20q13.33 Microdeletion and 17q25.3 Microduplication

Distal subtelomeric rearrangements of 20q and 17q: 20q13.33 microdeletion (neonatal epilepsy due to haploinsufficiency of KCNQ2*), 17q25.3 microduplication and distal trisomy 17q, the combined form der(20)t(17;20) and reciprocal entities.*

Literature and regulatory information updated: 28 October 2026.

0. Initial Reference Table

In this table, DD denotes psychomotor developmental delay; ID, intellectual disability; ASD, autism spectrum disorder; CNV, copy number variation; FISH, fluorescence in situ hybridisation; ILAE, International League Against Epilepsy; ERN, European Reference Network; ClinGen, Clinical Genome Resource.

1. Introduction

1.1. Common syndromic description

The 20q13.33 microdeletion and the 17q25.3 microduplication belong to the group of subtelomeric imbalances, that is, losses or gains of segments located immediately before the telomeric repeats, in the most distal sub-bands of a chromosome arm. They share with other chromosomal disorders what the classic literature called the «chromosomal phenotype»: psychomotor developmental delay (DD), intellectual disability (ID), growth abnormalities, facial dysmorphism and, frequently, malformations of several organs and behavioural disorders [14]. Since it was shown that some microdeletions owe their phenotype to haploinsufficiency of a single gene, the boundary between monogenic syndromic ID and chromosomal disease has blurred, and the clinical pattern has become mainly a reason for genomic investigation (chromosomal microarray, panel, exome or genome) rather than a diagnosis in itself [14].

In the 20q13.33 deletion, the feature that gives the group its clinical identity is neonatal-onset epilepsy, explained by loss of one copy of KCNQ2, a gene whose haploinsufficiency is established as a cause of self-limited familial neonatal epilepsy [6, 27]. Apart from this feature, the published series have not identified a dysmorphic constellation that would allow the deletion to be recognised on physical examination; diagnosis depends on chromosomal microarray analysis (CMA) or another genomic test with detection of copy number variations (CNVs) [8, 33]. In the 17q25.3 duplication, the picture is that of distal trisomy 17q, a syndrome with more consistent dysmorphism (bitemporal narrowing, frontal bossing, wide mouth with thin upper lip, short neck) to which DD, short stature, microcephaly and, in about half of cases, congenital heart disease are added [3, 4].

The two entities are grouped because their coexistence in the same patient is the typical result of unbalanced segregation of a balanced reciprocal translocation between 17q and 20q, which gives rise to a derivative chromosome with monosomy 20q13.33 and trisomy 17q25.3 [5, 11]. This article therefore covers the class of distal subtelomeric rearrangements of 20q and 17q uniformly: the two isolated entities, the combined form and the reciprocal or neighbouring entities that enter the differential diagnosis.

1.2. Founding papers and historical milestones

The history of the 20q13.33 deletion crosses two lines of research. The first is that of familial neonatal convulsions: Rett and Teubel described in 1964 a family with neonatal convulsions over three generations, and Bjerre and Corelius added the qualifier «benign» in 1968; the International League Against Epilepsy (ILAE) replaced «benign» with «self-limited» in 2017, so the entity is now called self-limited familial neonatal epilepsy (SLFNE) [27]. The identification of KCNQ2, located at 20q13.33, as the main gene of this epilepsy made it predictable that deletion of the terminal region of 20q would be accompanied by neonatal seizures [27]. The first rearrangement of this region associated with the disease was described in the gene identification work itself: Singh and colleagues (1998) found, in a family with SLFNE, a small 20q deletion encompassing KCNQ2, confirmed by FISH in a patient with seizures from day 3 of life, 118 generalised seizures up to day 23, an isolated seizure at 3.5 months during a febrile otitis media and no seizures thereafter [15]. In 2007, Heron and colleagues identified deletions or duplications of more than one exon of KCNQ2 in 4 of 9 families (44%) with SLFNE and a negative search for coding or splicing variants, and proposed MLPA as a second-line test [34].

The second line is that of subtelomeric cytogenetics. In a collaborative survey by the Association des Cytogénéticiens de Langue Française (ACLF) published in 2007, 1511 patients with unexplained ID were studied by fluorescence in situ hybridisation (FISH) with subtelomeric probes; 115 (7.6%) had a clinically significant subtelomeric anomaly, among them two isolated de novo 20q13.33 deletions, with a common region of about 1.33 Mb and 40 genes [35]. In the same year, Béna and colleagues described a 4-year-old girl with a de novo deletion of 1.1 to 1.6 Mb, then the smallest subterminal 20q deletion described, with learning difficulties, joint hyperlaxity and strabismus, without evident dysmorphism and without epilepsy [36]. Kroepfl and colleagues reported in 2008 a subtelomeric deletion restricted to MYT1 and PCMTD2 in a girl with severe ID [37].

In 2009, Kurahashi and colleagues, studying 22 Japanese patients with benign familial neonatal convulsions by multiplex ligation-dependent probe amplification (MLPA), found multi-exon deletions of KCNQ2 in four, two of which also included CHRNA4; all had the typical course of familial neonatal epilepsy, without the nocturnal frontal lobe epilepsy phenotype associated with CHRNA4 variants [7]. In 2010, Traylor and colleagues published the first «genotype-first» series, with six individuals from the United States and Australia identified by microarray, and concluded that there is no recognisable dysmorphic constellation [8]. There followed the report by Mefford and colleagues (2012) of a boy with a 1.5 Mb terminal deletion treated for seven years as pyridoxine-dependent epilepsy [38], the series by Pascual and colleagues (2013), which proposed that the larger contiguous KCNQ2–CHRNA4 deletion constitutes a disorder distinct from familial neonatal epilepsy [2], and the Japanese series by Okumura and colleagues (2015), which related the extent of the deletion to developmental prognosis [33].

Distal trisomy 17q was first described in 1978 by Berberich and colleagues, in three cousins with trisomy 17q23→qter resulting from a familial translocation, according to the review by Upadia and colleagues [4]. In 2010, Lukusa and Fryns described the first pure 17q25.3 duplication characterised by array comparative genomic hybridisation (aCGH), with a maximum of 2.46 Mb, in a child with growth delay, DD and distal arthrogryposis, and proposed the 17q25.3→qter segment as the critical region for the dysmorphism of the syndrome [39]. Probst and colleagues (2015) brought together five deletions and three duplications of 17q25.3 and proposed the region as a susceptibility locus for cardiovascular malformations [13]; Sahajpal and colleagues (2023) described 15 17q25.3 CNVs in an audit of 18,542 clinical microarrays [9].

The combined form was first documented by Marques and colleagues in 2015, in a boy with a 2.1 Mb 20q13.33 deletion, a 1.4 Mb 17q25.3 duplication and craniosynostosis; this paper is known only from citations in later publications [10, 11]. In 2020, Ürel-Demir and colleagues described three Turkish boys, sons of two sisters carrying a balanced translocation t(17;20)(q25;q13.3) inherited from their maternal grandmother [5], and in 2024 Zhuang and colleagues added a fifth, Chinese, patient with both alterations [11].

1.3. Current nomenclature and classifications

Orphanet classifies the deletion as «20q13.33 microdeletion syndrome» (ORPHA:261311; synonym «monosomy 20q13.33»), of the malformation syndrome type, with code Q93.5 of the International Classification of Diseases, 10th revision (ICD-10) [1]. The 17q25.3 duplication has no entry of its own; it falls under «Distal duplication 17q syndrome» (ORPHA:3379; synonym «distal trisomy 17q») [3]. Orphanet also maintains group entries for partial duplication of the long arm of chromosome 17 (ORPHA:262968), partial duplication of the long arm of chromosome 20 (ORPHA:262995) and partial deletion of the long arm of chromosome 20 (ORPHA:262164) [1]. Neither region has a phenotype entry in the Online Mendelian Inheritance in Man (OMIM) catalogue or a region curated by the Clinical Genome Resource (ClinGen) dosage sensitivity programme [6].

Results are described according to the International System for Human Cytogenomic Nomenclature (ISCN), which requires the reference genome version to be stated; publications on these regions use coordinates in hg18 (NCBI36), hg19 (GRCh37) and GRCh38, which are not directly comparable and should not be converted without a dedicated tool [5, 8, 40]. A terminal deletion is written, for example, as arr[GRCh37] 20q13.33(61041280_62915555)x1 and the corresponding duplication as arr[GRCh37] 17q25.3(76203763_81041938)x3 [11]; in the karyotype, the chromosome carrying the translocated segment is described as a derivative, for example der(20)add(20)(q13.3) when the origin of the additional material is not identified by the karyotype [11]. Pathogenicity classification follows the 2020 joint technical standards of the American College of Medical Genetics and Genomics (ACMG) and ClinGen, with quantitative scoring and five classes [41].

In epilepsy, the terminology in use is that of the ILAE: SLFNE for the self-limited familial neonatal form and developmental and epileptic encephalopathy (DEE) for the forms with developmental impairment attributable to epileptic activity and to the aetiology itself; the severe KCNQ2-associated neonatal form is called NEO-DEE [27].

1.4. Scope of the article and types in the class

This article covers as principal entities the 20q13.33 microdeletion, isolated or accompanied by another CNV, and the 17q25.3 microduplication, pure or in the context of distal trisomy 17q; the combined form der(20)t(17;20) receives its own treatment, as it is the reason for the grouping. 17q25.3 deletions and 20qter duplications are included as reciprocal entities, and the remaining alterations of the class as differential diagnoses. The genes contained in the regions also cause their own monogenic disorders: KCNQ2 genetic epilepsies, RTEL1 telomere disorders, SOX18 lymphoedemas, GNAS disorders, CBX2 46,XY differences of sex development, and COL9A3 Stickler syndrome and multiple epiphyseal dysplasia.

2. Molecular Genetics and Pathophysiology

2.1. Subtelomeric architecture and mechanisms of formation

The ends of all chromosomes terminate in telomeric repeats (TTAGGG)n. Immediately before them lie distal subtelomeric sequences, short and shared by many chromosomes (including degenerate telomeric repeats), then proximal subtelomeric sequences, longer and shared by few chromosomes, and finally the unique sequence of each chromosome, which in the subtelomeric regions is particularly gene-rich [14]. This gene density explains why small terminal imbalances can have serious clinical consequences [14].

When a chromosome loses its end, the new tip must be stabilised. Three mechanisms are recognised: de novo synthesis of telomeric repeats at the breakpoint («telomere healing»), retention of the original telomere with loss of an internal segment, which makes the deletion interstitial, and «capture» of the telomere of another chromosome by a rearrangement that forms a derivative chromosome («telomere capture») [14]. This last mechanism, like unbalanced segregation of a balanced parental reciprocal translocation, generates the combination of a terminal deletion of one chromosome with a terminal duplication of another [5, 14].

