4]. The table summarises the four entities; in it, ID denotes intellectual disability, ASD autism spectrum disorder, ADHD attention deficit hyperactivity disorder, MCA multiple congenital anomalies, AD and AR autosomal dominant and recessive inheritance, ES/GS exome or genome sequencing, CMA chromosomal microarray, VUS variant of uncertain significance, MANE the reference transcript agreed between NCBI and EMBL-EBI (Matched Annotation from NCBI and EMBL-EBI) and ERN European Reference Network.

1. Introduction

1.1. Scope and definition of the entities

SETD2-related neurodevelopmental disorders form a clinical spectrum of monogenic cause, with autosomal dominant inheritance, in which severity and growth pattern depend on the type of variant and its position in the gene [3, 4]. The GeneReviews describes two clinical groups: SETD2-NDD with or without macrocephaly and overgrowth, which includes Luscan-Lumish syndrome and the small subgroup with normal growth, and SETD2-NDD with multiple congenital anomalies, associated with the c.5218C>T p.(Arg1740Trp) variant [3]. OMIM, for its part, separates three phenotypic entries: Luscan-Lumish syndrome (616831), defined by macrocephaly, ID, speech delay, poor sociability and behavioural problems, with postnatal overgrowth, obesity, advanced carpal ossification and seizures as variable features [16, 25]; Rabin-Pappas syndrome (620155), a multisystem disorder with severe global delay from infancy, feeding difficulties with growth retardation, small head circumference and facial dysmorphism, in which patients do not acquire walking or meaningful speech, and with variable involvement of the skeletal, genitourinary, cardiac and possibly endocrine systems [9, 26]; and MRD70 (620157), defined by mild global delay, moderate ID with speech difficulties and behavioural changes, with hypotonia and dysmorphism as variable features [1, 10]. The three entries attribute the phenotypes to heterozygous variants of SETD2 and, in the two codon 1740 entries, to a single specific missense substitution [7].

MRT70 is a distinct entity that shares only the number of the OMIM phenotypic series. It is an autosomal recessive ID caused by biallelic loss of function of RSRC1, a gene encoding a protein of the serine/arginine-rich protein family involved in splicing of pre-messenger RNA [2, 15]. OMIM defines it by impaired intellectual development, with mild facial dysmorphism, febrile seizures and behavioural changes in some patients [2, 13]. Because its name coincides with that of MRD70, it is covered in this article in subsections of its own, without assimilating it to the SETD2 class.

Sotos syndrome (NSD1), Tatton-Brown-Rahman syndrome (DNMT3A), genetic macrocephaly, NSD2-related disorder and posterior fossa malformations enter the differential, and the somatic role of SETD2 in renal cell carcinoma is only mentioned.

1.2. Historical overview of SETD2

The first de novo variants of SETD2 emerged in 2012, in the exome sequencing and targeted sequencing studies of children with sporadic ASD by O'Roak and colleagues, without a syndrome being described at the time [3]. In the 209 trios of the Simons Simplex Collection (SSC), a North American collection of families with a single child with ASD, four individuals with heterozygous SETD2 variants were found: two inherited nonsense variants, one from the father and the other from the mother, the latter p.(Gln7Ter), a de novo missense p.(Ile41Phe) and a de novo frameshift, NM_014159.7:c.6341del p.(Asn2114IlefsTer33), in a girl later known to have had growth retardation, non-febrile seizures from 4 years, motor delay, low-normal non-verbal intelligence quotient (IQ) and macrocephaly [4, 16]. In 2014, analysis of more than 2500 simplex families with ASD, mostly from the same collection, added a single-nucleotide deletion and a missense variant [16]. The maternal variant p.(Gln7Ter) is the same one that, years later, proved to be recurrent and of uncertain interpretation (section 2.6). OMIM writes the SSC missense as I41F in the syndrome entry and as I42F in the gene entry; the table of Parra and colleagues gives c.121A>T p.(Ile41Phe) [4, 7, 16]. In 2014, Luscan and colleagues sequenced, with a panel of 14 genes of the H3K27 pathway and 8 of the H3K36 pathway, 16 French patients with a diagnosis of Sotos, «Sotos-like» or Weaver without an NSD1 or EZH2 variant, and found two heterozygous SETD2 variants in «Sotos-like» patients: p.(Leu1815Trp) de novo in a male patient and p.(Gln274Ter) in an adopted female patient whose biological parents could not be studied [27]. According to OMIM, they were adults at the time of description, a 26-year-old French man and a 23-year-old woman, with long, large hands and feet, a prominent forehead with a high frontal hairline, downslanting palpebral fissures, a long nose and face, malar hypoplasia and a prominent mandible; one of them had mild ventricular dilatation and nodular and punctate white matter hyperintensities in the anterior corona radiata and the centrum semiovale, and behavioural difficulties (attention deficit, tantrums, aggression, shyness and poor sociability) impaired schooling and employment [7, 16]. The two shared postnatal overgrowth, macrocephaly, obesity, speech delay and advanced carpal ossification, and the authors proposed that Sotos and similar forms were epigenetic disorders due to loss of function of «writers» of the H3K36 mark [27]. In 2015, Lumish and colleagues described a 17-year-old girl with ASD, ID, epilepsy, Chiari I malformation, macrocephaly and short stature, carrying the de novo variant c.2028delT p.(Pro677LeufsTer19) [28]. The full description includes compulsions, anxiety, ADHD, generalised tonic-clonic seizures from 10 years, mild to moderate hydrocephalus of the third and lateral ventricles, syringomyelia and progressive macrocephaly; the variant was absent from about 6000 individuals of the exome sequencing project of the US National Heart, Lung, and Blood Institute (NHLBI) and from more than 9000 clinical exomes [7, 16]. The eponym Luscan-Lumish derives from these two articles [27, 28].

The yield of SETD2 in overgrowth cohorts proved to be low. In the French cohort of 210 «Sotos-like» index cases without an NSD1 variant, Tlemsani and colleagues identified a single de novo frameshift variant in SETD2 (1 in 210) and DNMT3A variants in 7 patients, and noted that the phenotype associated with SETD2 was not yet well delineated [29]. The Smith textbook notes that an NSD1 variant is found in only 60–90% of patients identified as Sotos or «Sotos-like», that facial dysmorphism is less characteristic with SETD2 or DNMT3A and that the role of these genes in non-syndromic ID without overgrowth still required study [30]. There followed the descriptions by van Rij and colleagues in 2018, with two patients and new features such as nasal polyps, a large furrowed tongue and a high pain threshold [5], and the review by Marzin and colleagues in 2019, with 4 new patients and 9 published [31].

The next milestone was the 2020 article by Rabin and colleagues, which brought together 15 individuals with de novo variants at codon 1740: 12 with c.5218C>T p.(Arg1740Trp), with microcephaly, profound ID, multisystem congenital anomalies and similar facies, and 3 with c.5219G>A p.(Arg1740Gln), with moderate to severe ID, low-normal head circumference and no major congenital anomalies [14]. From this series derived OMIM entries 620155 (RAPAS) and 620157 (MRD70) [4]. The GeneReviews was published in December 2021, with 30 published individuals, and revised in September 2022 to include the methylation episignature [3]. In 2023, the Spanish series of the SOGRI registry (Spanish OverGrowth Registry Initiative), with 18 new patients and a review of 33 published, consolidated the tripartition into LLS, RAPAS and MRD70 [4], and the methylation study by Lee and colleagues showed that loss-of-function variants and codon 1740 variants have opposite methylation profiles [32]. Between 2025 and 2026, tumour phenotypes in germline carriers and endocrine manifestations in adults were described [33–35].

1.3. Nomenclature, classifications and the Orphanet grouping

The current classifications do not coincide completely, and the divergence has practical consequences for coding and for reading the literature. The table compares them.

Orphanet assigns MRD70 to the syndrome with microcephaly, severe ID and multiple congenital anomalies (ORPHA:597743), whereas the OMIM definition and the GeneReviews description place patients with p.(Arg1740Gln) in a picture without microcephaly, without major congenital anomalies and with speech present at 2 years [1, 3, 6]. The Orphanet grouping is consistent with the molecular criterion, because the two variants affect the same residue, share a predominantly hypermethylated methylation profile, opposite to that of loss of function, and hypermethylation is more intense with p.(Arg1740Trp), correlating with severity [32]. From a clinical point of view, however, the three patients with p.(Arg1740Gln) do not fit the name of the Orphanet entity, because they have neither microcephaly nor multiple congenital anomalies [3, 14]. In this article, MRD70 is described as a clinical entity in its own right and as the mild end of the codon 1740 spectrum, and the Orphanet coding should be read with this caveat. OMIM itself, which separates the two entries, records that Rabin and colleagues considered the phenotype of each variant distinct from that of the other variant at the same codon [9, 10].

The severity of ID in MRD70 also differs between sources: Rabin's abstract describes moderate to severe ID in the p.(Arg1740Gln) group [14], OMIM defines moderate impairment in the entry description and mild to moderate in the clinical description, with an IQ between 67 and 76 in the patient assessed [1, 10], and Parra's table records mild ID in all three patients [4]. As the three patients are the same, the divergence reflects the reading of the sources and not a difference between cohorts.

1.4. Historical overview of RSRC1

In 2018, two groups linked RSRC1 to autosomal recessive ID. Perez and colleagues combined homozygosity mapping and exome sequencing in a consanguineous Bedouin family with ID, aberrant behaviour, hypotonia and mild facial dysmorphism with normal brain magnetic resonance imaging (MRI), and showed that the variant triggered nonsense-mediated messenger RNA decay (NMD) in fibroblasts [36]. In the same year, Maddirevula and colleagues, studying natural human «knockouts» of genes previously linked only by genome-wide association studies, found a homozygous truncating RSRC1 variant in a family that Scala and colleagues identify as Malay, with three affected siblings [15, 37]. In 2020, Scala and colleagues described 17 patients from 7 consanguineous families, bringing the total to 25 patients from 9 families, and characterised the disease as mild to moderate ID with hypotonia and behavioural changes [15]. In March 2026, the ClinGen ID and autism panel classified the relationship of RSRC1 with autosomal recessive complex neurodevelopmental disorder as definitive [20].

2. Molecular Genetics and Pathophysiology

2.1. The SETD2 gene and the protein

SETD2 is located at 3p21.31 and encodes the histone lysine methyltransferase SETD2 (synonyms HYPB, KMT3A; HGNC:18420; UniProt Q9BYW2) [3, 21]. The MANE Select reference transcript is NM_014159.7 and the corresponding protein NP_054878.5 [3, 8]. According to Zhang and colleagues, the gene has 23 exons and spans about 147 kb [38]; the GRCh38 coordinates given by OMIM (3:47 016 436–47 164 840) correspond to about 148 kb [7]. The full-length protein, cloned in 2001 under the name HBP231, has 2061 amino acids and about 231 kDa, and the transcript, ubiquitously expressed at levels varying between tissues, measures about 7.5 kb; the synonyms HYPB and HBP231 reflect the earlier identification of a C-terminal fragment as a protein that binds, through its WW domain, to the proline-rich region of huntingtin, an interaction enhanced by lengthening of the adjacent glutamine tract [7]. The protein is organised into several domains, including the AWS domain (associated with SET), the catalytic SET domain (lysine N-methyltransferase), the post-SET domain, a low-charge region (LCR), the WW domain and, in the C-terminal region, the SRI domain, required for binding and methylation of α-tubulin [4, 39].

2.2. Function and mechanism

SETD2 is the main, and essentially non-redundant, writer of histone H3 lysine 36 trimethylation (H3K36me3), using as substrate the H3K36me2 dimethylation deposited by enzymes such as NSD1 [3, 21]. The H3K36me3 mark labels actively transcribed chromatin, coordinates recruitment of the FACT complex and binds hyperphosphorylated RNA polymerase II [21]. It also has genome maintenance functions: it recruits MSH6, a component of the MutSα mismatch repair complex, at the beginning of G1/S phase, promotes recruitment of RAD51 and homologous recombination repair, and recruits DNMT3A, the DNA methyltransferase that reads the H3K36me mark [21]. SETD2 is a dual-function methyltransferase, because it also methylates lysine 40 of α-tubulin in microtubules and the STAT1 protein, which involves it in transcriptional regulation, genomic stability and the cytoskeleton [3, 14, 21]. α-Tubulin methylation is carried out by the SET domain during mitosis and cytokinesis; in mouse embryonic fibroblasts lacking Setd2 this methylation is lost and polyploidy, polynucleation and defects of mitosis and cytokinesis appear [7]. In human cells, SET domain substitutions found in tumours, such as p.(Arg1625Cys), destabilise the protein to different degrees and reduce H3K36me3 through weaker substrate binding, and the H3K36me3 deposited by SETD2 is coupled to efficient repair of double-strand breaks [7]. The same Arg1625 residue is replaced by histidine in a patient with LLS in the Marzin series (section 2.4) [4].