Unlike recurrent CNVs mediated by low-copy repeats (LCRs), which arise by non-allelic homologous recombination (NAHR) between segmental duplications and have constant breakpoints, the 20q13.33 and 17q25.3 CNVs are non-recurrent: breakpoints vary from patient to patient and the sizes described range from tens of kilobases to several megabases [8, 9]. There are no segmental duplications in sub-band 17q25.3, which leads Sahajpal and colleagues to attribute these CNVs to non-homologous end joining (NHEJ) or to replicative mechanisms rather than to NAHR [9]. The practical consequence is that there is no single «critical region»: the phenotype depends on the genes actually lost or gained, and each CNV must be interpreted according to its content [9, 13].

Some deletions are complex. Traylor and colleagues described a patient with a duplication of about 2 Mb immediately proximal to a 1 Mb terminal deletion, and another patient with three non-contiguous deletions totalling 6.8 Mb [8]. Pascual and colleagues cite a pericentric insertion of chromosome 20 with a 4.7 Mb terminal duplication of 20p and a 1.6 Mb terminal deletion of 20q [2]. In the 17q25.3 duplication, gains of three and four copies, mosaic marker chromosomes derived from chromosome 17 and duplications translocated to the short arm of acrocentric chromosomes (22p, 14p) have been described [9, 10, 13].

2.2. Coordinates and gene content

Sub-band 20q13.33 extends to the telomere of the long arm of chromosome 20. In the GRCh38 reference genome, KCNQ2 occupies chr20:63,400,208–63,472,655, CHRNA4 chr20:63,343,223–63,361,349 and EEF1A2 chr20:63,488,014–63,499,083 [6]. The terminal deletions described in GRCh37 by Zhuang and by Ürel-Demir end near 62.9 Mb, which in that genome corresponds to the end of 20q, and include KCNQ2 [5, 11]. A terminal deletion of 1.0 to 1.8 Mb contains 26 to 42 genes catalogued in OMIM [11]; a 1.6 Mb deletion contains 41 [5]; Pascual's 1.4 Mb deletion contained 64 genes, 32 of them with an OMIM entry [2].

Sub-band 17q25.3 is the most distal of chromosome 17, the fifth most gene-rich human chromosome: 31 of the 282 genes with a disease catalogued in OMIM on chromosome 17 lie in this sub-band [9]. Probst and colleagues counted 57 genes in the terminal 2 Mb [13]; the 4.4 to 4.8 Mb 17q25.3 duplications of the combined forms contain about 75 OMIM genes [5, 11], and the 9.3 Mb 17q25.1q25.3 duplication described by Chen and colleagues contains 156 disease-associated genes [10].

The coordinates in publications are in different genome versions (hg18 in Traylor, Solomon and Probst; GRCh37 in Ürel-Demir, Zhuang, Kolaitis, Sahajpal and Chen; GRCh38 in Loukas and in ClinGen) and are presented in this article as published [8, 12, 13, 40].

2.3. 20q13.33 genes and dosage sensitivity

Among the genes in the region, only KCNQ2 has haploinsufficiency established by ClinGen (score 3, sufficient evidence for dosage pathogenicity). CHRNA4 and EEF1A2 have a score of 0 (no evidence), OSBPL2 has a score of 1 (little evidence), and the remaining genes of the sub-band, including ARFGAP1, MYT1, SOX18, RTEL1, DNAJC5 and COL9A3, have no dosage curation; no 20q13.33 region is curated [6]. The correct reading of these data is that the only predictable consequence of the deletion, gene by gene, is loss of function of KCNQ2; the other genes may contribute, but the evidence is observational.

In this table, AD means autosomal dominant and AR autosomal recessive; ADSHE is the abbreviation for autosomal dominant sleep-related hypermotor epilepsy, which replaced ADNFLE (autosomal dominant nocturnal frontal lobe epilepsy); HI is the abbreviation for haploinsufficiency. The statement that deletion of SOX18 or COL9A3 does not reproduce the respective disorders is based on the absence of these phenotypes in patients with the deletion, not on functional studies [5, 8]. MIM numbers are those of the OMIM catalogue; BFNS1 is the OMIM designation for KCNQ2-linked SLFNE (seizures, benign familial neonatal, 1); ENFL1 denotes nocturnal frontal lobe epilepsy type 1; MRD38, AD intellectual developmental disorder 38; HLTS and HLTRS, the hypotrichosis-lymphoedema-telangiectasia syndromes without and with renal defect; EDM3, multiple epiphyseal dysplasia type 3; DKCA4 and DKCB5, dyskeratosis congenita AD 4 and AR 5; PFBMFT3, telomere-related pulmonary fibrosis and/or bone marrow failure type 3; CLN4, neuronal ceroid lipofuscinosis type 4.

The OMIM entries make it possible to compare, gene by gene, the Mendelian phenotypes with what is observed in deletion carriers. In HLTRS, with dominant transmission, the four manifestations (hypotrichosis, lymphoedema, telangiectasias and renal disease) begin in early childhood and progress; in recessive HLTS, the first three begin at birth or in early childhood and also progress [51, 52]. EDM3 is characterised by early-onset short stature, a waddling gait and stiffness or pain of the knees and, sometimes, other joints [53]. CLN4 is a neurodegenerative disease of adults, with psychiatric manifestations, seizures, cerebellar ataxia and cognitive decline, without retinal degeneration; in the families summarised in OMIM, onset was between 24 and 46 years [59]. DEE7 has refractory seizures from the neonatal period, an initial EEG with burst-suppression compatible with Ohtahara syndrome and, in some patients, basal ganglia lesions; seizures usually remit by 3 or 4 years, but neurological deficits persist [60]. DEE33 combines seizures of several types in the first months of life with severe global DD, with poor or absent speech [61]; MRD38 was described in two Japanese girls aged 8 and 12 years with severe ID, absent speech, neonatal hypotonia, very late walking, sleep disturbance, autistic features, facial dysmorphism, epilepsy of variable onset and mild cerebral atrophy on magnetic resonance imaging [62]. None of these pictures, with the exception of the KCNQ2-linked neonatal seizures, has been described in the 20q13.33 deletion carriers in the sources consulted [5, 8]; for SOX18, COL9A3, DNAJC5 and EEF1A2, this absence is compatible with causal variants that do not act through simple loss of one copy, an interpretation that results from the comparison and not from functional studies in deletion carriers.

2.4. KCNQ2 and the M-current

KCNQ2 encodes the Kv7.2 subunit of voltage-gated potassium channels, which form homomeric or heteromeric tetramers with Kv7.3 and generate the M-current, a slow potassium current, activated near the resting potential, that limits repetitive neuronal firing [27]. In SLFNE, the causal variants reduce M-current density by 20 to 30% when co-expressed with normal subunits, which corresponds to functional haploinsufficiency; whole-gene deletions belong to this group [27]. In NEO-DEE, the variants are de novo missense or small in-frame deletions that reduce the current by more than 50% through a dominant negative effect and are concentrated in four areas of the protein (S4 voltage sensor, pore, proximal C-terminal segment and helix B) [27]. This distinction has clinical consequences: deletion of KCNQ2 should, by its mechanism, produce the self-limited end of the spectrum, and the additional severity observed in many 20q13.33 deletions must be sought in other genes or associated factors [2, 27].

The KCNQ2 reference transcript used by GeneReviews is NM_172107.4 [27]. Deletion reports do not describe point variants; the relevant nomenclature is the ISCN for the CNV, with the genome version.

2.5. Correlation between deletion extent and phenotype

The published series outline a gradient. Small deletions, restricted to CHRNA4, KCNQ2 and COL20A1 (46 to 245 kb in Kurahashi's patients), are associated with the typical course of SLFNE with normal development [7, 27, 33]. In the two Kurahashi families in which the deletion also included CHRNA4, of 136.4 and 171.8 kb, the phenotype was indistinguishable from that of families with a deletion restricted to KCNQ2, and no patient had nocturnal frontal lobe epilepsy [7, 34]. Deletions of 0.5 to 1.6 Mb that include KCNQ2 and CHRNA4, with or without ARFGAP1, EEF1A2 and MYT1, are usually accompanied by neonatal seizures requiring antiepileptic drugs and by DD [2, 5, 8]. Larger or complex deletions are associated with malformations and, in one case, death in the first year [8]. Béri-Deixheimer and colleagues proposed two phenotypes: mild ID when CHRNA4 and ARFGAP1 are preserved and a complex, severe picture when they are included [35].

There is an unresolved divergence between authors. Kurahashi (2009) and Okumura (2015) considered that joint deletion of KCNQ2 and CHRNA4 does not alter the epileptic phenotype, which is that of SLFNE [7, 33]; Pascual (2013) described three patients with deletions of 0.5 to 1.4 Mb, all with DD and requiring antiepileptic drugs, and suggested that the contiguous deletion constitutes a distinct entity [2]. Ürel-Demir (2020) sided with Pascual, because in their three patients seizures began in the neonatal period and disappeared without treatment in only one of them [5]. The two positions are compatible if it is accepted that the size of the deletion, rather than loss of CHRNA4 itself, separates the two groups: Kurahashi's small deletions and Okumura's three-gene deletions had a favourable course, and the larger deletions had DD [2, 33]. In the combined forms, trisomy 17q25.3 adds its own effect, which prevents the DD from being attributed solely to the deletion [5].

The animal models cited in the series support the plausibility of the KCNQ2 effect: the Szt1 mouse (seizure threshold 1), identified by Yang and colleagues (2003) in an electroshock seizure threshold screen, has a 300 kb deletion on chromosome 2 that includes Kcnq2, Arfgap1 and Chrna4 and increased seizure susceptibility, and because heterozygotes and homozygotes reproduce the phenotype of Kcnq2-deficient mice, Kcnq2 haploinsufficiency is the proposed explanation [15]; the Chrna4-deficient mouse has increased anxiety [8]. For MYT1, a transcription factor expressed in oligodendrocyte progenitors, the hypothesis of a contribution to ID derives from Kroepfl's minimal deletion, which included only MYT1 and PCMTD2 [8, 37].

2.6. Proximal interstitial 20q13.33 deletions

A de novo interstitial deletion of about 0.7 Mb in the proximal part of 20q13.33 (hg18 chr20:59,671,821–60,329,092), with CDH4, TAF4, LSM14B, PSMA7, SS18L1, GTPBP5, HRH3, OSBPL2, LAMA5 and ADRM1, was described in an infant with oesophageal atresia and tracheo-oesophageal fistula, two ventricular septal defects, hypospadias, hydrocele and cervical cystic hygroma [12]. The deletion was absent in 745 controls studied with high-density microarrays; the authors proposed GTPBP5 as a candidate gene for the oesophageal atresia and LAMA5 as a secondary candidate, noting that LAMA5 deletions exist in controls and that the hypothesis of a second affected allele was not tested [12]. This case does not include KCNQ2 and shows that not all 20q13.33 deletions present with seizures.

2.7. 17q25.3 genes and dosage effect

No 17q25.3 gene has dosage sensitivity established by ClinGen; the curated genes of the sub-band (CANT1, CCDC40, DCXR, EIF4A3, TMC6, TMC8) have the classification reserved for recessive disease genes, and CARD14 has a score of 0 [6]. The attribution of phenotypes to specific genes is therefore based on case overlap and biological plausibility.

Probst and colleagues built a cardiac pathogenicity score for the 57 genes of the terminal 2 Mb, trained on 251 known cardiac genes: ACTG1 and ARHGDIA had the highest scores, and ARHGDIA, MAFG, CSNK1D, RAC3, HGS and SIRT7 were shared by at least three of the individuals with cardiovascular malformation [13]. No common minimal region was found among the four deletions with cardiovascular malformation, which suggests a contribution from several genes [13]. Overexpression of ARHGDIA disrupts heart tube formation in the animal model, whereas biallelic loss causes nephrotic syndrome, so the authors considered a contribution from this gene more likely when duplicated [13]. A 588 kb de novo deletion with RAC3 and CSNK1D, diagnosed prenatally in a fetus with total anomalous pulmonary venous drainage and partial agenesis of the corpus callosum, converges with Probst's findings [42].

In this table, pLI denotes the probability of loss-of-function intolerance calculated from population databases.

2.8. Unmasking of recessive alleles and dual diagnoses

A hemizygous deletion reveals any recessive variant located on the homologous allele. Sahajpal and colleagues described a child with mucopolysaccharidosis IIIA in whom the SGSH variant c.1272_1282del11, which appeared homozygous on sequencing, was in fact in trans with a deletion of exons 2 to 8 of the same gene, detected by microarray [9]. The authors present this case as the first SGSH deletion described as causal; the transcript was not stated in the publication, so the variant is cited in its published form [9]. The lesson has general application: in a 17q25.3 or 20q13.33 deletion, an apparently homozygous point variant in a gene of the region should raise the possibility of hemizygosity, and parental studies clarify the situation [9, 14].

The same reasoning applies to RTEL1: a 20q13.33 deletion that includes the gene is, in principle, a null allele, and a pathogenic variant on the other allele would produce a biallelic telomere disorder [58]. None of the published 20q13.33 deletion cases in the sources consulted describes manifestations of telomere disease, and the occurrence of these manifestations in deletion carriers is an inference from the mechanism, not an observation [5, 58]. OMIM also records disease due to heterozygous RTEL1 variants: AD dyskeratosis congenita 4 and PFBMFT3. In the latter, in nine families described by Cogan and colleagues (2015), interstitial pneumonia was diagnosed between 45 and 87 years (mean 64.8 years), all carriers, affected or not, had telomeres below the 10th centile for age and no family had bone marrow failure, haematological malignancy or signs of dyskeratosis congenita [57]. Heterozygous relatives of patients with Hoyeraal-Hreidarsson syndrome had short telomeres without clinical disease, and one of them died of pulmonary fibrosis at 58 years [22]. These data make an adult pulmonary risk plausible also in the heterozygous carrier of a deletion including RTEL1; none of the sources consulted studied telomere length or lung function in 20q13.33 deletion carriers, so this risk is an inference and has not been quantified.

Dual diagnoses are frequent in the series: half of Sahajpal's patients with a 17q25.3 CNV had another reportable CNV, one had trisomy 21 and another a monogenic explanation [9]; Kolaitis's Greek boy had a 47,XYY karyotype, a 7q11.23 duplication and an 11p15.5 deletion, in addition to the 20q13.33 deletion [68]; and Qi's infant had a 4.68 Mb 13q34 duplication classified as of uncertain significance [29].

2.9. Penetrance and expressivity

The penetrance of seizures in the 20q13.33 deletion is incomplete. Of Traylor's six individuals, two had no seizures despite losing KCNQ2 [8]; Béna's patient and other cases cited by Zhuang did not have them either [11, 36]. In SLFNE due to point variants, penetrance is 77 to 85% [27]. In the 17q25.3 duplication, small duplications with TBCD and B3GNTL1 were inherited from unaffected mothers, which indicates incomplete penetrance [9], and a 362 kb interstitial duplication was inherited from the father [9]. The 560 kb interstitial deletion of Traylor's individual 4 was inherited from the father, whose phenotype was not described [8].

Expressivity varies even between relatives with the same imbalance. In the Turkish family, the three cousins shared almost identical deletions and duplications, but only two had microcephaly, one had a single palmar crease and one had structural heart disease, whereas the other two had mitral regurgitation [5].

3. Clinical Spectrum and Manifestations by System

3.1. Nature of the available data

There are no population-based cohorts, patient registries or longitudinal studies for any of the entities in this article. Clinical knowledge derives from case reports and small series identified by cytogenetics laboratories, with short follow-up and heterogeneous description; the percentages presented are proportions of published cases, subject to publication bias (severe cases and cases with other interesting findings are published more often) and should not be read as individual risk [4, 8, 9]. Zhuang and colleagues estimated in 2024 that fewer than 30 cases of 20q13.33 microdeletion had been described [11]; the KCNQ2 GeneReviews counted 13 individuals with large contiguous deletions that included the gene [27]; Orphanet records 30 cases or families with distal trisomy 17q [3].

3.2. 20q13.33 microdeletion

3.2.1. Epilepsy

Seizures are the most frequent and the earliest feature. Of the eight descriptions of isolated 20q13.33 deletion brought together by Zhuang (five by Traylor, Béna, Mefford and Lewis), six had seizures [11]. Pascual's three patients, with deletions of 0.5 to 1.4 Mb, had seizures with onset between day 2 and day 7 of life, all required antiepileptic drugs and two required more than one drug [2]. In Okumura's four Japanese children, seizures began mainly in the neonatal period and ceased by 4 months, in a pattern similar to that of SLFNE [33]. In Qi's Chinese infant, seizures began on day 7, with loss of consciousness, upward gaze deviation, generalised stiffening, cyanosis and deviation of the corner of the mouth, followed by startles during sleep with stiffening, episodes of neck extension and seizures provoked by auditory and tactile stimuli, with three to five episodes a week [29]. In the Greek Rare-ID cohort, a newborn with a deletion of about 938 kb had infantile spasms with onset on day 3 [40].

The semiology, when described, is that of the focal neonatal seizures with a tonic component, apnoea and cyanosis that characterises KCNQ2-related epilepsy: in SLFNE, seizures begin between day 2 and day 8 after a term delivery, after a seizure-free interval, have a sudden onset and marked motor involvement, and on video-electroencephalography (video-EEG) show focal onset with tonic stiffening of one or more limbs [27]. The interictal EEG in deletions ranges from normal to multifocal spikes with abnormal background activity; in Qi's infant, the EEG at 13 days showed delayed maturation and multifocal spikes and polyspikes without a burst-suppression pattern, and at 17 months it was normal [2, 29].

There are cases without seizures, which confirms incomplete penetrance: two of Traylor's six individuals, Béna's patient and the patients of Béri-Deixheimer, Mosca-Boidron and Roberts cited by Zhuang [8, 11, 36]. There are also cases with a single afebrile seizure (at 6 months in Traylor's individual 1; at 2 months in one of Béri-Deixheimer's patients) [8]. The course of the seizures varies between spontaneous remission in the first months and persistent epilepsy: Traylor's patient 2 progressed to focal seizures with impaired awareness, persistent and difficult to control, and Lewis's patient had generalised epilepsy under treatment at 7 years [8, 69]. Two patients with large terminal 20q deletions described in the earlier literature had severe generalised tonic seizures [8]. Mefford and colleagues described a boy treated for seven years as pyridoxine-dependent epilepsy, without molecular or biochemical confirmation, in whom the 1.5 Mb terminal deletion explained the neonatal epilepsy and the developmental disabilities; the response to pyridoxine was interpreted as coincidental [38].

3.2.2. Development and cognition

DD is present in practically all published cases with a deletion that includes KCNQ2 and extends beyond the three minimal genes, with variable severity [8, 11]. Traylor's individual 1 sat at 9 months, walked at 15.5 months and at 9 years had a full-scale intelligence quotient of 40 on the Wechsler scale (WISC), with motor dyspraxia [8]. Patient 2 had minimal expressive language at 4 years and did not feed herself; individual 3 was at a 12 to 15 month level at 32 months [8]. Lewis's patient crawled at 2 years, stood at 3, at 7 years took steps with help and used a wheelchair for longer distances, had no verbal language and functioned at a level of about 18 months [69]. Among Pascual's patients, the oldest said two words at 42 months [2]. At the other extreme, Béna's patient had only learning difficulties and the two Japanese children with a three-gene deletion had normal development [33, 36]. Qi's infant had general developmental quotients on the Griffiths scale of 60, 59 and 69 at 3, 12 and 17 months, with a more marked deficit in hearing-language and performance (44), and Alberta Infant Motor Scale scores below the 5th centile in three assessments [29]. Language is the most affected domain in almost all reports [1, 8].

3.2.3. Behaviour and psychiatry

The behaviours described include autistic features and minimal social interaction, repetitive behaviours, hyperactivity and destructiveness, anxiety and sleep disturbance [8]. The Orphanet definition lists hyperactivity, social interaction problems and autism spectrum disorder (ASD) as frequent [1]. Kolaitis and colleagues described an 11-year-old Greek boy with conduct disorder, attention deficit hyperactivity disorder (ADHD), borderline intellectual functioning and severe reading and writing difficulties, with a 907 kb 20q13.33 deletion that included KCNQ2, CHRNA4, EEF1A2 and RTEL1, but also a 47,XYY karyotype and two other CNVs; the authors themselves considered the picture multifactorial [68]. The association, proposed in that paper, between the deletion and early-onset psychotic disorders through HAR1A has no evidence beyond plausibility [68].

Behavioural crises may have a somatic cause. In Lewis's patient, episodes of crying and screaming lasting about 20 minutes (sometimes up to 5 hours), two to three times a week, with stiffening, kicking and biting, had no correlate on video-EEG; gastroenterological investigation was normal, and faltering weight gain due to insufficient intake proved to be the main cause [69].

3.2.4. Growth and feeding

Orphanet includes pre- and postnatal growth delay, feeding difficulties and microcephaly in the definition of the syndrome [1]. In individual cases, anthropometry ranges from normal (Traylor's individual 1; patients of the Turkish family, except one with microcephaly) to short stature at the 1st centile (Traylor's patient 2) and severe faltering weight gain [5, 8]. At 7 years, Lewis's patient measured 114 cm (z-score −2.07), weighed 16.9 kg (z-score −2.78), had a body mass index (BMI) of 13 kg/m² and a head circumference of 46 cm (below the 3rd centile) [69]. In Qi's infant, head growth slowed to the 3rd centile at 17 months, although the publication gives two different values for head circumference [29].

3.2.5. Dysmorphism and malformations

There is no recognisable facial pattern [8, 33]. The features described most often are bitemporal narrowing, upslanting palpebral fissures, hypertelorism, epicanthus, a bulbous nose, a thin upper lip and low-set or posteriorly rotated ears; several patients have no dysmorphism [1, 8]. Orphanet adds a high forehead, a broad nasal root, a small chin and malformations of the hands and feet [1].