The NSD1–SETD2–DNMT3A relationship explains the overlap between Sotos, Luscan-Lumish and Tatton-Brown-Rahman syndromes: NSD1 and SETD2 are writers of the H3K36me mark and DNMT3A is a reader of that mark [30]. Loss of function of SETD2 is associated with loss of H3K36me3 and DNA hypomethylation, a pattern shared with Sotos and Tatton-Brown-Rahman and associated with overgrowth [3, 32]. For the p.(Arg1740Trp) variant, the GeneReviews reports evidence of hypermethylation of regions regulated by the Polycomb complex and an association with microcephalic dwarfism, and considers a loss-of-function mechanism possible [3]. Rabin and colleagues proposed for codon 1740 a mechanism distinct from simple loss of function, through gain of function, an epigenetic effect or post-translational modification of the cytoskeleton [14]. ClinGen assigns SETD2 a haploinsufficiency score of 3, that is, sufficient evidence that loss of one copy causes disease, and a triplosensitivity score of 0 [21].

Codon 1740 does not belong to a known functional domain: it lies in an entirely α-helical region immediately after the post-SET domain, called DAS (domain after SET), conserved across species such as zebrafish and Xenopus, whose AlphaFold-predicted structure resembles the region of Iws1 that interacts with Spt6 [32]. In the model of Parra and colleagues, Arg1740 lies in an α-helix and interacts with Arg1744, which forms three hydrogen bonds with Glu1718; introduction of an aromatic tryptophan predicts a greater structural change than that of a glutamine, which parallels the difference in severity between RAPAS and MRD70 [4].

2.3. Experimental models

Animal models are preclinical and do not establish direct correlations with human disease. In the mouse, the α-tubulin K40me3 mark exists in brain microtubules and in primary neurons; with the SRI domain inactivated (Setd2^SRI allele), at least one normal allele is required for survival, and heterozygotes show an anxiety-like phenotype and deficits in axonal length and dendritic arborisation, without changes in chromatin methylation or gene expression [39]. Conditional knockout of Setd2 in the neuroepithelium causes neonatal death with intracerebral haemorrhage and vascular anomalies, whereas the equivalent for Nsd1 is viable with a smaller brain [40]. Parra and colleagues cite murine studies with defects of cortical arealisation and corticothalamic projections and deficits in social interaction, motor learning and spatial memory [4]. In the mouse oocyte, depletion of Setd2 abolishes H3K36me3, alters global DNA methylation, redistributes the H3K4me3 and H3K27me3 marks, prevents establishment of maternal imprints and causes female sterility, with embryos arrested at the one-cell stage; these data describe the function of Setd2 in the mouse female germline and have no described clinical counterpart in human female carriers [7]. A 2023 review summarises the functions of SETD2 in the central nervous system [41].

2.4. Variant spectrum

Up to 2023, 51 patients had been published with 34 different variants: 16 missense, 9 frameshift, 7 nonsense, 1 in-frame deletion and 1 splicing; by the classification of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP), 15 were pathogenic, 5 likely pathogenic and 14 of uncertain significance (VUS) [4]. In a review of 51 point variants, frameshift and nonsense variants accounted for 68.5% [42]; in Marzin's review, truncating variants made up 69% and missense 31% [31]. Likely gene-disrupting (LGD) variants cluster in two blocks, between codons ~270 and ~700 and in a region of low variant burden, and are absent from the AWS-SET-post-SET domains, which the authors interpret as possible lethality [4]. In 2026, ClinVar listed 72 germline pathogenic or likely pathogenic records for SETD2 [43].

The table brings together the variants of particular clinical significance, normalised in VariantValidator, an HGVS nomenclature validation tool, on the GRCh38 genome. The codon 1740 variants are the only ones associated with phenotypes with an OMIM entry of their own; the others illustrate the LLS spectrum or the difficulty of interpretation.

The two four-nucleotide deletions c.4451_4454del and c.4457_4460del have different genomic coordinates, about 3.4 kb apart, although the predicted protein consequence is the same; they are treated as distinct variants, as published [4, 8, 35]. The variant of Lucain and colleagues was consulted only at the protein level, p.(Ser1658Leu), because the abstract does not give the c. notation [33]. The variants added from the OMIM entries, which describe them on NM_014159.6, were transcribed from the table of Parra and colleagues, which uses NM_014159.7 with the same c. numbering; the ACMG/AMP class is that of this table [4, 7]. OMIM states that the four Marzin variants lie in the catalytic domain; two of them, however, are nonsense (p.Lys1426Ter and p.Tyr2157Ter), and the variant map of Parra and colleagues shows no LGD variants in the AWS-SET-post-SET block, so location in the catalytic domain applies with certainty only to the two missense variants [4, 16]. Chen and colleagues reassessed 19 published de novo variants (8 frameshift, 1 nonsense, 7 missense, 1 in-frame deletion and the 2 from their cohort) and classified 13 as pathogenic, 5 as likely pathogenic and 1 missense as VUS; all missense variants affected conserved residues [16, 44].

2.5. Genotype-phenotype correlation: codon 1740

The most robust correlation is that of codon 1740. Loss-of-function variants distributed along almost the whole gene cause LLS; the p.(Arg1740Trp) substitution causes RAPAS and the p.(Arg1740Gln) substitution causes MRD70 [3, 4]. Rabin and colleagues described both variants as de novo in all patients [14]. Both were absent from gnomAD; the patients were brought together through collaboration after the variant had been identified in clinical genetics services, the phenotype was delineated retrospectively and no functional studies of the variants or of patient cells were performed, so the separation between RAPAS and MRD70 rests on clinical comparison and, later, on the methylation profile [9, 10, 32]. In the methylation analysis of Lee and colleagues, loss-of-function variants (n=4) produced 778 differentially methylated CpG positions (DMP), 767 of them hypomethylated, whereas codon 1740 variants (n=6) produced 7566 DMP, 6777 of them hypermethylated; 513 DMP were common to both groups, but in opposite directions, and hypermethylation was more intense with p.(Arg1740Trp) than with p.(Arg1740Gln) [32]. The genes with DMP in the codon 1740 group include growth genes such as IGF1R (hypermethylated), NRP2, LTBP3 and IGF2BP1 [32]. This opposite profile is consistent with the clinical contrast between macrocephaly and overgrowth in LLS and microcephaly in RAPAS [32].

Outside codon 1740, a review of 51 point variants detected no genotype-phenotype association [42]. In the Parra series, 18 of the 23 patients with macrocephaly had an LGD variant, which suggests greater expression of macrocephaly with unequivocal loss of function [4]. Two patients with a RAPAS-like phenotype and without p.(Arg1740Trp), carrying p.(Glu1718Lys) and p.(Asp2251Glu), lacked the characteristic brain malformations; Glu1718 is precisely the residue that, in the structural model, stabilises the Arg1740 helix [4].

2.6. Penetrance, expressivity and modifiers

Most variants arise de novo, and the penetrance and intrafamilial variability of inherited variants have not been determined [3]. Expressivity is variable: the case of Suda and colleagues, with p.(Leu79His), had tall stature (188.2 cm, +3.18 standard deviations [SD]) without ID or speech delay [45], and an individual with mosaicism had normal intelligence with hearing loss, Chiari, epilepsy and hypoglycaemia [3]. Vertical transmission is documented mainly for variants classified as VUS (maternal c.19C>T in two patients; paternal p.(His866_Tyr871del) and p.(Asn1257Tyr); maternal p.(Glu33Lys)) and for the likely pathogenic variant p.(Cys394Ter), inherited from the father [4]. These two inherited nonsense variants, maternal p.(Gln7Ter) and paternal p.(Cys394Ter), come from the SSC ASD cohort; OMIM writes the second as C94X, and Parra's table gives NM_014159.7:c.1182T>A p.(Cys394Ter) [4, 16]. Parra's patient 2, with a head circumference above +5 SD, had the in-frame deletion p.(His866_Tyr871del) of SETD2 and the PTEN variant NM_000314.8:c.464A>G p.(Tyr155Cys), both inherited from the macrocephalic father, which suggests an additive effect [4].

The recurrent variant c.19C>T p.(Gln7Ter) was found in 5 patients compatible with LLS, with maternal transmission confirmed in 2; gnomAD records 40 alleles, 39 in the Latino subpopulation (frequency 0.000353 in exomes and 0.00229 in genomes of that population); it lies in exon 1 of the canonical transcript, but in the 5' untranslated region of the other transcripts, and codon 12 is a methionine that may serve as an alternative start [4]. For these reasons it was classified as VUS, and it should not be used on its own to confirm the diagnosis [4].

2.7. 3p21.31 deletion

Deletions that include SETD2 are rare. Lovrecic and colleagues described a de novo interstitial 3p21.31 deletion with 29 OMIM genes, including SETD2, in a 7-year-old boy with global delay, dysmorphism, hydronephrosis and hypothyroidism [47]. The GeneReviews notes the overlap with SETD2-NDD with macrocephaly: long face, downslanting palpebral fissures, broad nasal tip, deep philtrum and dysmorphic low-set ears [3]. The authors accept a contribution from other genes in the interval, such as CSPG5, PTH1R and SMARCC1 [47].

2.8. Somatic role of SETD2, distinct from the germline disease

SETD2 is a tumour suppressor gene with somatic variants in clear cell renal cell carcinoma, gastrointestinal, lung and pancreatic tumours, osteosarcoma, primary central nervous system tumours and leukaemia; in these isolated tumours the variants are somatic and do not indicate hereditary predisposition [3]. In the TCGA project (The Cancer Genome Atlas), loss of 3p, involving VHL, PBRM1, BAP1 and SETD2, is present in 91% of clear cell renal carcinomas, and SETD2 is among the most frequently mutated genes; in type 2 papillary carcinoma, SETD2 mutations are part of the molecular characterisation [48]. In monomorphic epitheliotropic intestinal T-cell lymphoma, JAK3/STAT5 mutations and SETD2 inactivation help distinguish this entity from enteropathy-associated T-cell lymphoma [49]. The occurrence of tumours in germline carriers is discussed in section 3.7.

2.9. The RSRC1 gene and the mechanism of MRT70

RSRC1 (arginine and serine rich coiled-coil 1; synonyms SRrp53, SFRS21) is located at 3q25.32 and its MANE Select transcript is NM_001271838.2; the literature uses version .1, with the same c. numbering [8, 11]. The transcript has 10 exons and encodes a protein of 334 amino acids (about 53 kDa) with an RS domain, which interacts with SF2/ASF and U2AF35 and participates in the second step of pre-messenger RNA splicing, and a coiled-coil domain, which interacts with oestrogen receptor β and increases its SUMOylation [15]. The protein localises to nuclear speckles and is ubiquitously expressed [11]. The protein was isolated in 2005 by Cazalla and colleagues, in a screen for proteins targeted to nuclear speckles in mouse cells; the human sequence deduced in that work had 331 residues and the murine one 334, and the name SRrp53 comes from the apparent mass of 53 kDa on Western blot, which falls after dephosphorylation [12]. The protein shuttles between the nucleus and the cytoplasm and has orthologues only in vertebrates [12]. The amino-terminal RS domain binds SF2/ASF, SRp40, U2AF35 and LUC7, and the carboxy-terminal region binds HCC1; in HeLa cell nuclear extracts depleted of SRrp53, splicing of test substrates was not completed, addition of recombinant protein restored it, and increasing its concentration shifted splice site choice and activated a weak 3′ acceptor site, pointing to a role in constitutive and alternative splicing [12]. Perez and colleagues found expression in all human tissues tested, somewhat higher in the brain, cerebellum, liver, colon, prostate, testis, placenta and whole blood; despite the absence of normal expression in the cerebellum, none of the Bedouin patients had ataxia or any other cerebellar sign, which the authors attribute to functional redundancy in that organ [12].