Malformations are occasional and concentrated in cases with larger, complex or proximal deletions. Traylor's individual 3 had clubfoot, congenital hip dislocation, hypospadias, a hypoplastic scrotum, cryptorchidism, a hypoplastic nipple and a sacral dimple; patient 6, with three deletions totalling 6.8 Mb, was born at 30 weeks, had a hypoplastic aortic arch, a perimembranous ventricular septal defect (VSD), an ostium secundum atrial septal defect (ASD), hydronephrosis and severe recurrent thrombocytopenia, and died at 8 months after necrotising enterocolitis with total intestinal necrosis [8]. Solomon's infant, with a proximal interstitial deletion, had oesophageal atresia with tracheo-oesophageal fistula, two VSDs, hypospadias and cervical cystic hygroma [12]. Zhuang's patient 1, with a 1.0 Mb terminal deletion and a 5.2 Mb 14q32 duplication, had hypertelorism, strabismus and low-set ears [11]. Quinn and colleagues reported unilateral microtia with a de novo 20q13.33 deletion and posed the causal relationship as a question, in light of the role of MYT1 in the oculo-auriculo-vertebral spectrum [48, 50]. A DECIPHER repository case with an 870 kb de novo deletion had ID, an abnormal EEG and micropenis [11].

3.2.6. Other systems

Vision is affected mainly by strabismus (convergent in Béna's patient; also in patients of the Chinese and Turkish series) [5, 11, 36]. Mild to moderate hearing loss and frequent otitis were described in one of Pascual's patients, who also had idiopathic macrocytosis, severe eczema and asthma [2]. Brain magnetic resonance imaging (MRI) is normal or shows non-specific changes: prominent perivascular spaces, delayed temporal myelination, a thin corpus callosum, mild ventriculomegaly or enlarged subarachnoid spaces [8, 11, 29]. Joint hyperlaxity and flat feet appear in several reports [8, 36].

3.2.7. Published cases of 20q13.33 deletion without 17q duplication

Pascual's three patients were of Mexican or Native American ancestry, and the families declined parental testing [2]. Zhuang's Table 1 gives Traylor's individual 5 an age of 6 years, but the original publication states 23 months, and this prevails [8, 11].

3.3. 17q25.3 microduplication and distal trisomy 17q

3.3.1. Phenotype of distal trisomy 17q

Distal trisomy 17q is the parent syndrome into which the 17q25.3 duplication fits. Upadia and colleagues reviewed about 20 published cases and calculated the frequency of each feature, using as denominator the cases in which the feature had been described as present or absent [4]. The phenotype is relatively consistent with or without an associated terminal monosomy, which indicates that distal trisomy 17q is the main determinant [4].

Source: Upadia et al. 2018, Table 1 [4].

Heart disease occurs in about half of cases and includes pulmonary stenosis, ASD, subaortic stenosis, patent ductus arteriosus (PDA) and tetralogy of Fallot; brain anomalies occur in about 62% and include cerebral atrophy; renal anomalies (duplex kidney, renal agenesis or hypoplasia) are rare [4]. The mean birth weight of the inherited cases was 2913 g, mostly within the normal range [4]. Orphanet also describes brachyrhizomelia, poly- and syndactyly, joint hyperlaxity and urogenital anomalies [3]. Chen and colleagues proposed ventriculomegaly and hypophosphataemia as new features, from two siblings with a 9.3 Mb 17q25.1q25.3 duplication [10].

3.3.2. Small 17q25.3 duplications

The first pure 17q25.3 duplication characterised by microarray, of at most 2.46 Mb, was described in a 3-year-old child with growth delay, DD, most of the dysmorphic features of trisomy 17q and marked distal arthrogryposis [39]. Wang and colleagues described a 4-year-old Chinese boy with multiple congenital anomalies and global DD and a 5.7 Mb 17q25.3→qter duplication inherited from his mother, who carried a balanced translocation [70].

The three duplications in Probst's series were heterogeneous: a 0.14 Mb de novo duplication (TBCD, B3GNTL1) in a boy with bilateral congenital cataracts, hypogonadism, a thin corpus callosum, cortical dysplasia, contractures, polysplenia and nocturnal hypoventilation, non-verbal and not walking at 3 years; an 8.06 Mb duplication (17q25.1-q25.3) translocated to the short arm of chromosome 22, in an infant with PDA, loss of brain volume, short stature and faltering weight gain, whose 500-band karyotype revealed the alteration only retrospectively; and a 1.08 Mb terminal duplication in an 8-year-old girl with multiple craniosynostosis, microcephaly, ADHD and anxiety [13].

In Sahajpal's series (15 patients, 10 male, mean age at diagnosis 7.5 years), 80% (12/15) had ASD, ID or DD; 33% (5/15) expressive language disorder; 26% (4/15) cardiovascular malformation; and isolated DD was the most frequent single feature (46%, 7/15); most had weight, height and head circumference below the mean [9]. The authors stress that, because these are retrospective data from microarray requests, the percentages are minimum estimates [9]. None of the CNVs in this series reached the telomere of chromosome 17, which excludes segregation of a parental translocation as the mechanism, and all were classified as variants of uncertain significance (VUS), except the intragenic SGSH deletion [9].

3.3.3. Heart disease: difference between series

The frequency of cardiovascular malformation differs between series: about 60% (5/8) in Probst and 26% (4/15) in Sahajpal [9, 13]. Sahajpal attributes the difference to different regions, genes and inheritance patterns; Probst identified the patients from about 60,000 microarrays in a reference laboratory and included a patient recruited in a study of syndromic cardiovascular malformations, which increases the proportion of heart disease [9, 13]. In classic distal trisomy 17q, the frequency is about 50% (7/12) [4].

3.4. 17q25.3 microdeletion

Probst's five 17q25.3 deletions were all de novo, of 0.08 to 1.42 Mb [13]. Four had cardiovascular malformation: VSD with ASD, with heart failure in the first week and spontaneous closure at 4 years; infradiaphragmatic total anomalous pulmonary venous drainage with VSD, ASD, PDA, hypoplasia of the left heart chambers and a bicuspid aortic valve, with death on day 13; coarctation of the aorta with multiple VSDs; and VSD with PDA [13]. Associated findings included polysplenia and a unilobed left lung, agenesis of the corpus callosum, ectopic neurohypophysis, Chiari I malformation, submucous cleft lip and palate, severe speech apraxia, conductive hearing loss, subglottic stenosis, tracheo-oesophageal fistula, tethered cord, cryptorchidism and hypospadias [13]. All individuals older than 1 year had neurocognitive deficits, and brain imaging was abnormal in 6 of the 8 individuals in the series (deletions and duplications) [13]. Prenatally, Chen and colleagues described a fetus with a 588 kb de novo deletion with partial agenesis of the corpus callosum, reduced brain volume, colpocephaly, micrognathia and total anomalous pulmonary venous drainage [42].

3.5. Combined form: monosomy 20q13.33 with trisomy 17q25.3

The five published patients with both alterations are all male, aged between 4 and 15 years at description [5, 11]. All have DD, ID and seizures; seizures began in the neonatal period in the four in whom the age was stated (days 10, 11 and 13 and the first week) [5, 11].

Zhuang's Table 3 classifies Ürel-Demir's patient 3 as having no heart disease, but the original publication describes peripheral pulmonary stenosis and ASD, and this prevails; in patients 1 and 2 the heart disease corresponds to mitral regurgitation, not to a structural malformation [5, 11]. Craniosynostosis, present in Marques's patient, was not present in the three Turkish patients, whose segments were larger, so Ürel-Demir considered it a non-essential feature of the combination [5]. The combined phenotype adds the neonatal epilepsy of monosomy 20q13.33 to the features of trisomy 17q (ID, microcephaly, short stature, dysmorphism, cryptorchidism, joint laxity) [5].

3.6. Prenatal phenotype

The prenatal manifestations described are non-specific. In distal trisomy 17q they include polyhydramnios from 15 weeks, pleural effusions, short long bones and cleft lip (Upadia), and ventriculomegaly with moderate hydrocephalus (fetus terminated at 33 weeks in Chen's family) [4, 10]. In the 17q25.3 deletion, intrauterine growth restriction (Probst) and partial agenesis of the corpus callosum with anomalous pulmonary venous drainage (Chen 2025) [13, 42]. In the 20q13.33 deletion, oligohydramnios and preterm delivery in Traylor's patient with a complex deletion [8]. Orphanet indicates antenatal or neonatal onset for distal 20q duplication and neonatal onset for the 20q13.33 deletion and for distal trisomy 17q [1, 3, 44].

3.7. Natural history and treated disease

The reports mix the spontaneous course with the course under treatment. In epilepsy, remission without treatment is documented (Ürel-Demir's patient 1; seizures that ceased by 4 months in the Japanese children) [5, 33], and in SLFNE due to point variants about 30% of patients become seizure-free without medication [71]. In the remaining cases, cessation of seizures occurred under antiepileptic drugs, and the contribution of the drug cannot be separated from the natural history [2, 29]. The other manifestations (ID, malformations, behaviour) have no disease-modifying treatment, and the follow-up described is limited, in most cases, to the first decade of life [5, 8].

4. Clinical Recognition and Warning Signs

4.1. When to suspect

Because the 20q13.33 deletion has no recognisable dysmorphism, clinical suspicion arises from contexts rather than from a facial gestalt [8, 33]. The most characteristic context is the term newborn who, after a seizure-free interval of a few days, develops focal tonic seizures with apnoea and cyanosis: at this age, KCNQ2 is the gene most frequently implicated, and a deletion including the gene is one of the possible forms [27]. The clues that, in the presence of neonatal seizures of this type, point to a contiguous deletion rather than a point variant are the absence of a family history, the presence of DD, persistence of seizures beyond the first months, associated malformations or growth delay [2, 33]. Detection of a KCNQ2 deletion by MLPA or panel analysis should always prompt determination of its extent [27].

Outside the neonatal period, the deletion appears as a finding on microarray requested for DD or ID, ASD, ADHD or multiple malformations, and sometimes in an unexpected context (iris coloboma in Kolaitis's boy; oesophageal atresia in Solomon's infant) [12, 68]. A previous diagnosis of pyridoxine-dependent epilepsy without biochemical or molecular confirmation is another context described: in Mefford's case, review of the diagnosis after seven years led to detection of the deletion [38].

A large or terminal 17q25.3 duplication may be recognised by the pattern of distal trisomy 17q: bitemporal narrowing with frontal bossing, a wide mouth with thin upper lip and downturned corners, a flat nasal bridge, low-set rotated ears, a short neck with low posterior hairline, widely spaced nipples, short stature and microcephaly, frequently with heart disease and cryptorchidism [3, 4]. Small 17q25.3 duplications have no recognisable phenotype and appear as microarray findings in children with neurodevelopmental disorders [9].