The mechanism of MRT70 is biallelic loss of function. The variant of Perez and colleagues caused NMD in fibroblasts; RSRC1 silencing in a neuronal line altered alternative splicing and transcription, and neural progenitor cells derived from the patient's induced pluripotent stem cells had a 9.6-fold reduction in IGFBP3 expression [36]. In the silencing model in the SH-SY5Y neuroblastoma line, 147 genes had altered expression and 113 had differential exon usage, with enrichment in RNA processing and post-transcriptional modification functions; in the patients' neural progenitors, 19 of 25 genes tested by quantitative PCR reproduced the effect of silencing, among them seven genes associated with ID or with hypotonia and myopathy, and the most marked reduction was that of IGFBP3 (about 9.6-fold, near-zero expression), followed by IGFBP5 (about 2.8-fold) [12]. These are research findings, without translation into clinical tests [11]. The earlier genome-wide association signals (schizophrenia, height, depression) have not been confirmed or are of uncertain interpretation and do not constitute Mendelian phenotypes [15].

None of the point variants in the table had homozygotes in gnomAD; c.532-1G>A and c.3G>T appeared only in the heterozygous state, with allele frequencies of 0.000018 and 0.000032, and c.205C>T was found once in the heterozygous state among 300 Bedouin controls [12]. The OMIM gene entry describes p.(Arg90Ter) on transcript NM_016625.3, with the same position c.268 [12]. The two deletions were detected by high-resolution CMA after a negative exome, and the authors do not exclude a contribution of MLF1 to the dysmorphism of the Amish family [15]. The deletions cannot be normalised in Human Genome Variation Society (HGVS) nomenclature without exact coordinates. In 2026, ClinVar listed 14 germline pathogenic or likely pathogenic records for RSRC1 [43].

2.10. Gene-disease validity

In October 2023, the ClinGen ID and autism panel classified the relationship of SETD2 with SETD2-NDD without or with macrocephaly/overgrowth as definitive and the relationship with the microcephaly, severe ID and MCA syndrome as strong, both autosomal dominant [19]. In March 2026 it classified the relationship of RSRC1 with autosomal recessive complex neurodevelopmental disorder as definitive [20]. No phenotype other than those of this class and the tumour phenotype under discussion has been described for heterozygous germline SETD2 variants [3, 33].

3. Clinical Spectrum and Manifestations by System

3.1. Sources of clinical data and their limits

Clinical knowledge rests on small series and case reports, all of patients not treated with targeted therapy, so they describe the natural history under symptomatic care. The GeneReviews was based on 30 individuals published up to 2021 (18 in the group with or without macrocephaly and 12 with MCA), excluding the 3p21.31 deletions [3]. The review by Parra and colleagues added 18 new patients from the Spanish SOGRI registry and centres in Spain, France, Turkey and Colombia to 33 published, for a total of 51 (34 LLS, 14 RAPAS and 3 MRD70) [4]. In 2025, Lucain and colleagues referred to about 50 published patients [33]. Denominators vary because many features were not examined in all patients, and Parra's table contains inconsistencies in the coding of some Human Phenotype Ontology (HPO) terms and a duplicated row for retinal telangiectasia [4]. For MRT70, the data come from 25 patients from 9 consanguineous families [15].

3.2. Luscan-Lumish syndrome (SETD2-NDD with or without macrocephaly/overgrowth)

Growth. Growth at birth is usually normal, although macrocephaly may be present from birth; obesity and tall stature develop in childhood, and stature may normalise with age [3]. A subgroup maintains normal growth throughout life, with height tending to remain above the 50th centile, and bone age is often advanced [3]. In the series of 51 patients, macrocephaly occurred in 67.6% and overgrowth in 50% of patients with LLS, and the combination of both in 15 of 34 (44.1%) [4]. In the review of 15 patients by Zhang and colleagues, head circumference (HC) was above the 97th centile in 13 of 15 (87%) and stature above the mean in 56% [38]. In Marzin's review, almost all had macrocephaly and half had advanced stature and obesity [31].

Development and cognition. Developmental delay ranges from severe to normal intelligence with behavioural problems, with moderate ID predominating; speech is the most affected area [3]. Hypotonia may be present, but without the need for feeding therapy or tube feeding, unlike RAPAS [3]. In the series of 51 patients, ID was recorded in 47.1%, speech delay in 44.1% and motor delay in 32.4% of patients with LLS [4]; in Marzin's review, with 13 patients, ID reached 83% [31]. The difference reflects the way data were recorded and the inclusion, in the larger series, of patients with VUS and mild phenotypes.

Behaviour. The profile includes ASD, attention deficit, outbursts of aggression, self-injury, low frustration tolerance, anxiety, hyperphagia and stereotypies [3]. ASD was recorded in 50%, attention deficit hyperactivity disorder (ADHD) in 26.5% and aggressive behaviour in 14.7% of patients with LLS in the series of 51 [4]; in Marzin's review, ASD reached 89%, behavioural difficulties 100% and aggressive outbursts 83% [31].

Neurological and neuroimaging. Epilepsy is rare. One patient had generalised tonic-clonic seizures at 10 years and became seizure-free on lamotrigine monotherapy for at least 3 years; another patient had a single seizure at 3 years and a third had several seizures that did not recur after a ventriculoperitoneal shunt [3]. In the series of 51, seizures occurred in 8.8% of patients with LLS [4]. The malformations described include Chiari I, syringomyelia, hydrocephalus, ventriculomegaly and Dandy-Walker malformation [3]. In Zhang's review, 7 cases had abnormal MRI and Chiari I appeared in about 14–18% [38].

Endocrine and metabolic. The GeneReviews reports precocious puberty, polycystic ovary syndrome, hypothyroidism and growth hormone (GH) deficiency [3]. Suda and colleagues described a 20-year-old man with a height of 188.2 cm (+3.18 SD), body mass index (BMI) of 28.4 kg/m², acral overgrowth, prognathism and Chiari I, without ID or speech delay, with normal GH, insulin-like growth factor 1 (IGF-1) and GH suppression on the oral glucose tolerance test and no pituitary adenoma; the patient's fibroblasts grew faster and showed greater STAT5b phosphorylation and greater GH-induced IGF-1 expression [45]. In 2026, Huang and colleagues described in an adult woman severe obesity of rapid onset in adolescence, hypogonadotrophic hypogonadism, hyperprolactinaemia with a pituitary microadenoma, hirsutism with near-normal androgens and insulin resistance; a causal relationship of the microadenoma, hypothyroidism and depression with the variant was not established [35]. This case is detailed in section 10.

Sensory. Hearing loss is uncommon, and more frequent with p.(Arg1740Trp); strabismus and, rarely, cortical visual impairment and optic nerve hypoplasia have been described [3]. Astigmatism was recorded in 14.7% of patients with LLS [4].

Other systems. Recurrent infections (otitis media, sinusitis, respiratory infections), gastro-oesophageal reflux, constipation, congenital heart disease, poorly characterised sleep apnoea, hirsutism, scoliosis, joint hypermobility, cryptorchidism and naevi have been described [3]. In Marzin's review, joint hypermobility occurred in 29%, hirsutism in 33% and naevi in 50% [31]. Van Rij and colleagues added nasal polyps, a large furrowed tongue, a high pain threshold, constipation and cryptorchidism, and recommended obesity prevention [5]. The first patient, a 4.5-year-old boy, had macrocephaly, speech and motor delay, autistic behaviour, cryptorchidism, recurrent otitis media, frontal bossing, a high frontal hairline, an occipital port-wine stain (naevus flammeus), mild ptosis, soft elastic skin, multiple joint hyperlaxity, a normal brain MRI and delayed bone age on hand radiograph; the second, a 23-year-old woman, had macrocephaly, severe speech and language delay, mild motor delay, ASD, outbursts of aggression and self-injury with a high pain threshold, an asymmetric face, a broad high nasal bridge, a broad chin, a high palate, a deeply furrowed tongue, recurrent otitis media, nasal polyps operated on three times, truncal obesity with a BMI of 32.3 kg/m² and a slightly thickened corpus callosum [16]. The delayed bone age of the first patient contrasts with the advanced bone age reported in most descriptions [3, 16]. A Chinese ASD cohort identified speech and motor delay, ID, macrocephaly, ASD, overgrowth and recurrent otitis media as common features [44]. In these authors' review, with 2 patients of their own and 14 published, ID was recorded in 7 of 7 patients with that information, speech delay in 11 of 12, motor delay in 8 of 12, tall stature in 7 of 12 and ASD in 8 of 14; recurrent otitis media was recorded in 5 patients and accelerated bone maturation in 4 [16].

Facies. The dysmorphism is less characteristic than in Sotos syndrome [30]. Figure 1 of the GeneReviews, with patients of Marzin, shows a prominent forehead with a high frontal hairline, frontal bossing and low-set ears, and in another patient relative macrocephaly, a long face, a high forehead, a pointed chin, posteriorly rotated ears and malar hypoplasia [3]. Figure 2 of Parra and colleagues shows the dysmorphism of several patients from the Spanish series (https://pmc.ncbi.nlm.nih.gov/articles/PMC10297832/figure/genes-14-01179-f002/) [4].

3.3. MRD70 (p.Arg1740Gln)

The three patients of Rabin and colleagues (two boys and one girl) had an HC that could drift to the lower limit of normal without reaching microcephaly, all had some speech at 2 years and none had ASD [3]. One had anxiety, executive function deficits and slow processing speed; strabismus, myopia, laryngomalacia and constipation were recorded in one patient each [3]. Rabin's individual description, summarised by OMIM, adds that all three had mild global delay and speech delay, but all acquired independent walking [10]. Patient 1, a 15-year-old boy, attended a special school, had behavioural changes and a developmental level corresponding to 6 years, with upslanting palpebral fissures and straight upslanting eyebrows, brachycephaly, fifth finger clinodactyly and camptodactyly [10]. Patient 2, a 4.5-year-old boy, had poor speech, hypotonia, strabismus, joint hyperlaxity and normal neuroimaging, and the pregnancy had been complicated by polyhydramnios [10]. Patient 3, an 8-year-old girl, had an IQ between 67 and 76, behavioural changes, hypotonia, a high-arched palate, dental crowding, retrognathia, myopia, malar hypoplasia and broad eyebrows [10]. In Parra's table, the most frequent features were ID (3 of 3), developmental delay (3 of 3), speech delay (3 of 3), motor delay, hypotonia, skeletal anomaly and retrognathia (2 of 3 each) [4]. In the study by Lee and colleagues, two patients with p.(Arg1740Gln), a 12-year-old girl and a 5-year-old boy, had a phenotype similar to RAPAS but milder, with ID and small HC without significant congenital anomalies; it is not possible to know whether they overlap with those of Rabin [32]. The severity of ID differs between sources, as explained in section 1.3.

3.4. Rabin-Pappas syndrome (SETD2-NDD with MCA, p.Arg1740Trp)

Prenatal and neonatal period. Preterm birth is frequent; brain malformations become visible in the third trimester, cardiac and renal anomalies are sometimes detected before birth, and polyhydramnios and maternal pre-eclampsia are common [3]. Birth weight and length are normal in all [3].

Growth and feeding. Microcephaly is of prenatal onset in 2 of 9 patients and, in the others, develops in early childhood; it is progressive, at least 2.5 SD below the mean, and may reach −5.5 SD [3]. Weight remains below the 50th centile in childhood and height is variable [3]. Most patients need a nasogastric tube and later a gastrostomy, especially when aspiration is frequent; cleft palate with Pierre Robin sequence occurs in 10 of 12 [3].

Respiratory. Tracheomalacia, frequent aspiration, hypoventilation, desaturations and obstructive and central sleep apnoea have been described; 3 of 12 patients required tracheostomy, another needed nocturnal oxygen and another nocturnal continuous positive airway pressure (CPAP) [3].

Development and neurology. All have severe to profound ID and are non-verbal and non-ambulatory; two took a few steps in late childhood and some sit unaided; regression and behavioural changes have not been described [3]. Epilepsy begins in infancy and is difficult to control, with migrating focal seizures, infantile spasms, apnoeic seizures, absences and generalised myoclonic seizures; one patient had refractory seizures until phenobarbital was used with a ketogenic diet or modified Atkins diet, and another had better control with cannabidiol oil [3].

Neuroimaging. In all patients studied, the triad of hypoplasia of the corpus callosum, pons and cerebellum is seen, with shallow sulci, ventriculomegaly and mega cisterna magna [3]. Figure 2 of the GeneReviews, with six patients of Rabin, shows a low craniofacial ratio, a short thin corpus callosum, a drooping appearance of the tips of the frontal horns, simplified gyri, mega cisterna magna, prominent supracerebellar cisterns and slightly everted hippocampi; one patient had a subdural haemorrhage, possibly from birth trauma, another white matter loss with dilatation of the third and lateral ventricles, three had a probable persistent Blake's pouch cyst and three an altered anteroposterior midbrain-hindbrain pattern [3].