The combined form should be considered when a boy or girl with neonatal seizures and ID also has features of trisomy 17q, and especially when there are several affected relatives in collateral lines and spontaneous miscarriages: in the Turkish family, the presence of three affected boys, sons of two sisters, initially suggested X-linked recessive inheritance, and it was the microarray that revealed the translocation imbalance [5].

4.2. Warning and emergency signs

Neonatal seizures are a neurological emergency regardless of the cause and should be confirmed by EEG, ideally video-EEG, and treated immediately [30]. The absence of seizures in the neonatal period does not exclude later epilepsy, and the appearance of new seizures or seizures of a different type justifies video-EEG [27]. Paroxysmal episodes of crying, stiffening or agitation in a child with a known deletion should not automatically be attributed to epilepsy or to the syndrome: in Lewis's case, video-EEG excluded seizures and the cause was chronic hunger due to insufficient intake [69].

In 17q25.3 duplication and deletion, the warning signs are those of congenital heart disease (murmur, cyanosis, respiratory distress, heart failure in the first weeks) and, in cases with severe malformations, neonatal respiratory distress, polysplenia or anomalous pulmonary venous drainage [13, 42]. Central apnoea, nocturnal hypoventilation and feeding difficulties requiring tube feeding have been described in infants with 17q25.3 duplications [9, 13].

4.3. Newborn screening

None of the entities is the subject of newborn screening. Prenatal detection occurs when microarray is performed for ultrasound findings or for a known parental translocation [4, 42].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Diagnostic criterion

There are no clinical criteria. Diagnosis is molecular and requires demonstration of a copy loss at 20q13.33 or a gain at 17q25.3, with coordinates, genome version, gene content and pathogenicity classification [1, 41]. Interpretation must take into account that there is no common minimal region: a 20q13.33 deletion that includes KCNQ2 affects a gene of established haploinsufficiency and can be classified as pathogenic on the basis of that gene [6, 29], whereas many small 17q25.3 duplications remain VUS [9].

5.2. Tests in order and their limitations

The International Standards for Cytogenomic Arrays (ISCA) consortium reviewed 33 studies with 21,698 patients and found a yield of 15 to 20% for microarray in unexplained DD or ID, ASD or multiple congenital anomalies, against about 3% for the karyotype, excluding Down syndrome and other recognisable chromosomal syndromes; it recommended microarray as the first-line test and reserved the karyotype for obvious chromosomal syndromes, a family history of rearrangement or multiple spontaneous miscarriages [28]. The ACMG made an equivalent recommendation [72]. In epilepsy, a systematic review of 154 studies found yields of 48% for the genome, 24% for the exome, 19% for multigene panels and 9% for microarray, higher in DEEs and when there is neurodevelopmental comorbidity [73]; the ILAE Genetics Commission recommends prioritising genetic testing when the probability of an informative result is high and accompanying it with pre- and post-test counselling [74].

In KCNQ2 sequencing, sequence analysis detects more than 90% of the causal variants of gene-related epilepsy and targeted deletion/duplication analysis less than 10%; these proportions refer to published variants and not to the clinical sensitivity of the test in a given patient [27]. A negative microarray result excludes neither a balanced translocation nor low-level mosaicism, and a negative panel without CNV analysis does not exclude a deletion [27, 28].

5.3. Classification and report content

The report should state the type of test and platform, the ISCN nomenclature with the genome version, the size, the genes included (highlighting those of known dosage sensitivity), the five-tier classification according to the ACMG/ClinGen standard and, when studied, the parental origin [41]. The standard separates classification of the variant from its implications for the individual [41]. In Qi's infant, the 20q13.33 deletion scored 2.05 points (criteria 1A, 2A, 3C and 5A), sufficient for the pathogenic class, whereas the associated 13q34 duplication scored 0.25 points and remained a VUS [29]. In the combined forms, each CNV is classified separately, and the coexistence of a terminal loss on one chromosome with a terminal gain on another should be flagged in the report as suggestive of a translocation-derived chromosome, with a recommendation for parental studies [5, 11]. The preprint by Leslie and colleagues draws attention to complex CNVs, whose real effect on the gene is not captured by current classification frameworks [75].

5.4. Diagnostic algorithm

The ISCA consortium algorithm, adopted by the Oxford Desk Reference, starts from the microarray: an abnormal or uncertain result leads to consultation of DECIPHER (gene content, phenotypes of patients with similar CNVs, inheritance pattern), to confirmation in the proband when necessary (FISH, G-banding, quantitative PCR or MLPA) and to parental studies to distinguish a de novo from an inherited alteration and to identify balanced rearrangements [14]. Applied to these entities, the pathway can be summarised as follows, as a synthesis of the sources and not as a published algorithm: first, microarray, or exome or genome with validated CNV calling, in the child with neonatal seizures, DD, ID or multiple malformations [28, 73]; second, when a KCNQ2 deletion is detected by panel or MLPA, microarray to define its extent [27]; third, when a terminal loss of 20q13.33 is accompanied by a terminal gain on another chromosome (17q25.3, 14q32.3 or other), suspect a derivative chromosome and study both parents with subtelomeric FISH or locus-specific probes, because microarray and conventional karyotype of carriers are normal [5, 11]; fourth, when a small isolated 17q25.3 duplication is found, study the parents by microarray to assess inheritance, bearing in mind that inheritance from a healthy parent does not prove benignity [9, 14].

5.5. Parental studies and mosaicism

Parental studies are essential in subtelomeric rearrangements, because one parent may carry a cryptic balanced translocation, with implications for future pregnancies and for the extended family [14]. Conventional karyotyping does not detect balanced translocations when the exchanged segments are smaller than 5 Mb, and the microarray of carriers is normal; the indicated method is FISH with subtelomeric probes for the chromosomes involved, high-resolution karyotyping when the segment is larger, or genome sequencing [5, 14]. In the Turkish family, the subtelomeric probe kit for 17q, 20p and 20q confirmed the translocation in the two sisters and the grandmother [5]; in Chen's Chinese family, probes for 17qter and for the centromeres of 14 and 17 showed the t(14;17) translocation in the mother [10].

Mosaicism has been described in distal trisomy 17q (mosaic de novo cases; a mosaic 31.3 Mb duplication; a chromosome 17-derived marker chromosome in 16 of 30 metaphases) [4, 9, 76]. In KCNQ2-related epilepsy, 1 to 30% leucocyte mosaicism was found in parents of children with NEO-DEE, and these parents had normal development, some with neonatal seizures [27]. SNP microarray is more sensitive to mosaicism than aCGH, but quantifies it poorly [14].

5.6. Prenatal and preimplantation diagnosis

When a parent carries a balanced translocation, or when the family has an identified CNV, prenatal diagnosis is made by chorionic villus sampling or amniocentesis with microarray, complemented by FISH when it is necessary to identify the derivative chromosome [14, 42]. In Upadia's family, the amniotic fluid karyotype at 18 weeks had already revealed the derivative chromosome der(10)t(10;17)(q26.3;q22), and the microarray quantified a gain of about 24.3 Mb [4]. In Taiwan, aCGH on uncultured amniocytes at 25 weeks identified a de novo 17q25.3 deletion in a fetus with partial agenesis of the corpus callosum and total anomalous pulmonary venous drainage [42]. Preimplantation genetic testing for structural rearrangements is possible after characterisation of the parental translocation; the choice of technique rests with the reference laboratory [14, 27].

6. Differential Diagnosis

The differential diagnosis has two faces. In the presence of neonatal seizures, the differential is that of genetic and structural neonatal epilepsies, in which the 20q13.33 deletion is one of the causes of KCNQ2-related epilepsy. In the presence of DD, ID and dysmorphism, the differential is that of other chromosomal alterations, in particular subtelomeric imbalances and other alterations of chromosome 20 and of 17q. In both cases, the discriminating test is genetic.

In this table, AD means autosomal dominant and AR autosomal recessive.

6.1. 20q13.33 deletion and SLFNE due to a point variant

This distinction is the most frequent in neonatal practice. In SLFNE due to a point variant, the term newborn has seizures with onset between day 2 and day 8, normal examination, tests and neuroimaging before, during and after the seizures, and spontaneous remission between the 1st and the 6th to 12th month; a family history exists in most cases, although it may require questioning of older relatives [27]. A 20q13.33 deletion with more than three genes adds to this picture DD, persistence of seizures and, sometimes, malformations and growth delay [2, 33]. Because small KCNQ2 and CHRNA4 deletions have a phenotype indistinguishable from SLFNE [7], and because a panel without CNV analysis does not detect them, investigation of a family with SLFNE and negative sequencing should include a search for deletions [7, 27]; in Heron's series, multi-exon deletions or duplications explained 4 of 9 families in these circumstances [34].

6.2. 20q13.33 deletion and pyridoxine-dependent epilepsy

The two entities may be confused because both present with neonatal seizures and because spontaneous remission of the seizures of the deletion may coincide with the introduction of pyridoxine [38]. The ILAE guideline recommends a pyridoxine trial in newborns with suggestive clinical or EEG features and in those who do not respond to second-line treatment without an identified aetiology [30]. The lesson of Mefford's case is that a diagnosis of pyridoxine-dependent epilepsy without biomarkers or molecular confirmation should be re-evaluated, and that microarray is part of the investigation of epilepsy of unknown cause [38].

6.3. Ring chromosome 20

Ring chromosome 20 has a different presentation: drug-resistant epilepsy with onset between childhood and adulthood, an EEG with a high-voltage pattern and ID of variable degree, with behavioural problems [79, 80]. The ring may be mosaic and is best detected by G-banded karyotype [80]. Orphanet records 50 published cases [79].

6.4. Other 20q alterations and the effect of parental origin

More proximal interstitial 20q deletions have distinct phenotypes. Paternal 20q13.2q13.3 deletion causes severe pre- and postnatal growth delay and intractable feeding difficulties with mild DD [81]. A maternal 20q13.31–q13.33 deletion with loss of GNAS has been associated with pseudohypoparathyroidism type Ia, and a paternal 20q13.13–q13.32 deletion with pseudopseudohypoparathyroidism [82]. Thus, a 20q deletion extending to 20q13.32 should be interpreted in light of parental origin, which does not apply to deletions restricted to 20q13.33, which do not include GNAS [8, 82]. Okihiro syndrome due to a 20q13.13–q13.2 microdeletion combines the Duane anomaly and radial ray defects of SALL4 with ID when the deletion includes other genes [83].

6.5. Trisomy 17q and syndromes with overlapping dysmorphism

The dysmorphism of distal trisomy 17q (bitemporal narrowing, frontal bossing, short palpebral fissures, flat nasal bridge, short webbed neck with low hairline) and its association with heart disease, oral cleft and genital anomalies overlap with those of 22q11.2 deletion, trisomy 13, tetrasomy 18p, trisomy 21 and some peroxisomal disorders [4]. Microarray distinguishes the chromosomal alterations; the peroxisomal biochemical profile distinguishes the metabolic disorders. A 17q25.1→qter duplication with 1p36.1 monosomy has been described with a picture resembling Pfeiffer-type cardiocranial syndrome, which illustrates that the associated monosomy may modify the picture [10].