Hearing and vision. Hearing loss is conductive or mixed, mild to severe, and is treated with hearing aids and tympanostomy tubes when there is effusion [3]. Coats disease, a retinal telangiectasia with tortuous vessels and sometimes exudation, occurs in 8 of 10 patients examined, together with optic nerve hypoplasia, glaucoma and cataracts, with ophthalmological onset in infancy [3].

Heart, kidneys and genital tract. Heart defects include ventricular and atrial septal defects, patent ductus arteriosus, tetralogy of Fallot, double outlet right ventricle, pulmonary stenosis, persistent left superior vena cava, dysplastic pulmonary valve, pulmonary artery hypoplasia, hypoplastic aortic valve, transverse arch hypoplasia and coarctation, with multiple defects in most [3]. Dilated or duplex renal collecting systems and multicystic dysplastic kidneys have been described, with progression to end-stage kidney disease in one patient; all boys have cryptorchidism, some micropenis and shawl scrotum; two girls had an anteriorly placed anus and one a short vagina with absent cervix and midline Müllerian structures [3].

Endocrine and metabolic. Hyponatraemia occurs in infancy in 8 of 12 patients; it was initially attributed to the syndrome of inappropriate antidiuretic hormone secretion (SIADH), but this was not found in any of the patients assessed, and the hyponatraemia resolved with sodium supplementation [3]. Acquired hypothyroidism and hypothalamic hamartoma have been described in one patient each [3].

Skeleton. All patients have skeletal anomalies: hip dysplasia, contractures of the fingers, knees and elbows, thoracic dysplasia, sagittal and metopic craniosynostosis, neuromuscular scoliosis, brachydactyly, camptodactyly, syndactyly, proximally placed triphalangeal thumbs, broad proximally placed halluces, hypoplastic distal phalanges and nails, rocker-bottom feet, small hands and feet and persistent fetal finger pads [3].

Facies. Figure 3 of the GeneReviews, with patients aged 2 weeks to 12 years, shows widely spaced eyes, micrognathia, a small upturned nose, biparietal narrowing, a small forehead, a flat face, short palpebral fissures, arched eyebrows, strabismus, a broad nasal bridge and tip with a low columella, maxillary and mandibular hypoplasia and slightly anteverted ears [3].

Rabin's original series. The 12 unrelated patients, aged between 1 month and 12 years, all had feeding difficulties with growth retardation, and most needed tube feeding; nine were born preterm and four of the mothers of these preterm infants had pre-eclampsia [9]. None had signs of overgrowth; several had small head circumference or frank microcephaly down to −4 SD, a value lower than the maximum of −5.5 SD given by the GeneReviews for the later course [3, 9]. Respiratory insufficiency (hypoventilation, aspiration, sleep apnoea) was frequent; seven had epileptic seizures, many refractory; all had structural abnormalities on neuroimaging; all patients older than 2 months developed ophthalmological abnormalities, including retinal telangiectasia with exudates resembling Coats disease, retinal detachment, optic nerve coloboma and cataracts; eight had mixed hearing loss and eight hyponatraemia in infancy [9]. OMIM counts eight patients with mixed hearing loss among the 12, whereas the GeneReviews table records conductive or mixed hearing loss in 7 of 9 assessed; the difference depends on the denominator used [3, 9]. Optic nerve coloboma, mentioned by OMIM, is not in the ophthalmological description of the GeneReviews, which mentions optic nerve hypoplasia and includes retinal detachment among the findings to look for on fundus examination [3, 9].

3.5. Comparative frequencies

The GeneReviews table compares the two clinical groups; the group with or without macrocephaly includes the three patients with p.(Arg1740Gln).

Source: GeneReviews, based on O'Roak 2012, Luscan 2014, Lumish 2015, Tlemsani 2016, van Rij 2018, Marzin 2019, Rabin 2020 and Suda 2021 [3].

The following table reproduces the frequencies from the review of 51 patients, with the three OMIM entities separated. The values are numbers of patients with the feature recorded, without a denominator of their own per feature, so absence of a record does not equal absence of the sign.

Source: Parra et al. 2023, table 3; in the source, the HPO code assigned to scoliosis corresponds to retrognathia, and the MRD70 data are the three patients of Rabin 2020 [4].

In Parra's own cohort (18 patients: 16 LLS and 2 with a RAPAS-like phenotype), the frequencies were: macrocephaly 11 (61.1%), ID 9 (50%), overgrowth 8 (44.4%), motor delay 8 (44.4%), prominent forehead 7, speech delay 7 (38.9%), ASD 6 (33.3%), hypotonia 6, scoliosis 5 (27.8%), congenital heart disease 5 (27.8%), astigmatism 4, obesity 4, tall stature 4 (22.2%), anxiety 3, ADHD 3 (16.7%), seizures 2 (11.1%), microcephaly 2, renal anomaly 2, naevi 2, strabismus 2, and one patient each with advanced bone age, ventriculomegaly, enlarged cisterna magna, laryngomalacia, sleep apnoea and retinal telangiectasia [4].

3.6. Differences by subgroup in the methylation study

In the study by Lee and colleagues, the four patients with a frameshift variant all had macrocephaly and mild to moderate ID; the four with p.(Arg1740Trp), aged 0.5 to 12 years, had microcephaly, severe ID, renal, cardiac and central nervous system congenital anomalies and vascular retinopathy; the two with p.(Arg1740Gln) had a similar, milder phenotype [32]. The data reinforce the clinical distinction between the two ends of the spectrum.

3.7. Tumours in germline carriers

The tumour risk of germline carriers has not been quantified, and the available data are case reports. The GeneReviews reports osteosarcoma in two individuals with RAPAS, at 12 and 15 years, by personal communication [3]. Of 10 individuals with SETD2 variants studied by Lee and colleagues, two had a tumour: multiple brainstem gliomas from 6 years in a carrier of a loss-of-function variant and metastatic high-grade chondroblastic osteosarcoma of the right proximal tibia and the mandible at 15 years in a carrier of p.(Arg1740Trp), who received palliative treatment and died shortly afterwards [32]. The same authors mention a hypothalamic hamartoma in another carrier of p.(Arg1740Trp), an additional unpublished osteosarcoma, five records of p.(Arg1740Trp) in the COSMIC somatic mutation catalogue (among 2938 unique samples with a SETD2 mutation) and, for comparison, an overall tumour risk of about 3% in Sotos syndrome and 2% in Weaver syndrome [32].

In 2025, Lucain and colleagues described an adult woman with normal cognition, distinctive facies and multiple tumours: sacral osteoblastoma at 7 years, benign femoral bone tumour at 17, pseudomyxoma peritonei at 27, and pituitary macroadenoma and low-grade optochiasmatic glioma at 37; trio exome sequencing revealed the de novo missense variant p.(Ser1658Leu), classified as VUS, and the methylation episignature was compatible with SETD2 disorders, which led the authors to propose a syndromic multiple tumour phenotype [33]. A preprint posted in December 2025 on Research Square, not yet peer reviewed, describes a 34-year-old woman with neurodevelopmental delay, ID, hypertrichosis and café-au-lait macules, with a giant malignant phyllodes tumour of the breast and multiple uterine leiomyomas, whose mother had a vestibular schwannoma and similar features; the variant NM_014159.7:c.2557_2558del p.(Lys853AlafsTer5) was classified as likely pathogenic, and the disease progressed despite surgery, radiotherapy and chemotherapy with doxorubicin and ifosfamide, with death [34]. These reports, including a preprint, do not allow the incidence of tumours to be estimated or a tumour spectrum to be established.

3.8. MRT70 (RSRC1)

In the series of Scala and colleagues, all 17 new patients had global psychomotor delay and mild to moderate ID, 12 of 17 had a behavioural disorder and all had generalised hypotonia, present from birth in 5 [15]. Hyporeflexia was observed in 6 (35%) and gait ataxia in 5, one of them with bradykinesia, and truncal ataxia in 1 [15]. Seizures occurred in 6 patients (35%), 4 of them febrile, and 2 patients had only febrile seizures [13, 15]; patients 7, 12 and 13 had febrile and afebrile tonic-clonic seizures, and definite epilepsy was confirmed only in patient 12 and in one case of Perez, with focal impaired awareness seizures, sometimes evolving to tonic-clonic, treated with valproic acid [15]. There was no psychomotor regression [15]. The most frequent dysmorphic features were deep-set eyes, a broad nasal base and a high-arched palate, and flat feet, calcaneus valgus, redundant skin, mitral valve prolapse, recurrent respiratory infections in the first year and tracheomalacia were described in isolated patients [15]. Perez's original patients had normal brain MRI [36]. In the OMIM synopsis, the five Bedouin siblings had global delay without regression, mild to moderate ID, walking acquired between 3 and 4 years and, even in adolescence, verbal expression limited to a few isolated words; all had febrile seizures in childhood, all had fine motor deficits and incontinence without impaired coordination, and the behavioural changes included tantrums, self-injury and ADHD, with autistic traits in one sibling; ophthalmological examination and hearing were normal [13]. For the three Malay siblings of Maddirevula, OMIM describes absence of dysmorphism and normal brain MRI, with febrile seizures in one of them, whereas Scala's table records temporal lobe atrophy in one of the three; the two sources summarise the same article, and the sources consulted do not allow a choice between the two descriptions [13, 15]. MedGen also lists, as HPO features, sialorrhoea, hypertelorism, retrognathia, urinary incontinence, ADHD, severe tantrums and microcephaly [2].

Source: Scala et al. 2020, table 1 and text; in the source, «+» denotes mild ID and «++» moderate ID, and the intensity of hypotonia is graded from + to +++ [15]. The authors conclude that MRT70 is a non-syndromic ID with hypotonia and behavioural changes, in which dysmorphism and minor features have little diagnostic value and neuroimaging has limited value [15]. The spectrum of severity beyond mild to moderate, the natural history in adulthood, the risk of epilepsy beyond febrile seizures and extraneurological involvement have not been established [11].

4. Clinical Recognition and Warning Signs

4.1. When to suspect SETD2-NDD

There are no consensus clinical criteria, and the suggestive findings are non-specific [3]. Suspicion of LLS arises in a child with macrocephaly, with or without ventriculomegaly, Chiari I or syringomyelia, developmental delay centred on speech and language, usually moderate ID, ASD or outbursts of aggression and, in some cases, overgrowth with obesity and advanced bone age [3]. The most typical setting is a «Sotos-like» form without an NSD1 variant, in which the dysmorphism is less characteristic than in Sotos syndrome [29, 30]. Absence of macrocephaly does not exclude the diagnosis: a subgroup has normal growth throughout life, some patients have only speech and motor delay without overgrowth, and MRD70 occurs without macrocephaly [3, 42].

Suspicion of RAPAS arises in a newborn or infant with microcephaly that develops or progresses, cleft palate or Pierre Robin sequence, severe feeding and respiratory difficulties, heart disease, urogenital anomalies, conductive or mixed hearing loss and the triad of hypoplasia of the corpus callosum, pons and cerebellum [3]. Coats disease in an infant with this picture is a finding of diagnostic value, because it is absent in the entities of the direct differential, such as Smith-Lemli-Opitz syndrome and Zhu-Tokita-Takenouchi-Kim syndrome [3].

4.2. Warning signs by age

4.3. Emergency signs

In RAPAS, the emergency signs are respiratory failure due to tracheomalacia or hypoventilation, especially during sleep, recurrent aspiration, hyponatraemia in infancy and early-onset refractory seizures; newborns benefit from care in a level IV neonatal intensive care unit (NICU) [3]. In LLS, new neurological symptoms in a child with Chiari I or syringomyelia, growth of a syrinx and epileptic seizures require targeted assessment [3, 50]. Severe aggression justifies referral to child and adolescent psychiatry [3].

4.4. Newborn screening

The sources consulted describe no newborn screening for any of the entities in this article, which have no biochemical biomarker or specific early treatment [3, 11].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Diagnostic criteria

There are no consensus clinical criteria for SETD2-NDD. The diagnosis is established in a proband with suggestive findings and a heterozygous pathogenic or likely pathogenic SETD2 variant identified by molecular genetic testing; a VUS neither establishes nor excludes the diagnosis [3]. Variant classification follows the 2015 ACMG/AMP standards [3, 38]. For MRT70, the diagnosis requires biallelic pathogenic variants of RSRC1, and no non-molecular test confirms it [11].

5.2. General approach to the child with ID or global delay

The 2021 ACMG guideline, based on a systematic review and health technology assessment, strongly recommends that exome or genome sequencing be considered as a first- or second-tier test in paediatric patients with one or more congenital anomalies with onset before 1 year or with developmental delay or ID with onset before 18 years, because it has a higher diagnostic yield than conventional tests and may be more cost-effective when requested early [22]. The 2014 American Academy of Pediatrics guideline recommended CMA as first-tier, fragile X testing, consideration of inborn errors of metabolism and brain MRI in selected patients [51]. The divergence is temporal: the 2021 ACMG recommendation places ES/GS ahead of CMA, and CMA remains useful for deletions that include SETD2 or RSRC1 [15, 22, 47].

The Oxford Desk Reference summarises reference yields in ID: recognisable clinical diagnosis in about 25% of cases, karyotype in 4%, CMA with a further 14% (mean yield of 18% as first-tier) and exome up to 50% in severe sporadic ID [52]. Trio analysis facilitates interpretation, and female sex, parental age and absence of consanguinity increase the probability of a de novo dominant variant; in consanguineous families, about 5% of children with a developmental disorder nevertheless have a de novo variant, and single nucleotide polymorphism microarrays detect regions of homozygosity useful in the study of recessive disorders [52]. MRI is indicated in the presence of microcephaly, macrocephaly or neurological signs; the electroencephalogram (EEG), when seizures or regression are suspected; FMR1 testing should be considered; and metabolic investigation follows a tiered scheme, with baseline tests (glucose, lactate, ammonia, blood gases, full blood count, liver function, creatine kinase, phosphate, uric acid, thyroid function, maternal phenylalanine, creatine metabolites, urinary glycosaminoglycans, purines and pyrimidines) and additional tests with neurological signs or dysmorphism [52].

5.3. Molecular tests for SETD2

The GeneReviews describes two strategies. In the presence of the distinctive RAPAS phenotype, targeted SETD2 sequencing, followed by deletion/duplication analysis, is appropriate [3]. When the diagnosis has not been considered, as is usual in LLS and MRD70, a multigene overgrowth, macrocephaly, ASD or ID panel that includes SETD2, or ES/GS, which is the most commonly used route, is employed [3].

The 30/30 proportion means that all published variants were detected by sequencing; it does not measure the probability that a patient with the phenotype has a SETD2 variant, which is low in «Sotos-like» cohorts (1 in 210 French index cases) [3, 29]. A negative sequencing result does not exclude the diagnosis, because intragenic deletions, deep intronic variants and low-level mosaicism may escape the method used [3]. Mosaicism may not be detected in leucocytes [3].

5.4. Methylation episignature

The 2022 revision of the GeneReviews added the DNA methylation episignature in leucocytes, to be considered in two situations: a suggestive picture without a SETD2 variant identified by sequencing or genomic analysis, and a suggestive picture with a VUS in SETD2 [3]. The LLS episignature was derived from 4 samples and included in version 3 of EpiSign, with 57 episignatures covering 74 syndromes; an unresolved case with a probability score of 0.93 clustered with the LLS samples [23]. In the targeted bisulfite sequencing study of about 2 million CpG dinucleotides, loss-of-function variants produced a predominantly hypomethylated pattern, as in Sotos and Tatton-Brown-Rahman syndromes, and codon 1740 variants a predominantly hypermethylated pattern, with 62 differentially methylated regions and 281 CpG islands [32]. Consequently, a negative LLS episignature does not exclude a codon 1740 variant, and interpretation must take the variant type into account.

In the EpiSign clinical network, with 2399 cases, global screening for episignatures, imprinting and promoters in 1667 patients was positive in 18.7% (312 of 1667), and targeted analysis for reclassification of VUS or copy number variants (CNV), or to confirm a clinical diagnosis, was positive in 32.4% (237 of 732); the same work sets out recommendations for interpretation and reporting [53]. The episignature was used to support the VUS p.(Ser1658Leu) in the multiple tumour phenotype case [33].

5.5. Variant interpretation, VUS and segregation

The proportion of VUS in the SETD2 literature is high: 14 of the 34 variants reviewed by Parra, mainly missense variants and the recurrent variant c.19C>T [4]. Even p.(Arg1740Gln), which defines MRD70, appears as VUS in the automated classification of Parra's table, despite the published genotype-phenotype correlation [4, 14]. Reclassification relies on parental testing (de novo variant with confirmed parentage), phenotypic concordance, the episignature and population frequency [4, 53]. c.19C>T calls for caution, because of its frequency in the Latino population, transmission from mothers not described as affected and its position in the 5' untranslated region of alternative transcripts [4].

The laboratory report should state the gene, the transcript and its version (NM_014159.7 for SETD2; NM_001271838.2 for RSRC1), the variant in HGVS nomenclature at the c. and p. levels, the genomic coordinate with the reference genome version, zygosity, the ACMG/AMP class with the criteria applied and, when available, parental origin [3, 8]. For MRT70, it should confirm the biallelic configuration, homozygous or compound heterozygous, by parental testing [15].

5.6. Diagnosis of MRT70

In the Scala series, the variants were identified by trio, quartet or proband-only exome sequencing, with Sanger confirmation, and the deletions by array comparative genomic hybridisation; all were classified as pathogenic or likely pathogenic [15]. In the Amish family, the deletion was detected by array only after a negative exome, which illustrates the limit of exome sequencing for small copy number variants [15]. Homozygosity mapping is useful in consanguineous families, and a normal MRI does not exclude the diagnosis [11, 36]. The authors recommend including RSRC1 in ID panels [15].

5.7. Non-molecular complementary investigations

Non-molecular investigations do not confirm the diagnosis, but define the phenotype and guide follow-up: brain MRI, serial HC and growth, bone age, developmental and ASD assessment, thyroid-stimulating hormone (TSH) and free thyroxine (FT4), electrolytes in RAPAS, echocardiogram, renal ultrasound, dilated fundus examination, audiological assessment, EEG and swallowing study in RAPAS [21]. The assessments recommended after diagnosis are in section 11.

5.8. Practical algorithm

5.9. Prenatal diagnosis

In RAPAS, brain malformations become visible in the third trimester and cardiac and renal anomalies may be detected on ultrasound, together with polyhydramnios; these findings are non-specific and diagnosis is possible only by molecular testing [3]. Once the familial variant is known, prenatal diagnosis and preimplantation genetic testing are possible (section 8) [3].

6. Differential Diagnosis

6.1. Principles

The differential depends on the presenting phenotype. Without macrocephaly or congenital anomalies, SETD2-NDD enters the differential of all ID without distinguishing findings, in the autosomal dominant, recessive and X-linked OMIM phenotypic series [3]. With macrocephaly and overgrowth, the differential comprises the overgrowth syndromes with ID, especially those of the epigenetic regulators of the H3K36 axis [3, 30]. With microcephaly and multiple congenital anomalies, the differential is narrower [3]. MRT70 is easily confused with the other autosomal recessive non-syndromic ID, without a recognisable facial gestalt [15, 18]. In all scenarios, the discriminating test is molecular, and the episignature helps when the variant is of uncertain significance [3, 53].

6.2. Differential of SETD2-NDD with macrocephaly or overgrowth

The table reproduces the differential of the SETD2 GeneReviews. The Malan syndrome row is incomplete in the source, without inheritance or features; it was completed from the NFIX GeneReviews [54].

Four entities in the table, all rare, have data that help separate them from LLS. Tenorio syndrome was identified in 2014 in the Spanish overgrowth syndrome registry: among 270 families without a molecular diagnosis, a 9 Mb de novo deletion at 18q12 led to RNF125, and screening of the other families found three missense variants in five patients from three families, for a total of six patients from four families; RNF125 haploinsufficiency dysregulates the RIG-I, PI3K-AKT and interferon pathways, which relates to the inflammatory manifestations (Raynaud phenomenon, keratoconjunctivitis sicca, recurrent aphthous stomatitis) [55]. MDFPMR, described in four sibships of Colombian, Moroccan, Indian and Azerbaijani origin, combines persistent macrocephaly (up to +3 SD in the Moroccan adult) with increased weight and length at birth that normalise with age, hypotonia, epilepsy in some patients, severe myopia in two and ID ranging from mild to severe; magnetic resonance imaging was normal in some and showed communicating hydrocephalus, megalencephaly with a thick corpus callosum or a small cerebellum in others [56]. In fibroblasts, a truncating variant led to absence of the protein, whereas the missense variant p.(Arg4691Pro), in the HECT domain, increased mTORC1 complex activity and reduced autophagy, which suggests distinct mechanisms for different alleles [56]. In Thauvin-Robinet-Faivre syndrome, the review of eight patients from five families found tall stature and developmental delay in all, macrocephaly in 6 of 8, cardiovascular, genitourinary and skeletal anomalies in 5 of 8 each and ocular anomalies in 3 of 8; one patient had a Wilms tumour at 4 years, and the same 7 bp duplication in the homozygous state in the three Turkish families suggests a founder effect in that population [57]. In Imagawa-Matsumoto syndrome, caused by heterozygous variants of SUZ12, a subunit of Polycomb repressive complex 2 (PRC2) like EZH2 and EED, analysis of 13 patients gave a mean height of +2.53 SD in childhood and +3.75 SD in adulthood, a mean HC at birth of only +0.85 SD, cryptorchidism in 4 of 8 boys and structural brain changes in 4 of 10 patients; two patients had no overgrowth, and missense variants were associated with greater excess weight than truncating ones (+4.6 SD against +2.15 SD in mean maximum weight) [58]. The variant in the first SUZ12 case was de novo in the child, but was present as low-level mosaicism in the unaffected father, which has implications for recurrence risk [58].

6.3. Differential of SETD2-NDD with multiple congenital anomalies

6.4. Other chromatinopathies and diagnoses to consider

Neurodevelopmental disorders caused by other SET domain genes form a molecular and clinical differential: SETD1A-related disorder (OMIM 619056), Kabuki syndrome type 1 (KMT2D), Sotos syndrome and Weaver syndrome [59]. Lee and colleagues also include the chromatinopathies of the KMT2 methyltransferases: Wiedemann-Steiner (KMT2A), KMT2B-related dystonia, Kleefstra type 2 (KMT2C) and O'Donnell-Luria-Rodan (KMT2E) [32].

Neurodevelopmental disorder with speech impairment and dysmorphic facies (NEDSID, OMIM 619056) results from haploinsufficiency of SETD1A (16p11.2), a histone H3 lysine 4 (H3K4) methyltransferase. Kummeling and colleagues described 15 unrelated patients with 14 different de novo variants, almost all truncating or splicing and all with predicted loss of the SET domain; the picture combines global delay with mild motor delay, mild to moderate ID or learning difficulties, poor speech and language acquisition (speech apraxia in one patient), behavioural changes (aggression, attention deficit, anxiety, sleep disturbance, autistic traits), variable facial dysmorphism and distal limb anomalies with joint hypermobility, and two older patients had psychotic symptoms [60]. Loss-of-function variants of SETD1A have also been associated with schizophrenia, present in about 0.13% of cases, and most carriers with schizophrenia had learning difficulties [60]. Unlike LLS, macrocephaly and overgrowth are not among the manifestations described in NEDSID [60].

In adults, LLS may be confused with other causes of tall stature, severe obesity and endocrine changes. Suda's case shows that LLS enters the differential of gigantism without a pituitary tumour, with normal GH and IGF-1 [45]. In Huang's case, polycystic ovary syndrome and isolated hyperprolactinaemia were earlier incorrect diagnoses, and the picture of severe obesity of rapid onset in adolescence raised the hypothesis of monogenic obesity [35]. In cases with café-au-lait macules, RASopathies, including neurofibromatosis, were considered and excluded [34]. The combination of a SETD2 variant with a PTEN variant in a patient with extreme macrocephaly argues for analysing all macrocephaly genes, even after a variant has been identified [4].

6.5. Differential of MRT70

MRT70 belongs to the group of autosomal recessive non-syndromic ID (ORPHA:88616), and differential diagnosis from the other forms of this group is possible only by molecular study [15, 18]. Febrile seizures, generalised hypotonia and behavioural changes do not distinguish MRT70 from other recessive ID, and the deletion in the Amish family, which includes MLF1, shows that a CNV can explain additional features [15]. The general approach to ID is described in section 5.2.