6.6. 17q25.3 genes with Mendelian disease

A 17q25.3 duplication that includes the whole of SEPTIN9 is not equivalent to the intragenic duplications that cause hereditary neuralgic amyotrophy: these are tandem duplications that include a conserved exon and give rise to larger transcripts, whereas duplication of the whole gene did not produce an abnormal protein in the only case studied [64]. The ACTG1 missense variants that cause Baraitser-Winter syndrome act through gain of function, and duplication of the whole gene has an uncertain effect [5, 63].

7. Treatments and Risk Management Strategies

7.1. Principles

There is no specific treatment for any of the entities, nor clinical practice guidelines dedicated to the 20q13.33 deletion or the 17q25.3 duplication; the search of the sources consulted identified none [27]. The KCNQ2 GeneReviews states that there are also no published guidelines for disorders related to this gene [27]. Treatment is symptomatic and organised by problem: epilepsy, development and communication, behaviour, feeding and growth, and malformations. The recommendations that follow combine the ILAE guideline for neonatal seizures, which applies to all aetiologies [30], the KCNQ2 GeneReviews for epilepsy and neurodevelopment [27] and the official drug labels. Application to the deletion is an extrapolation, stated as such at each point.

7.2. Assessment after diagnosis

The recommendations for systematic echocardiography and renal ultrasound are inferences from the frequency of these anomalies in the series, not published formal recommendations.

7.3. Neonatal seizures

7.3.1. ILAE guideline

The guideline of the ILAE Task Force on Neonatal Seizures, published in 2023, is the first since that of the World Health Organization, the ILAE and the International Bureau for Epilepsy in 2011 [30]. It recommends phenobarbital as the first-line drug in newborns with seizures requiring treatment, regardless of aetiology (moderate strength, moderate to low quality evidence; 78% agreement in the Delphi panel) [30]. It adds, by consensus with high agreement, that when the family history makes a channelopathy likely, phenytoin or carbamazepine, sodium channel blockers, may be the first-line drug; the text of the recommendation uses «may», whereas the summary uses «should», and the text prevails [30]. If there is no response to first-line treatment, the second line is phenytoin or levetiracetam for most aetiologies, with midazolam or lidocaine as alternatives; when clinical data or the EEG suggest a channelopathy, the second line is a sodium channel blocker, phenytoin or carbamazepine, depending on the newborn's clinical status and the availability of formulations and drug level monitoring; in the presence of heart disease, levetiracetam may be preferred [30].

In the 20q13.33 deletion including KCNQ2, a channelopathy is present by definition, but the genetic diagnosis is rarely available in the first hours. The recommendation therefore applies in two ways: in the presence of neonatal seizures with a suggestive family history, a sodium channel blocker may be the first choice; with an established genetic diagnosis, or seizures with the typical focal tonic semiology, a sodium channel blocker is the preferred second line and the maintenance option [27, 30]. The guideline's dose table indicates that, when phenytoin is used in a channelopathy, maintenance should be switched to carbamazepine as soon as the oral route is possible [30]. In a randomised trial cited in the guideline, first-line phenobarbital and phenytoin controlled seizures in 43% (13/30) and 45% (13/29) of newborns, respectively [30].

Recommendation 3 of the guideline, which calls for antiseizure medication to be stopped before discharge when the seizures were acute symptomatic and there is no evidence of neonatal-onset epilepsy, does not apply to the 20q13.33 deletion, which is a genetic cause of epilepsy; the duration of treatment is decided individually, and this adaptation is an inference from the text of the guideline [30]. The guideline also recommends treating electrographic-only seizures, because reducing seizure burden may be associated with a better outcome (consensus, indirect evidence), and a pyridoxine trial in newborns with a picture suggestive of vitamin B6-dependent epilepsy or without response to second-line treatment and without an identified aetiology [30].

7.3.2. Specific evidence in KCNQ2-related epilepsy

A systematic review of 52 studies with 217 patients with KCNQ2-related epilepsy (133 with a self-limited course and 84 with early-onset encephalopathy) found seizure freedom in 92.5% of the self-limited group and in 65.5% of the encephalopathy group (p = 0.003); 30.1% of the self-limited group became seizure-free without medication, and phenobarbital and sodium channel blockers were the drugs most associated with seizure freedom; in encephalopathy, sodium channel blockers [71]. In an international collaboration with 19 newborns with familial neonatal epilepsy (14 with a KCNQ2 variant or deletion, 2 with KCNQ3), 12 had received several drugs before seizure cessation, and 17 (88%) became seizure-free within hours of starting oral carbamazepine or oxcarbazepine; earlier initiation of carbamazepine was associated with a shorter hospital stay (p < 0.01), no adverse effects were reported, and at a mean follow-up of 7.8 years development was normal and there were no seizures [87]. In 15 infants with KCNQ2 encephalopathy, carbamazepine controlled seizures within 2 weeks in 40% (6/15) and phenytoin left 33% (5/15) seizure-free [88]. These studies are observational and retrospective, without randomised comparison, and mainly include point variants; there are no treatment studies dedicated to deletions.

In 20q13.33 deletion cases, the drugs used were oxcarbazepine (with seizure control in the patients of Zhuang, Pascual and Qi), phenobarbital (with seizure cessation in one of Pascual's patients), levetiracetam, zonisamide and topiramate (with variable efficacy) [2, 11, 29]. In Pascual's patient 1, levetiracetam monotherapy was ineffective, and the addition of oxcarbazepine ended the seizures within 1 month [2]. In Qi's infant, levetiracetam was started at 1 month at 30 mg/kg/day, with vitamin B6, and increased to 50 and then 55 mg/kg/day; the introduction of oxcarbazepine reduced the seizures, which ceased at 5–6 months, and levetiracetam was withdrawn at 14 months, leaving the child on oxcarbazepine monotherapy; the publication gives the oxcarbazepine doses in millilitres without stating the concentration of the suspension, so they cannot be converted to mg/kg [29]. In Zhuang's patient 2, the parents stopped the antiseizure medication after about a year without recurrence [11].

7.3.3. Doses

The reference doses are those in Table 2 of the ILAE guideline, approved by 84% of the Delphi panel and derived from the literature and experience, with variations of opinion [30]. The official labels are cited for comparison. None of the drugs has an approved indication for the 20q13.33 deletion or for KCNQ2-related epilepsy, and only phenobarbital has, in the United States, an approved indication for neonatal seizures; use in the other situations is off-label [89].

The guideline also includes midazolam (loading 0.05–0.15 mg/kg and infusion of 1 μg/kg/min titratable up to 5 μg/kg/min) and lidocaine (loading 2 mg/kg IV over 10 minutes followed by a decreasing infusion), the latter contraindicated in congenital heart disease and in combination with phenytoin or fosphenytoin [30]. This contraindication is relevant in the forms with heart disease (17q25.3 duplication and deletion, combined form).

7.3.4. Duration and withdrawal

In SLFNE, seizures remit spontaneously between the 1st and 12th month, and about 30% of patients have later seizures (simple febrile seizures in 13%, seizures in childhood in 10% and seizures in adolescence or adulthood in 14%) [27]. In 20q13.33 deletions, the course was favourable in most treated cases, with withdrawal of medication between 3 months and about 1 year in several patients [2, 11, 29], but there was persistent epilepsy in others [8, 69]. The sources consulted do not define a time for withdrawal; the decision is individual and supported by the EEG and the course. Withdrawal of phenobarbital and levetiracetam should be gradual [89, 96].

7.4. Epilepsy beyond the neonatal period

Seizures that persist or appear in childhood are treated according to seizure type and electroclinical syndrome, with the same principles: sodium channel blockers have the best results in the KCNQ2 series [27, 71], and levetiracetam and topiramate have variable efficacy as add-on therapy [29]. In encephalopathy due to EEF1A2 point variants, valproate, lamotrigine and levetiracetam controlled seizures in 65% of 76 patients, but these data refer to missense variants and not to the deletion [77].

7.5. Development, communication and education

The KCNQ2 GeneReviews recommends early intervention from 0 to 3 years, developmental preschool from 3 to 5 years, an individual education plan, physiotherapy and occupational therapy, speech therapy and augmentative and alternative communication, which does not hinder the acquisition of speech; for autistic traits, applied behaviour analysis; for aggression, child and adolescent psychiatry [27]. The published cases describe attendance at a special education school with speech and cognitive therapy [10].

7.6. Behaviour and psychiatry

Treatment of behavioural disorders is multimodal. In Kolaitis's boy, a 2.5-month admission combined risperidone 2 mg/day, occupational therapy, psychoeducation, family meetings and positive reinforcement, with behavioural improvement that cannot be attributed to a single component; the authors preferred risperidone to an ADHD drug because behavioural problems predominated [68]. There is no specific guideline; the reference dose is the label dose.

The dose of 2 mg/day used by Kolaitis in a 73 kg boy is within the effective range of the US label for irritability in autistic disorder, but above the usual optimal dose of the Portuguese label for conduct disorder [68, 97, 98].

7.7. Feeding and growth

Feeding difficulties and faltering weight gain are frequent, and their cause should be investigated before attributing them to the syndrome [1, 69]. In Lewis's case, after a normal gastroenterological work-up and ineffective empirical treatments (proton pump inhibitor, simeticone, rifaximin), three months of high-calorie, high-fat, high-protein nutritional counselling produced a gain of about 3.2 kg in 4 months, a rise in weight from below the 1st centile to the 15th centile and in BMI to the 44th centile, almost complete resolution of the behavioural crises and greater walking endurance [69]. The KCNQ2 GeneReviews recommends feeding therapy and gastrostomy when needed, and monitoring for reflux and constipation [27].

7.8. Malformations and other manifestations

Congenital heart defects are treated according to paediatric cardiology practice; in the published cases, neonatal heart failure from a VSD with ASD was treated with spironolactone, digoxin and furosemide up to 2 years, with spontaneous closure of the defects at 4 years, and total anomalous pulmonary venous drainage required surgery and extracorporeal membrane oxygenation [13]. Cryptorchidism was corrected surgically in the Turkish patients and in Probst's individual 3 (orchidopexy at 22 months) [5, 13]. Oesophageal atresia, congenital hip dislocation, clubfoot, craniosynostosis and strabismus follow the usual treatment of each malformation [8, 12, 13]. Visual stimulation for cortical visual impairment, hearing aids and stretching for spasticity complete the supportive measures [27].

When the 20q13.33 deletion includes RTEL1, there are no data to justify systematic haematological, pulmonary or hepatic surveillance, because no published case had manifestations of telomere disease [5]. In the presence of unexplained cytopenias, pulmonary fibrosis or liver disease in a deletion carrier, the possibility of a second RTEL1 variant should be considered and assessment follows that of telomere disorders [58]; in adult pulmonary fibrosis, the loss of one copy of RTEL1 itself also enters the hypothesis, because PFBMFT3 is caused by heterozygous variants [57]. Hemizygosity for other recessive genes in the region should be considered in the same way [9].