7. Treatments and Risk Management Strategies

7.1. Principles and level of evidence

There is no targeted or disease-modifying therapy for any of the entities in this article, and there are no specific clinical practice guidelines; the management recommendations of the GeneReviews result from the authors' consensus, without trials [3, 21]. No drug has shown specific efficacy for seizures or behaviour in these patients [3]. Management is symptomatic, multidisciplinary and system-oriented, and the drugs mentioned below are used by extrapolation from indications approved for ASD, ADHD, epilepsy, insomnia or endocrinopathies, with the official label as the source of dosing. For MRT70 there is no specific treatment, and management is that of ID and behavioural changes [11].

7.2. Management by manifestation in Luscan-Lumish syndrome and MRD70

7.3. Management by manifestation in Rabin-Pappas syndrome

In the GeneReviews table, the dysplastic kidneys row assigns «standard treatment» to a neurologist, which is inconsistent with the manifestation; renal management and kidney replacement therapy belong to nephrology [3].

7.4. Development, education and behaviour

The GeneReviews describes the organisation of support in the North American system: early intervention from 0 to 3 years, developmental preschool with an individualised education plan from 3 to 5 years, an education plan reviewed annually, in the least restrictive environment possible, with services up to 21 years and a transition plan in adolescence [3]. The principles apply to European systems with local adaptations. For behavioural changes and ASD, applied behaviour analysis is recommended; a developmental paediatrician may prescribe drugs for ADHD, and severe aggression justifies referral to child and adolescent psychiatry [3]. Hypotonia and hypermobility benefit from physiotherapy and occupational therapy, and hearing loss from audiological and educational support [3].

7.5. Pharmacological therapy

The following drugs have no specific indication for SETD2-NDD or MRT70. The doses come from the US Food and Drug Administration (FDA) label or the European Medicines Agency (EMA) summary of product characteristics (SmPC) for the closest indication, and the extrapolation is stated in each case. The Portuguese national SmPCs and the Brazilian package inserts were not consulted; risperidone, methylphenidate, lamotrigine and valproate have national authorisations in the European Union (EU).

7.5.1. Irritability and aggression associated with ASD

ASD is recorded in half of patients with LLS and aggression is frequent [4, 31]. Risperidone (Risperdal®) has an FDA label indication for irritability associated with autistic disorder, including aggression, deliberate self-injury, tantrums and quickly changing moods, with efficacy established in three short-term trials in children and adolescents aged 5 to 17 years [62]. The starting dose is 0.25 mg/day below 20 kg and 0.5 mg/day from 20 kg; after at least 4 days, it is increased to the recommended dose of 0.5 mg/day (below 20 kg) or 1.0 mg/day (from 20 kg), maintained for at least 14 days, with subsequent increases of 0.25 mg/day or 0.5 mg/day, respectively, at intervals of at least 2 weeks; the effective range is 0.5 to 3 mg/day, as a single dose or divided into two, with no maximum dose defined in the label for this indication, and there are no dosing data below 15 kg [62]. In the EU, risperidone has no indication in ASD: it is authorised from 5 years only for short-term (up to 6 weeks) symptomatic treatment of persistent aggression in conduct disorder, in children and adolescents with below-average intellectual functioning or intellectual disability, with a starting dose of 0.25 mg/day below 50 kg (optimum 0.5 mg/day; maximum 0.75 mg/day) and of 0.5 mg/day from 50 kg (optimum 1 mg/day; maximum 1.5 mg/day) [63]. Persistent somnolence may be managed by taking the dose at bedtime or by dose reduction [62]. The label warnings include metabolic changes, hyperprolactinaemia, orthostatic hypotension, leucopenia and neutropenia, tardive dyskinesia, neuroleptic malignant syndrome, seizures, dysphagia, priapism and disrupted body temperature regulation [62]. In these patients, the obesity seen in about one third of LLS cases, the hyperprolactinaemia described in one adult case and epileptic seizures weigh on the choice and on monitoring [4, 35].

Aripiprazole (Abilify®) has an FDA label indication for irritability associated with autistic disorder from 6 to 17 years, with a starting dose of 2 mg/day, increase to 5 mg/day and then, if needed, to 10 or 15 mg/day, in adjustments of up to 5 mg/day at intervals of at least one week; the recommended range is 5 to 15 mg/day (maximum 15 mg/day), and in CYP2D6 poor metabolisers half the dose is used [64]. In the EU, the European public assessment report (EPAR) for Abilify does not include this indication (the indications are schizophrenia in adults and from 15 years and manic episodes of bipolar I disorder in adults and, for up to 12 weeks, from 13 years), so use for irritability in ASD is off-label in the EU [65].

7.5.2. ADHD

ADHD occurs in 26.5% of patients with LLS [4]. Methylphenidate (Ritalin® in the United States) is started, from 6 years, at 5 mg twice daily, before breakfast and lunch, with weekly increases of 5 to 10 mg; doses above 60 mg/day are not recommended, and the drug should be discontinued if there is no improvement after one month of titration [66]. Before starting, the label requires assessment for heart disease, by personal history, family history of sudden death or ventricular arrhythmia and physical examination, and for tics or Tourette syndrome [66]. Tics were described in four of the five Bedouin patients with MRT70 [15], and epileptic seizures in 8.8% of patients with LLS and 57.1% of patients with RAPAS [4].

7.5.3. Insomnia

Prolonged-release melatonin Slenyto® was authorised in the EU on 20 September 2018 for insomnia in children and adolescents aged 2 to 18 years with ASD and/or Smith-Magenis syndrome. The Commission decision of 26 August 2024 extended the indication to neurogenetic disorders with aberrant diurnal melatonin secretion and/or nocturnal awakenings, and that of 17 March 2025 added insomnia from 6 to 17 years with ADHD, whenever sleep hygiene measures are insufficient [67]. It is presented as 1 mg and 5 mg prolonged-release tablets, to be swallowed whole, without breaking, crushing or chewing, which may be mixed with yoghurt, orange juice or ice cream and taken immediately [67]. In ASD and neurogenetic disorders, the starting dose is 2 mg, increased to 5 mg if the response is insufficient, up to a maximum of 10 mg, once daily, 0.5 to 1 hour before bedtime, with or after food; there are data for up to 2 years of treatment, the effect is assessed after at least 3 months and the patient should be reassessed at least every 6 months [67]. In ADHD, the starting dose is 1 to 2 mg, titrated up to 5 mg, with a maximum of 10 mg, and with withdrawal attempts at least annually [67]. Daytime somnolence and fatigue may worsen inattention and behaviour in children with ADHD, concomitant use of fluvoxamine, alcohol, benzodiazepine and non-benzodiazepine hypnotics, thioridazine and imipramine is not recommended, and the drug is not recommended in hepatic impairment and contains lactose [67]. The most common adverse effects are somnolence, fatigue, mood swings, headache, irritability and aggression [67]. The inclusion of neurogenetic disorders in the indication covers, by extension, SETD2-NDD and MRT70, although these entities have not been specifically studied.

7.5.4. Epilepsy

Epilepsy is rare in LLS and frequent and difficult to control in RAPAS [3]. The drugs cited in published patients are lamotrigine monotherapy (LLS), phenobarbital combined with a ketogenic or modified Atkins diet and cannabidiol (RAPAS), and valproic acid (MRT70) [3, 15]. The sources do not describe the doses used in these patients; the doses below are those of the labels.

Lamotrigine (Lamictal®) has an FDA label indication as adjunctive therapy from 2 years (focal seizures, primary generalised tonic-clonic seizures and Lennox-Gastaut syndrome) and conversion to monotherapy from 16 years [68]. From 2 to 12 years, without valproate or enzyme inducers, it is started at 0.3 mg/kg/day in weeks 1 and 2 and 0.6 mg/kg/day in weeks 3 and 4, in one or two doses, rounding down to the nearest whole tablet, with increases of 0.6 mg/kg/day every 1 to 2 weeks up to maintenance of 4.5 to 7.5 mg/kg/day (maximum 300 mg/day in two doses) [68]. With valproate, the doses are 0.15 mg/kg/day and 0.3 mg/kg/day in weeks 1–2 and 3–4, increases of 0.3 mg/kg/day and maintenance of 1 to 5 mg/kg/day (maximum 200 mg/day), or 1 to 3 mg/kg/day with valproate alone; with carbamazepine, phenytoin, phenobarbital or primidone without valproate, 0.6 and 1.2 mg/kg/day, increases of 1.2 mg/kg/day and maintenance of 5 to 15 mg/kg/day (maximum 400 mg/day); below 30 kg maintenance may need to be increased by up to 50% [68]. Above 12 years, without valproate or inducers, the dose is 25 mg/day in weeks 1 and 2 and 50 mg/day in weeks 3 and 4, with increases of 50 mg/day every 1 to 2 weeks up to maintenance of 225 to 375 mg/day in two doses; with valproate, 25 mg every other day, then 25 mg/day, with increases of 25 to 50 mg/day and maintenance of 100 to 200 mg/day (100 to 400 mg/day with valproate and inducers); with inducers, 50 mg/day and 100 mg/day, with increases of 100 mg/day and maintenance of 300 to 500 mg/day [68]. Above 12 years, the label gives these usual maintenance ranges, without a defined maximum dose [68]. The label has a boxed warning about serious rash and prohibits exceeding the recommended starting dose and titration rate [68].

Valproic acid, used in one patient with MRT70 [15], has in the FDA label of divalproex (Depakote®), for complex partial seizures in adults and children from 10 years, a starting dose of 10 to 15 mg/kg/day, with weekly increases of 5 to 10 mg/kg/day, and, for absence seizures, a starting dose of 15 mg/kg/day; the recommended maximum is 60 mg/kg/day [69]. The boxed warning refers to fatal hepatotoxicity, with greater risk below 2 years, especially with polytherapy, congenital metabolic disorders, severe epilepsy with ID or organic brain disease, contraindication in mitochondrial disorders due to POLG variants, and fetal risk of major malformations, in particular neural tube defects, and of reduced intelligence quotient [69]. Fetal risk is decisive in girls and women of reproductive potential.

Phenobarbital, used in one patient with RAPAS [3], does not have in the United States a label approved through a marketing authorisation process; the available label gives, for anticonvulsant use, 3 to 6 mg/kg/day in children and 60 to 200 mg/day in adults, with a loading dose of 15 to 20 mg/kg in children and infants, producing serum levels of about 20 µg/mL, and adjustment by serum levels [70]. Adverse effects include central nervous system depression, respiratory depression and, in children, irritability and hyperactivity [70].

Cannabidiol (Epidiolex® in the United States; Epidyolex® in the EU) has an FDA label indication for seizures of Lennox-Gastaut and Dravet syndromes and tuberous sclerosis complex: it is started at 2.5 mg/kg twice daily (5 mg/kg/day), increased after one week to maintenance of 5 mg/kg twice daily (10 mg/kg/day) and may go up to a maximum of 10 mg/kg twice daily (20 mg/kg/day), in weekly increases of 2.5 mg/kg twice daily; in tuberous sclerosis complex, maintenance is 12.5 mg/kg twice daily (25 mg/kg/day) [71]. Transaminases and bilirubin should be measured before starting, and the dose is adjusted in moderate or severe hepatic impairment [71]. Use in SETD2-NDD is off-label, and the «cannabidiol oil» mentioned in the GeneReviews is not necessarily the authorised medicine [3].

The ketogenic diet and the modified Atkins diet are options for refractory seizures [3]. The 2018 recommendations of the International Ketogenic Diet Study Group address patient selection, pre-diet counselling, choice of diet, supplementation, follow-up, adverse effects and discontinuation [61]. In infants with RAPAS, gastrostomy feeding facilitates administration of ketogenic formulas, but the sources do not describe specific experience.

7.5.5. Endocrine therapy

Somatropin (Genotropin®) has in the FDA label, for paediatric GH deficiency, a dose of 0.16 to 0.24 mg/kg/week [72]. The GeneReviews recommends treatment of confirmed GH deficiency by an endocrinologist [3]. SETD2 is a tumour suppressor gene, tumours have been described in germline carriers and one LLS case suggests increased GH signalling; these observations do not contraindicate treatment, but justify an individual and documented decision [3, 32, 45].

Leuprorelin (Lupron Depot-PED® in the United States) has in the FDA label, for central precocious puberty, the monthly intramuscular formulation of 7.5 mg up to 25 kg, 11.25 mg above 25 kg and up to 37.5 kg and 15 mg above 37.5 kg, with escalation to the next dose if suppression is inadequate, and the 3-monthly formulation of 11.25 mg or 30 mg every 12 weeks; suppression is checked 1 to 2 months after starting, with a gonadotrophin-releasing hormone stimulation test, basal luteinising hormone (LH) or sex steroids, and height and bone age every 6 to 12 months [73]. The GeneReviews recommends standard treatment of precocious puberty, with hormonal suppression according to age [3].