7.9. Regulatory status

No medicine is approved by the United States Food and Drug Administration (FDA) or the European Medicines Agency (EMA) for the 20q13.33 deletion, the 17q25.3 duplication or KCNQ2-related epilepsy.

Registration data and package leaflets of Brazil's National Health Surveillance Agency (ANVISA) were not consulted for these drugs.

7.10. Registered trials and studies

NEOLEV2 is the only randomised trial and compared two drugs in newborns with seizures of any aetiology, mostly non-genetic; its extrapolation to KCNQ2-related epilepsy is indirect [89]. The KCNQ2 series are retrospective, without a control group, with different doses and timing of introduction, and allow no direct comparison between drugs or between studies [71, 87, 88]. EPIK was terminated with 8 patients, without efficacy results published in the sources consulted, and was aimed at DEE due to missense variants, not at the haploinsufficiency of the deletion [100]. ClinicalTrials.gov also lists a French registry of neonatal epileptic encephalopathies that is recruiting (NCT04802135, Marseille, target of 200 patients) and two Chinese cohorts of unknown status (NCT03934268, NCT05157737); there are no trials aimed at the 20q13.33 deletion or the 17q25.3 duplication [101].

7.11. Developments in the last 12 months

Between 2025 and October 2026, the relevant publications were case reports and descriptive studies, with no trials or specific regulatory decisions; those from 2026 fall within the 12-month window. In 2026, Qi and colleagues published a case of a 1.62 Mb de novo deletion detected by trio exome sequencing with CNV analysis and confirmed by MLPA, with seizure control on oxcarbazepine and a developmental quotient of 69 at 17 months (case report) [29]. The Greek Rare-ID cohort, with 25 symptomatic newborns and infants studied by exome or genome sequencing between 2019 and 2022, had a diagnostic yield of 28.0% (7/25; 95% confidence interval, 95% CI, 14.3–47.6), including a de novo 20q13.33 deletion of about 938 kb detected by genome sequencing (descriptive study) [40]. In 2025, a prenatal diagnosis of a 17q25.3 deletion with RAC3 and CSNK1D reinforced the association between this region and anomalous pulmonary venous drainage (case report) [42]. In a genetic isolate in northern Italy, 15 of 30 relatives assessed carried a partial 20qter trisomy on a chromosome 22-derived chromosome, and 5 of the 15 carriers (33.3%; 95% CI 11.8–61.6) had features of the oculo-auriculo-vertebral spectrum (family study) [43]. A preprint from May 2026, not yet peer reviewed, showed by long-read sequencing that a homozygous TBCD duplication classified as likely pathogenic was a complex rearrangement that left the gene intact [75]. No new regulatory decisions were identified for the drugs used.

7.12. Agents and situations to avoid

Carbamazepine requires genotyping for the HLA-B*15:02 allele before initiation in patients from at-risk populations, because the allele is associated with Stevens-Johnson syndrome and toxic epidermal necrolysis [91, 92]. The Portuguese SmPC gives carrier frequencies of about 10% in Han Chinese, Thai and Taiwanese populations, above 15% in populations of the Philippines, Malaysia, Hong Kong and Thailand, about 4% in northern China, 2 to 4% in South Asia, below 1% in Japan and Korea, and negligible in Europeans, Africans, Native Americans and Hispanics [92]. Four of the published patients with these entities were Chinese [10, 11, 29].

Lidocaine is contraindicated in congenital heart disease and in combination with phenytoin, which matters in the forms with heart disease [30]. GeneReviews warns that Kv7 channel openers may be contraindicated in KCNQ2 gain-of-function variants; the deletion is a loss of function, and this warning does not apply to it [27]. The sources consulted do not identify other agents to be avoided specifically in these entities.

7.13. Pregnancy, perioperative care and transition

Pregnancy in a woman with KCNQ2-related epilepsy is managed like that of any pregnant woman with epilepsy [27]. Women carrying a balanced t(17;20) or t(14;17) translocation are phenotypically healthy and their reproductive risk is covered in section 8 [5, 10]. The sources consulted do not describe anaesthetic complications specific to these entities; in patients with heart disease, preoperative assessment follows that of the underlying heart disease. There are no data on adults with these entities: the oldest patient described was 23 years old [9], and transition to adult care is based on the individual problems (epilepsy, ID, behaviour).

7.14. Guideline recommendations and discrepancies

8. Reproductive Options and Family Counselling

8.1. Origin of the imbalances

The origin determines all counselling. The isolated 20q13.33 deletions studied in the parents were mostly de novo: three of Traylor's individuals (confirmed by parental FISH), the two of Béri-Deixheimer, and those of Béna, Kroepfl, Solomon, Qi and Loukas [8, 12, 29, 35–37, 40]. The documented exception is the 560 kb interstitial deletion of Traylor's individual 4, inherited from the father, whose phenotype was not described [8]. Small deletions restricted to KCNQ2 and CHRNA4 behave like SLFNE, with familial transmission [7]. Distal trisomy 17q results in about 85% of cases from unbalanced segregation of a balanced reciprocal translocation in a parent, with concomitant partial monosomy of the other chromosome, although there are de novo and mosaic cases [4]. Small and interstitial 17q25.3 duplications may be de novo or inherited from parents without an apparent phenotype [9, 13]. All 17q25.3 events studied in the parents by Probst were de novo [13]. The published combined forms with family studies resulted from a maternal translocation [5].

8.2. Recurrence risks by scenario

The sources consulted do not give an empirical numerical risk for carriers of t(17;20) or t(14;17) translocations. The risk depends on the size of the segments, the chromosomes involved and the sex of the carrier, and should be estimated case by case by a clinical geneticist; the absence of a published figure does not mean that the risk is low [14].

8.3. Interpretation of an inherited CNV

When a parent without the phenotype has the same CNV, interpretation should consider several hypotheses: a polymorphism without effect, incomplete penetrance, unmasking of a recessive allele in the child, an imprinting effect, complex inheritance with other factors, or alteration of the CNV on transmission (expansion of a deletion or a duplication becoming a triplication) [14]. In Sahajpal's series, two duplications with TBCD and B3GNTL1 were inherited from unaffected mothers, and a 362 kb duplication was inherited from the father, which shows incomplete penetrance for small alterations in this region [9]. In deletion of the KCNQ2 region, mosaic parents may have normal development with or without neonatal seizures [27].

8.4. Cascade testing

In families with a translocation, testing should be extended to relatives at risk of being balanced carriers, because the translocation segregates over generations: in the Turkish family, the translocation was identified in the two sisters and the maternal grandmother [5]; in Wang's family, the mother, maternal grandmother and an uncle were carriers, and an aunt was not [70]; in Chen's family, the mother carrying t(14;17) had an affected fetus, terminated at 33 weeks, and an affected son [10]. The method for studying relatives is FISH with subtelomeric probes or high-resolution karyotyping, because the microarray is normal in balanced carriers [5, 14]. In families with a small KCNQ2 deletion and SLFNE, studying relatives with neonatal or infantile seizures makes it possible to identify other carriers [27].

8.5. Prenatal diagnosis and preimplantation genetic testing

When the CNV is de novo and isolated, prenatal diagnosis by chorionic villus sampling or amniocentesis is possible and may be offered for reassurance, after confirming that the rearrangement is pathogenic [14]. When a parent has the same CNV, prenatal diagnosis is offered if the CNV causes an abnormality, with caution in view of variable penetrance; without an apparent phenotype in the parent, the CNV may be a polymorphism without an indication for prenatal diagnosis [14]. Some laboratories do not routinely report, prenatally, CNVs with substantial incomplete penetrance [14]. In translocation carriers, prenatal diagnosis is made by microarray on chorionic villi or amniocytes, possibly complemented by FISH, and preimplantation genetic testing for structural rearrangements is an alternative after characterisation of the translocation [14, 27]. Counselling should ideally take place before pregnancy [27].

8.6. Counselling of minors and of parents with learning difficulties

Testing minors without symptoms for carrier status of a balanced translocation has no immediate clinical benefit, and its timing should be discussed with the family; the sources consulted give no specific recommendations on this point for these entities. When the parents have learning difficulties, counselling requires sufficient time and attention to consent for any intervention [14].

9. Special Considerations: Population Diversity and Epidemiology

9.1. What the available figures measure

There is no population-based estimate of prevalence or incidence for the 20q13.33 deletion, the 17q25.3 duplication or the combined form. Orphanet classifies the prevalence of the 20q13.33 deletion as unknown, qualified as «class only» and with a non-validated status [1], and that of distal trisomy 17q in the class below 1 per 1,000,000, based on 30 published cases or families [3, 76]. The figures that exist measure different things, and none of them is a prevalence.

Figures from microarray laboratories depend on referral criteria and platform and cannot be extrapolated to the general population [9]. The Scottish incidence of KCNQ2-related epilepsy came from a study in which 333 of the 343 eligible children with epilepsy before 36 months were tested with a 104-gene panel, with a diagnosis in 24% (80/333); KCNQ2 was the most frequent gene in infants with onset before 6 months, and the overall incidence of monogenic epilepsies was 47.2 per 100,000 (95% CI 36.9–57.5) [102]. This value mainly includes point variants and does not estimate the frequency of the 20q13.33 deletion [102]. Pascual's statement that KCNQ2 deletions explain about 20% of families with SLFNE derives from a reference cited by the authors and not from a population study [2].

9.2. Data by region and population

The published cases with origin stated in the sources come from the United States and Australia (Traylor's series; the series of Probst and of Sahajpal; Pascual's patients, of Mexican and Native American ancestry; Lewis), Europe (French-speaking countries in the ACLF series; Greece with Kolaitis and the Rare-ID cohort; an isolate in northern Italy), Turkey (Ürel-Demir's family), China (Zhuang, Qi, Chen 2024, Wang, Zheng), Taiwan (Chen 2025) and Japan (Kurahashi, Okumura) [2, 5, 7–11, 13, 29, 33, 35, 40, 42, 43, 68–70, 76]. The abstracts of Béna, Kroepfl, Mefford, Lukusa and Quinn, the only parts read, do not state the origin of the patients.

No data from Portugal were identified in the sources consulted. From Brazil, the sources mention a case of distal 17q duplication published in São Paulo in 1984, known only from Chen's review table [10], and a study of 73 patients with oculo-auriculo-vertebral spectrum in which a rare MYT1 variant was found in 5 unrelated patients, all with hearing loss and orbital asymmetry, and in which CNVs in the topologically associating domain neighbouring MYT1 were enriched in patients compared with 455 Brazilian controls [103]. These data concern MYT1 and not the 20q13.33 deletion. The absence of data from other countries in the sources consulted does not mean an absence of cases.