In the adult case of Huang and colleagues, the doses used were cabergoline 0.5 mg twice weekly for 5 years, which normalised prolactin; metformin 500 mg twice daily and semaglutide 0.25 mg/week, both discontinued, the latter because of gastrointestinal intolerance; spironolactone 100 mg/day for 6 months, with minimal benefit; finasteride 5 mg/day, with marked improvement of hirsutism; tirzepatide 2.5 mg subcutaneously per week, increased to 5 mg; and hormone therapy with transdermal estradiol 0.025 mg/day and oral progesterone 100 mg at night, after a normal mammogram [35]. These are the measures taken in a single case, not recommendations.

7.5.6. Hyponatraemia in RAPAS

Hyponatraemia in infancy resolved in the patients described with sodium supplementation, after SIADH had been excluded [3]. The GeneReviews does not give the dose, formulation or duration, and no label or paediatric recommendation for this indication was found in the sources consulted; the dose should be individualised by the nephrology or neonatology team based on serum sodium and fluid balance.

7.5.7. Dosing table

7.6. Chiari I malformation

Chiari I malformation has been described in several patients with LLS, including Lumish's patient, Suda's patient and Huang's adult patient, operated on in 2012 [28, 35, 45]. The international consensus document on Chiari type 1 malformation in children, obtained by a three-round Delphi method with 34 experts and 58 statements (24 on diagnosis and 34 on treatment), applies to these patients [50]. The consensus defines the malformation as herniation of the cerebellar tonsils of at least 5 mm below McRae's line, or of 3 to 5 mm with syringomyelia or peg-shaped tonsils [50]. In the asymptomatic child with isolated Chiari I without syringomyelia, surgery is not indicated (94.1% agreement); in the asymptomatic child with syringomyelia, surgery is indicated if the syrinx is larger than 5 to 8 mm or if a smaller syrinx grows (82.4%) [50]. In children with Chiari I and cognitive or behavioural disorders, such as autism, without clear symptoms of the malformation, surgery is not indicated to improve that picture (91.2%), nor is it offered to improve epilepsy control [50]. An ectopia of 20 mm or more without a syrinx in an asymptomatic patient does not by itself justify the decision to operate (88.2%), and hydrocephalus should be treated first [50]. This consensus is relevant because autism and epilepsy are frequent in LLS and the discovery of a Chiari I on a routine MRI may lead to requests for surgery with no expected benefit. The recommended follow-up is in section 11.

7.7. Tumours: surveillance and prevention

There is no tumour surveillance recommendation for germline carriers of SETD2 variants. Lee and colleagues, who described a glioma and an osteosarcoma in 10 patients, do not recommend a surveillance programme until the risks and tumour types are confirmed and cost-effectiveness can be estimated [32]. The preprint by Goda and colleagues calls for studies to define surveillance strategies [34]. GeneGuidance does not recommend tumour surveillance and ClinGen has not assessed the actionability of SETD2 [21]. In practice, clinical attention is directed at signs and symptoms suggestive of a tumour, including in patients with RAPAS, in whom the osteosarcomas were described [3, 32], and the subject should be discussed with the family, as in Huang's case [35].

7.8. Guidelines and positions: synthesis and divergences

There is no specific guideline for SETD2-NDD or MRT70 in the sources consulted, and the absence of trials means that the recommendations are extrapolations from analogous conditions [3, 11].

7.9. Regulatory status of the drugs mentioned

7.10. Clinical trials and drug evidence

There are no interventional trials in patients with SETD2-NDD or MRT70. A search of ClinicalTrials.gov in October 2026 found 17 studies with «SETD2», all oncological or unrelated, with the exception of Simons Searchlight (NCT01238250), an observational online registry of people with genetic changes and autism features that includes SETD2 and was recruiting; searches for «Luscan-Lumish», «RSRC1», «Rabin-Pappas» and «Sotos-like» returned no studies [74]. The table summarises the trial evidence for the symptomatic drugs with numerical data in the sources consulted.

The melatonin SmPC presents the results without confidence intervals, only with p values, and the population consisted almost entirely of children with ASD; extrapolation to SETD2-NDD is based on the indication, which includes neurogenetic disorders, and not on data from these patients [67]. Indirect comparison between trials of different drugs is not possible, and the differences in minutes of sleep should be read against baseline values, which were about 457 to 460 minutes [67]. No negative trials, suspensions or withdrawals were found for these entities, which reflects the absence of trials and is not proof that no research exists in other sources [74].

7.11. Developments in the last 12 months

The publications between October 2025 and October 2026 are case reports, reviews and one preprint, without therapeutic data. The case of Huang and colleagues, published on 5 October 2026, extends the adult endocrine phenotype of LLS (published result, single case) [35]. Ünsel-Bolat and colleagues described in 2026 a 17-year-old boy with dysmorphism, epilepsy, ADHD and moderate ID, carrying the de novo variant NM_014159.7:c.7084C>T p.(Gln2362Ter), with a phenotype overlapping LLS (case report) [46]. The review by Ohguri and colleagues, published on 21 October 2026, on SET domain genes in neurodevelopmental disorders, reports that studies in models show partial reversibility of molecular and behavioural changes by restoring the function of SET proteins, by inhibiting opposing enzymes, such as the demethylase LSD1, or by correcting downstream pathways; these are preclinical data and, in the abstract, not specific to SETD2 [59]. The preprint by Goda and colleagues, from December 2025, describes a malignant phyllodes tumour in a female germline carrier (not peer reviewed) [34]. In March 2026, ClinGen classified the relationship of RSRC1 with neurodevelopmental disorder as definitive (curation) [20]. Outside the window, but recent, are the multiple tumour phenotype with episignature of Lucain and colleagues and the murine model of Chen and colleagues, both from 2025 [33, 40]. No regulatory announcements, opinions or authorisations specific to these entities were identified [74].

7.12. Agents to avoid and precautions

The sources do not describe drugs specifically contraindicated in SETD2-NDD or MRT70. Precautions derive from the labels and the phenotype: methylphenidate requires assessment for tics, present in patients with MRT70 [15, 66]; antipsychotics increase metabolic risk and hyperprolactinaemia, already present in some patients with LLS [35, 62]; valproate is restricted because of fetal risk and hepatotoxicity in young children with ID and severe epilepsy [69]; lamotrigine requires the slow titration of the label, especially with valproate [68]; and melatonin should not be combined with fluvoxamine, alcohol, hypnotics, thioridazine or imipramine [67].

7.13. Pregnancy, lactation, perioperative care and transition

There are no published data on pregnancy in women with SETD2-NDD or MRT70 in the sources consulted. In Huang's adult patient, with hypogonadotrophic hypogonadism and secondary amenorrhoea since the age of 27, a combined oral contraceptive with norgestimate and ethinylestradiol was stopped because of prolonged bleeding of up to 16 days, and hormone therapy was deferred, because of a maternal history of oestrogen receptor-positive breast cancer, until a normal mammogram [35]. In a pregnancy with a fetus with RAPAS, preterm birth, polyhydramnios and maternal pre-eclampsia are frequent, and delivery should be planned in a centre with a level IV NICU [3]. As regards drugs, melatonin should preferably be avoided in pregnancy as a precaution and is probably excreted in breast milk [67], and valproate carries a fetal risk of major malformations and reduced intelligence quotient [69].

The sources do not describe anaesthetic experience in these patients. The Pierre Robin sequence, tracheomalacia, hypoventilation, aspiration and heart defects described in RAPAS, as well as severe obesity and Chiari I in LLS, are clinical data to be communicated to the anaesthetic team before any procedure [3, 35].

Transition to adult care should be prepared in adolescence, with an educational transition plan, counselling of the young adult on the risk to offspring and resources such as the «Transition to adulthood» section of Simons Searchlight [3, 75]. Huang's case shows that, in adults, endocrine and metabolic manifestations may dominate the picture and that the molecular diagnosis may come only in the fifth decade [35].

7.14. MRT70

There is no specific treatment for MRT70. Management is that of ID, hypotonia and behavioural changes, with early intervention, physiotherapy, occupational and speech therapy, educational support and treatment of seizures [11, 15]. Febrile seizures were the most frequent seizure type, and focal epilepsy was treated with valproic acid in the only patient with definite epilepsy in the Scala series [15]. The drugs for ADHD, irritability in ASD and insomnia described in section 7.5 apply by extrapolation, with the same sources and caveats.

8. Reproductive Options and Family Counselling

8.1. SETD2-NDD: autosomal dominant inheritance

SETD2-NDD is transmitted in an autosomal dominant manner, and most patients are the only case in the family because of a de novo variant [3, 4]. Parent-to-child transmission was described in one family of O'Roak, without information on whether the parent had features of the disease [3], and, in the Parra series, for the likely pathogenic variant p.(Cys394Ter), of paternal origin, and for several VUS [4]. Codon 1740 variants were always de novo in the patients described [14].

Molecular testing of the proband's parents is recommended [3]. If the variant is not found in either parent, the explanations are a de novo variant (or presumed de novo, if parentage has not been confirmed) or parental germline mosaicism [3]. Mosaicism was observed in a mildly affected individual, with hearing loss, Chiari, epilepsy, hypoglycaemia and normal intelligence, and mosaicism may not be detected in leucocyte DNA [3]. A negative family history is confirmed only by parental testing, because penetrance may be reduced and mild features may go unnoticed [3].

8.2. MRT70: autosomal recessive inheritance

All families with MRT70 described were consanguineous [15]. The parents of a patient are obligate heterozygotes, and in each pregnancy the risk of an affected child is 25%, that of an asymptomatic carrier child 50% and that of a non-carrier child 25%, according to the autosomal recessive pattern [11, 15]. The unaffected siblings of a patient have a two-thirds probability of being carriers. Cascade carrier testing is possible in the extended family once both variants have been identified, and is relevant in communities with frequent consanguinity, such as those described [15]. In non-specific ID without a molecular diagnosis, the Oxford Desk Reference recommends assuming a recurrence risk of 25% when the parents are consanguineous, until proven otherwise [52].

8.3. Prenatal diagnosis and preimplantation genetic testing

Once the pathogenic variant has been identified in the family, prenatal diagnosis and preimplantation genetic testing are possible, and the discussion should ideally take place before pregnancy [3]. In de novo SETD2-NDD, a request for prenatal diagnosis in a subsequent pregnancy arises mainly from the residual risk of germline mosaicism [3]. In the absence of a family history, third-trimester ultrasound may show brain, cardiac or renal malformations and polyhydramnios in a fetus with RAPAS, which only molecular testing confirms [3]. For MRT70, prenatal diagnosis requires prior identification of both familial variants [15].

8.4. Content of counselling

Counselling should explain the variability of severity within the SETD2 class, the correlation with codon 1740, the uncertainty about tumour risk and the absence of targeted therapy [3, 32]. For affected young adults, it should address the 50% risk to offspring [3, 35]. The interpretation of VUS, frequent in this class, deserves specific explanation, to avoid decisions based on an unclassified variant [4]. In asymptomatic minors, testing is directed at those with a phenotype or those who would benefit directly, and MRT70 carrier testing in minor siblings may wait until the age at which the individual can decide.

9. Special Considerations: Population Diversity and Epidemiology

9.1. Prevalence and what each figure measures

The prevalence of SETD2-NDD is unknown. The GeneReviews counted fewer than 40 published individuals in 2021–2022, 30 of them with a pathogenic SETD2 variant [3]; Parra's review counted 51 in 2023 (34 LLS, 14 RAPAS and 3 MRD70) [4]; and Lucain referred to about 50 in 2025 [33]. These are counts of published cases and not prevalence estimates. Orphanet assigns the two entities it codes the worldwide prevalence class of less than 1 in 1 000 000, with 11 cases counted for LLS and 12 for the syndrome with MCA; this class derives from the number of known cases and not from population studies [21]. Wu and colleagues consider that the incidence of LLS is unknown [42]. The yield of 1 in 210 (0.5%) in the French «Sotos-like» cohort without NSD1 measures the frequency in a selected population, not in the general population [29]. MRD70 has 3 patients described with certainty, and Lee's study adds 2 with p.(Arg1740Gln) who may be the same [14, 32]. MRT70 has 25 patients from 9 families [15].

The context of ID helps to situate these disorders: ID with an intelligence quotient below 70 affects 1% to 2.5% of the population, ID below 50 affects 0.3% to 0.5%, with a male:female sex ratio of 1.3:1, and, according to a systematic review cited by the Oxford Desk Reference, epilepsy occurs in 22%, anxiety in 17%, oppositional disorder in 12% and autism in 10% of people with ID [52]. The rarity of SETD2-NDD contrasts with the frequency of SETD2 as a mutated gene in somatic tumours, which is not informative for the germline disease [3, 48].

9.2. Geography, ancestry and founder populations

The series with an identified origin in the sources consulted include the French cohorts of Luscan and Tlemsani, the multicentre series of Parra, with centres in Spain, France, Turkey, Colombia and the United States, and the Chinese series of Chen and Zhang [4, 27, 29, 38, 44]. The Spanish series of the SOGRI registry, which includes more than 2200 individuals and relatives with overgrowth syndromes, is the largest European source of patients, but does not measure prevalence [4]. The c.19C>T variant, classified as VUS, is more frequent in the gnomAD Latino population (39 of the 40 alleles), which should be considered in interpretation in patients of Latin American ancestry [4].

In MRT70, all families were consanguineous, with European/Middle Eastern, Saudi, Egyptian, Old Order Amish of Pennsylvania and Indiana, Pakistani (two families), Persian, Malay and Bedouin ancestry [15]. The Amish family belongs to a North American founder population, and the 81 kb deletion is therefore a candidate founder variant in that community, although the sources do not estimate its frequency [15].

The sources consulted contain no data from Portugal or Brazil, and the Parra series includes no Portuguese or Brazilian centres; absence from the sources does not demonstrate absence of patients in those countries.

9.3. Special populations

Newborns with RAPAS are a special population because of the respiratory and feeding severity and the need for level IV intensive care [3]. Adults with LLS may present with endocrine and metabolic pictures without a prior diagnosis, as shown by the cases of Suda and Huang [35, 45]. People with ID and ASD need adaptation of communication and examinations, and carriers of variants with a mild phenotype, including mosaics, may come to the clinic only after the diagnosis of a child [3].

9.4. Reference networks and patient associations

The relevant European reference network is ERN ITHACA, dedicated to rare congenital anomalies and intellectual disability (https://ern-ithaca.eu/) [24]; La Paz University Hospital, in Madrid, the centre of the SOGRI series, is a member of the network [4]. Simons Searchlight maintains a page for SETD2, with resources for families, an observational registry and content on transition to adulthood [75]. The GeneReviews lists the Luscan-Lumish SETD2 Support association (www.luscan-lumish.org), whose website did not respond during data collection in October 2026, and general resources such as the American Association on Intellectual and Developmental Disabilities, the Autism Society and the National Center on Birth Defects and Developmental Disabilities of the Centers for Disease Control and Prevention [3]. The Oxford Desk Reference lists Mencap, in the United Kingdom, for ID in general [52].

10. Illustrative Clinical Case

10.1. Luscan-Lumish syndrome diagnosed at 47 years

Huang, Ashouri and Dominguez published in 2026 the case of a 47-year-old woman referred by neurology to endocrinology for hyperprolactinaemia of 140 ng/mL (reference 4–25 ng/mL) with a stable, non-enhancing 3 × 2 mm pituitary microadenoma [35]. Her history included epileptic seizures from 14 years, coinciding with the onset of rapid weight gain, Chiari I malformation treated by decompression in 2012, arterial hypertension, hypothyroidism since 34 years treated with levothyroxine, depression, developmental delay and secondary amenorrhoea [35]. She had been born appropriate for gestational age and had been slim until 14 years; from then on she gained about 27 kg (60 pounds) in 3 months and about 90 kg (200 pounds) over decades, without reported changes in diet or activity [35]. She did not speak until 6 years, had multiple learning difficulties, including auditory processing disorder, attended special education, and the hypothesis of ASD was considered without confirmation [35]. Menarche occurred at 14 years, with irregularity that progressed to secondary amenorrhoea at 27; at that time the hyperprolactinaemia and microadenoma were identified, treated with cabergoline 0.5 mg twice weekly for 5 years, with normalisation of prolactin [35]. The parents were not obese and did not have a similar phenotype; the mother had had oestrogen receptor-positive breast cancer and a sister had obesity and polycystic ovary syndrome [35].

On examination, BMI was 62.9 kg/m² (151 kg; 154.9 cm, below the familial target height of about 161 cm), blood pressure was 143/77 mmHg, and there was marked hirsutism of the upper lip and chin [35]. Laboratory assessment showed LH of 0.3 IU/L, follicle-stimulating hormone (FSH) of 0.5 IU/L and estradiol of 26.4–48 pg/mL, consistent with hypogonadotrophic hypogonadism; normal total testosterone (24 ng/dL), slightly raised free testosterone (5.1 pg/mL), minimally raised dehydroepiandrosterone sulfate (240 µg/dL), androstenedione of 109 ng/dL and normal 17-hydroxyprogesterone (11 ng/dL), which ruled out non-classic congenital adrenal hyperplasia; insulin of 37.9 µIU/mL with glucose of 95 mg/dL (homeostatic model assessment of insulin resistance, HOMA-IR, of 8.9) and glycated haemoglobin of 5.7%; triglycerides of 251 mg/dL, low-density lipoprotein cholesterol of 102 mg/dL and high-density lipoprotein cholesterol of 38 mg/dL; IGF-1 of 133 ng/mL, TSH of 2.1 and FT4 of 1.1, normal [35]. Polycystic ovary syndrome was considered and ruled out, because gonadotrophins were suppressed [35].

The combination of severe obesity of abrupt onset in adolescence, neurodevelopmental manifestations, seizures, Chiari I, an atypical hormonal profile and a phenotype distinct from that of the parents led to genetic testing, which identified the heterozygous variant NM_014159.7:c.4451_4454del p.(Lys1486ArgfsTer28), absent from gnomAD and classified as pathogenic by ACMG criteria, confirming LLS [8, 35]. Management included genetic counselling on autosomal dominant inheritance and the 50% risk to offspring, discussion of neoplastic risk, tirzepatide 2.5 mg weekly increased to 5 mg, finasteride 5 mg/day for hirsutism, hormone therapy with transdermal estradiol and oral progesterone after a normal mammogram, and conservative surveillance of the microadenoma, given its stability, the previous intolerance of dopamine agonists and the absence of reproductive plans [35]. Previously, metformin, semaglutide and spironolactone had been discontinued or had shown minimal benefit, and a combined oral contraceptive had been stopped because of prolonged bleeding [35]. At 4 months, tirzepatide was tolerated, with a fall from 151 to 149 kg in 3 weeks, the hirsutism had improved markedly, the microadenoma remained stable and there had been no new seizures [35].

Figure 1 of the article presents the chronology of the neurological and endocrine manifestations over more than three decades up to the molecular diagnosis (https://pmc.ncbi.nlm.nih.gov/articles/PMC13634679/figure/luag248-F1/), and figure 2 shows the central and truncal obesity, facial fullness and hirsutism (https://pmc.ncbi.nlm.nih.gov/articles/PMC13634679/figure/luag248-F2/); figure 3 reproduces the genetic test result [35]. The case illustrates three points: LLS may present in adults mainly with endocrine and metabolic changes, the absence of a unifying diagnosis for decades delayed counselling, and several measures (cabergoline, glucagon-like peptide 1 receptor agonists, finasteride, hormone therapy) are individual choices in a single case, not recommendations for LLS [35]. A causal relationship of the microadenoma, hypothyroidism and depression with the variant has not been established [35].

10.2. Paediatric comparison case

Zhang and colleagues described a boy aged 5 years and 7 months referred in November 2020 for «slow learning» at kindergarten [38]. He had been born by caesarean section at 36 weeks because of fetal distress, walked and said his first words at about 18 months, and his vocabulary expanded only close to 5 years; he had tall stature and macrocephaly [38]. On the Gesell scale, the quotients were 47 for adaptive behaviour, 45 for gross motor, 46 for fine motor, 33 for language and 39 for personal-social; full blood count, thyroid function, biochemistry and hearing were normal, and MRI showed a slightly short corpus callosum, with a thinner body [38]. The exome identified the de novo in-frame deletion c.2514_2516del p.(Ser838del) of SETD2, which the authors classified using the criteria PS2, PM2_Supporting and PM4 [38]. The case shows the typical paediatric presentation, centred on language delay, with macrocephaly and tall stature.

11. Prognosis and Long-term Follow-up

11.1. Prognosis

Prognostic data are scarce, and the sources contain no survival or mortality data [3]. In LLS, ID is predominantly moderate, and stature may normalise with age; Huang's case shows that endocrine manifestations and obesity may dominate adulthood [3, 35]. In MRD70, the three known patients had some speech at 2 years and had no congenital anomalies, which suggests a better functional prognosis than in RAPAS, without published long-term follow-up [3]. In RAPAS, all patients described were non-verbal and non-ambulatory, one progressed to end-stage kidney disease and two had osteosarcoma at 12 and 15 years, one of them with a fatal outcome shortly afterwards [3, 32]. In MRT70, ID is mild to moderate, without regression, but there is no literature on the course in adulthood [11, 15].

11.2. Assessments recommended after diagnosis

In LLS and MRD70, the GeneReviews recommends measuring height, weight and HC; assessing motor, adaptive, cognitive and language development, with referral for early intervention; neuropsychiatric assessment from 12 months (sleep, ADHD, anxiety, ASD); neurological assessment with brain MRI and EEG if there are seizures; TSH and FT4; screening for GH deficiency if growth velocity is low; clinical assessment for precocious puberty, with endocrinology if there are signs; assessment by orthopaedics, PRM, physiotherapy and occupational therapy; ophthalmology (acuity and strabismus); audiology; echocardiogram; examination for cryptorchidism; genetic counselling; and assessment of family support needs [3].

In RAPAS, the following are added: assessment of growth retardation; assessment by gastroenterology, nutrition and the feeding team, including the risk of aspiration and consideration of gastrostomy; screening for signs of hypoventilation and tracheomalacia, with respiratory medicine; ophthalmology with acuity, slit lamp (cataracts) and fundus examination (optic nerve hypoplasia, retinal telangiectasia, retinal detachment); renal ultrasound; electrolytes (at least sodium, potassium, chloride and bicarbonate), with investigation for SIADH if there is hyponatraemia; TSH and FT4; and orthopaedic assessment of contractures, clubfoot and kyphoscoliosis [3].

11.3. Surveillance

For MRT70 there are no published surveillance recommendations; developmental, behavioural and neurological assessments at every visit apply by extrapolation from ID guidance, with attention to febrile seizures and epilepsy [11, 15]. In ID without a diagnosis, the Oxford Desk Reference suggests review 1 year after the complete initial evaluation and again 2 years later, to reassess the phenotype and reanalyse the genomic data [52].

12. Summary and Final Considerations

The name «intellectual developmental disorder 70» designates two distinct diseases. MRD70 is the mildest form of an autosomal dominant spectrum caused by SETD2, a methyltransferase that deposits the H3K36me3 mark and methylates α-tubulin, in which loss-of-function variants cause Luscan-Lumish syndrome, with macrocephaly, overgrowth, usually moderate ID, ASD and Chiari I, and codon 1740 substitutions cause Rabin-Pappas syndrome, with p.(Arg1740Trp), microcephaly and multiple congenital anomalies, or MRD70, with p.(Arg1740Gln), ID without macrocephaly or malformations. The two ends of the spectrum have opposite methylation profiles, hypomethylated in loss of function and hypermethylated at codon 1740, which underpins the classification and makes the episignature useful in interpreting variants of uncertain significance, frequent in this class. Orphanet groups MRD70 with RAPAS by molecular criterion, whereas OMIM and the GeneReviews separate them by clinical picture.

MRT70 is an autosomal recessive ID due to biallelic loss of function of RSRC1, a splicing gene, described in 25 patients from 9 consanguineous families, with mild to moderate ID, hypotonia, behavioural changes and febrile seizures, and without diagnostic facial features. The diagnosis of all these entities is molecular, by exome or genome sequencing, complemented by copy number variant analysis, and the recurrence risk is low in de novo SETD2 forms and 25% in MRT70.

There is no targeted therapy and there are no clinical trials. Management is multidisciplinary and symptomatic, based on the GeneReviews, the general diagnostic guidelines for ID, the paediatric consensus on Chiari I, which advises against surgery to treat autism or epilepsy, and the drug labels for irritability, ADHD, insomnia, epilepsy and endocrinopathies. The description of tumours in germline carriers and of endocrine manifestations in adults extends the known spectrum, without there yet being a basis for a tumour surveillance programme. The small size of the series and the absence of data from Portugal, Brazil and systematic adult follow-up are the main limits of current knowledge.

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