There is no known founder effect; the CNVs are non-recurrent. In a genetic isolate in northern Italy, partial 20qter trisomy on a chromosome 22 derivative segregated in an extended family [43]. Data on the HLA-B*15:02 allele are relevant to the treatment of patients of Southeast Asian and Chinese ancestry [92].

9.3. Special populations

In male patients, genital anomalies (cryptorchidism, hypospadias, micropenis) are frequent in the forms with trisomy 17q and in some 20q13.33 deletions [5, 8, 11]. All five published patients with the combined form are male, a finding that, in such a small number, allows no conclusions [11]. Preterm newborns with seizures have different pharmacokinetics for phenobarbital (prolonged half-life) [30].

9.4. European reference network and patient associations

The European Reference Network (ERN) for rare malformation syndromes, intellectual disability and other neurodevelopmental disorders, ERN-ITHACA, is the relevant network for both entities [31]; the ERN for rare and complex epilepsies, EpiCARE, is relevant for the epilepsy [32]. The British association Unique (Rare Chromosome Disorder Support Group) provides information for families, including a children's book on 20q13.33 microdeletions [14, 104]. This illustrated book (version 1 of 2026, produced with McGill Rare from an original text by Seonaid Beaumont) explains to the child the loss of a small segment of chromosome 20, the variability between carriers, the delayed walking and speech of some children and the seizures of a minority, and supports the conversation with the child (see 8.6) [104]. ERN-ITHACA is one of the 24 ERNs approved by the ERN Board of Member States and is co-funded by the European Commission; it has the Clinical Patient Management System (CPMS) for virtual case discussion, the ILIAD registry, working groups dedicated to neurodevelopmental disorders and to fetal medicine and pathology, its own and endorsed guidelines, and calls for collaboration to gather new cases [31]. DECIPHER brings together data on patients with overlapping CNVs and is useful for interpretation [14].

10. Illustrative Clinical Case

10.1. Three cousins with monosomy 20q13.33 and trisomy 17q25.3 due to a maternal translocation

Ürel-Demir and colleagues, from Hacettepe University in Ankara, described in 2020 three Turkish boys from the same family [5]. The proband, aged 12 years, was referred to the paediatric genetics clinic for ID and dysmorphism. He had been born at term, by vaginal delivery, weighing 2800 g, to non-consanguineous parents; he had been diagnosed with epilepsy at 13 days of life, with remission after 4 years, DD and surgery for cryptorchidism. On examination he had brachycephaly, a long face, a prominent metopic suture, synophrys, anteverted ear lobes, macrostomia, a single palmar crease on the left, hyperextensibility of the metacarpophalangeal joints and kyphosis, with normal anthropometry, stereotyped movements and a happy expression. Karyotype, fragile X testing, brain MRI and abdominal ultrasound had been normal; the echocardiogram showed mitral regurgitation [5].

The two sons of his maternal aunt were invited for assessment. The 15-year-old cousin had been born at 36 weeks weighing 2300 g; he had had seizures from day 11, global DD and surgery for cryptorchidism and strabismus; he had microcephaly (head circumference 52 cm, −3.16 standard deviations), two hair whorls, bitemporal narrowing, sparse lateral eyebrows, deep-set eyes, upslanting palpebral fissures, a prominent nasal root and columella, a thin upper lip, malocclusion, anteverted ears, pectus carinatum, scoliosis and metacarpophalangeal laxity; karyotype, fragile X testing and FISH for Angelman syndrome had been normal, and the echocardiogram showed mitral regurgitation. This boy's mother had undergone surgery for a cleft palate [5]. His brother, aged 9 years, had had seizures in the first week of life and had DD, ID, peripheral pulmonary stenosis, an ostium secundum ASD, unilateral pyelectasis, a height of 121 cm (−2.07 standard deviations), a prominent forehead, hypertelorism, upslanting fissures, a high-arched palate, overfolded helices, pectus carinatum and flat feet; MRI and karyotype were normal [5].

Because there were three affected boys, sons of two sisters, the pedigree initially suggested X-linked recessive inheritance. Microarray, performed as a first-line test, showed the same imbalance in all three: in the proband and the younger cousin (60,000-probe platform), arr[hg19] 17q25.3(76,687,948-81,044,553)×3, of 4357 kb, and arr[hg19] 20q13.33(61,314,406-62,908,674)×1, of 1594 kb; in the older cousin (180,000 probes), a 4429 kb duplication and a 1635 kb deletion with the same proximal boundary as the cousins' deletion. The regions contained 75 and 41 OMIM genes, respectively, including KCNQ2 and CHRNA4 in the deletion [5]. The parents' microarrays and the mothers' karyotypes were normal; FISH with subtelomeric probes for 17q, 20p and 20q showed that the two sisters carried a balanced translocation t(17;20)(q25;q13.3), inherited from their mother [5]. Facial photographs of the three patients are in Figure 1, the microarray and the maternal subtelomeric FISH in Figure 2 and the pedigree in Figure 3 of the paper (https://pmc.ncbi.nlm.nih.gov/articles/PMC7109379/figure/F1/, …/F2/ and …/F3/) [5].

10.2. Clinical reading of the case

The case illustrates four points. First, the combination of a terminal deletion on one chromosome with a terminal duplication on another is the signature of a derivative chromosome, and the next step is to study the parents with a method that detects the balanced translocation: here, the microarray and karyotype of the carriers were normal, and only subtelomeric FISH revealed it [5]. Second, a pedigree with several affected boys in collateral lines can mimic X-linked inheritance when what segregates is an autosomal translocation [5]. Third, expressivity varied between patients with practically identical imbalances (microcephaly in two, abnormal cardiac structure in one, single palmar crease in one) [5]. Fourth, neonatal seizures were present in all three, and disappeared without treatment in only one of them, which the authors interpreted as supporting the hypothesis that the larger contiguous KCNQ2–CHRNA4 deletion differs from typical SLFNE; the contribution of trisomy 17q to the DD, however, prevents this picture from being attributed solely to the deletion [2, 5]. The paper does not describe the antiseizure drugs used, so the case does not inform the choice of treatment.

10.3. Isolated 20q13.33 deletion treated with oxcarbazepine

A second, more recent case shows the neonatal presentation and treatment response of a deletion without trisomy 17q. Qi and colleagues described a Chinese girl born at 38 weeks, with seizures from day 7 of life and an EEG with multifocal spikes at 13 days; trio exome sequencing with CNV analysis identified a de novo 20q13.33 deletion of about 1.62 Mb, pathogenic by ACMG/ClinGen scoring, and a 13q34 duplication of uncertain significance [29]. Levetiracetam started at 1 month and increased to 55 mg/kg/day did not control the seizures; the addition of oxcarbazepine reduced them, and the child became seizure-free from 5–6 months, with withdrawal of levetiracetam at 14 months. At 17 months, on oxcarbazepine monotherapy, she had been seizure-free for more than 12 months, with a normal EEG and a developmental quotient of 69 on the Griffiths scale, and a more marked deficit in language [29]. The authors designated the picture as DEE7; by the haploinsufficiency mechanism, deletion of KCNQ2 corresponds to the self-limited end of the spectrum, and the developmental delay may reflect other genes in the deletion and the 13q34 duplication [27, 29]. The initial choice of levetiracetam differs from the order proposed by the ILAE guideline, which gives first line to phenobarbital or, when a channelopathy is suspected, to a sodium channel blocker [30].

11. Prognosis and Long-Term Follow-Up

11.1. Prognosis

Prognosis depends on the content of the CNV and cannot be expressed in probabilities, because there are no cohorts with follow-up. In the 20q13.33 deletion, the epilepsy prognosis is generally favourable: most treated cases became seizure-free in the first months or years, and some without treatment [2, 5, 29, 33], but there was persistent epilepsy in some patients [8, 69]. Developmental prognosis follows the extent of the deletion: normal development in deletions restricted to CHRNA4, KCNQ2 and COL20A1; DD, ID of variable degree and behavioural problems in larger deletions [27, 33]. A single death has been described, at 8 months, in a patient with a complex 6.8 Mb deletion and multiple malformations [8].

In the 17q25.3 duplication and distal trisomy 17q, all individuals older than 1 year in the series had neurocognitive deficits [13], and most have short stature and microcephaly [4, 9]. Heart disease, present in 26 to 60% depending on the series, and severe malformations (anomalous pulmonary venous drainage, polysplenia) determine the early mortality described: a newborn with a 17q25.3 deletion died on day 13 [9, 13]. In the combined form, the published patients were aged between 4 and 15 years, all with ID; the follow-up described does not extend beyond adolescence [5, 11]. Life expectancy into adulthood has not been described.

11.2. Surveillance

There is no published surveillance protocol for these entities. The table combines the recommendations of the KCNQ2 GeneReviews for epilepsy and neurodevelopment with elements derived from the clinical series; the latter are proposals based on the frequency of the manifestations and not formal recommendations.

12. Summary and Final Considerations

The 20q13.33 microdeletion and the 17q25.3 microduplication are non-recurrent subtelomeric imbalances, rare and of unknown prevalence, which are grouped together because the t(17;20)(q25;q13.3) translocation produces, on unbalanced segregation, both alterations in the same patient. The 20q13.33 deletion has no recognisable dysmorphism; its most consistent feature is neonatal-onset epilepsy, explained by haploinsufficiency of KCNQ2, the only gene in the region with established dosage sensitivity. Small deletions, restricted to KCNQ2, CHRNA4 and COL20A1, behave like self-limited familial neonatal epilepsy, and larger ones add DD, ID and behavioural problems; the divergence between authors who consider the contiguous KCNQ2–CHRNA4 deletion a form of SLFNE and those who consider it a distinct entity is largely resolved by the size of the deletion. The large 17q25.3 duplication reproduces distal trisomy 17q, with more consistent dysmorphism, short stature, microcephaly and heart disease in about half of cases; small duplications are mostly variants of uncertain significance, sometimes inherited from parents without the phenotype.

Diagnosis is molecular: microarray, or exome or genome with CNV calling, in the child with neonatal seizures, DD, ID or malformations; microarray to define the extent of any KCNQ2 deletion found by panel or MLPA; and, when a terminal loss on one chromosome is accompanied by a terminal gain on another, parental studies with subtelomeric FISH, because the microarray and karyotype of balanced carriers are normal. Treatment is symptomatic: for neonatal seizures, the 2023 ILAE guideline gives first line to phenobarbital and allows a sodium channel blocker when a channelopathy is likely, and the KCNQ2 series show good responses to carbamazepine and oxcarbazepine, used off-label in newborns and infants and preceded by HLA-B*15:02 genotyping in patients of Asian ancestry. Initial assessment includes echocardiography, hearing and ophthalmological assessment, renal ultrasound and assessment of growth and feeding, and follow-up focuses on epilepsy, development, behaviour and nutrition. Counselling depends on the origin: low risk in confirmed de novo cases, 50% transmission in inherited CNVs and increased risk in translocation carriers, who should also be sought in the extended family.

13. References

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