Table 1.

Pathogenic loss-of-function variants in IQSEC2 in females with intellectual disability and other comorbidities.

cDNAExProteinDomFamilyDD/IDSeizuresBehavioural/Psychiatric/Physical featuresRef
c.55_151delinsAT1p.Ala19Ilefs*32P1Mild IDNoneSpeech deficits—pronunciation, syntax issues at 6.5 years. Tantrums, anxiety(29)
c.83_85del1p.Asp28delCC108286Rett likeNoneLoss of language. Regression stabilization, gait abnormalities(30)
c.273_282del1p.Asp91Lysfs*112P7Rett likeRegression stabilization, gait abnormalities, stereotypic hand movements, inappropriate laughing/screaming spells. Partial or loss of spoken language.(31)
c.566C>A1p.(S189*)Fin2Severe-profound IDGeneralised seizures (18 mo)Limited speech, low-set large ears, asymmetric facial features, mild hypertrichosis, mild ASD.This report
c.804delC3p.Tyr269Thrfs*348SeizuresLimited phenotype reported.(32)
c.854del3p.Pro285Leufs*21P11Severe IDSeizures (12 mo) tonic–clonicSays words at 16 years. Limb rigidity, walking instability.(29)
c.928G>T3p.Glu310*P16Mild-mod DDFENo ASD or other features. Nonverbal at 3 years.(33)
c.1556_1599delACCT5p.Tyr519Trpfs*87P10DD, Severe to profound IDNoneHypotonia, first word at 2 years, stereotypies, and dysmorphic features.(34)
c.1591C>T5p.Arg531*P3DD, Severe to profound IDTonic–clonic, absenceAutism, first words at 11 mo, hypotonia, stereotypies, ataxic gait(34)
c.1744_1763del5p.Arg582Cysfs*9P16Mild DDFocal epilepsy (17 mo)50–60 words at 3 years. Autistic behaviour, hypertonia.(29)
c.1983_1999del5p.Leu662Glnfs*25P17Global DDFocal epilepsy (11 mo)Babbling at 16 mo Hypertonia.(29)
c.2052_2053delCG5p.Cys684*47SeizuresLimited phenotype reported.(32)
c.2078delG5p.Gly693Valfs*29P18Mod global DDNoneNonverbal at 2.8 years. Self-injurious behaviour, hypotonia(29)
c.2203C>T5p.Gln735*T17563Mild IDSGE (5 years)—regression with nonconvulsive SE. Absence to tonic–clonic and myoclonic seizures, drop attacks. Offset at 38 years.(35)
c.2272C>T5p.Arg758*P19Severe IDMultifocal epilepsy (23 mo)3 words at 11.3 years. Self-injurious behaviours.(29)
P20Mod IDSeizures (9 years 4 mo) GTCS, focal, atypical absencesSpeaks sentences, reasoning difficulties
c.2317C>T6p.Gln773*Sec7P6Global DDSeizures (18 mo)Hypotonic, strabismus, dysmorphic face(36)
P23Mod IDSeizures (14 years), GTCS, absencesFew words at 43 years. ASD (13 years) aggressive.(29)
c.2317_2332del6p.Gln773Glyfs*25Sec7P24Seizures (6 years)Sentences at 11.3 years(29)
c.2679_2680insA8p.Asp894fs*10Sec7K2DD, Mod-severe IDEpilepsy4 affected sisters, nonverbal (2), language delay (1), aggressive when young and ASD traits (2)(37)
c.2776C>T9p.Arg926*Sec7P3Severe ID Rett likeEEASD (balance & hand stereotypies), pain sensitivity & aggressive. Speech delay, regression at 2 years. Now nonverbal(38)
P26Profound IDLGS (23 mo)Nonverbal at 11.3 years. Autistic behaviour, truncal hypotonia, strabismus.(29)
9p.Tyr933*Sec7M2189Global DD Mod IDASD, sleep disturbances, behavioural aspects, oral motor dyspraxia, strabismus. Marked speech delay, nonverbal at 14 years.(39)
c.2854C>T9p.Gln952*PHP27Severe IDEE (12 years), absences, GTCSNonverbal at 16 years. Autistic behaviour, dystonia, tremor, ataxia.(29)
c.2911C>T10p.Arg971*PHP8DD, Severe to profound IDSeizuresNo ASD. Stereotypies and dysmorphic features.(34)
P11DD, Severe to profound IDSeizuresAutism, first word at 2.3–3 years, stereotypies and dysmorphic features, ataxic gait(34)
c.3079delC11p.Leu1027Serfs*75PHP29Mod-severe IDNone10 words at 8 years(29)
c.3163C>T12p.Arg1055*PHPat19Severe IDEpilepsyBorderline macrocephaly, skewed X-inactivation (97:3)(40)
P31Mod-severe IDSeizures (5 years 8 mo) GTCS, focal dyscognitive3 word sentences, and 20 words at 8 years. Autistic behaviour, Global hypotonia, aggression, hyperactivity.(29)
c.3278C>A13p.Ser1093*P36Severe IDNoneFew words, rare sentences at 13 years.(29)
c.3322C>T13p.Gln1108*KOEE(41)
c.3433C>T13p.Arg1145*P39Severe IDFocal epilepsy (11 mo) focal, tonic, tonic–clonicNonverbal at 11 years. Autistic behaviour.(29)
c.3457del14p.Arg1153Glyfs*244P40Severe IDIS (7 mo) spasms, focal, absence, tonic, myoclonic jerksNonverbal at 20 years. Autistic behaviour, truncal hypotonia. MRI mild atrophy and cerebral white matter hyperintensities.(29)
c.4039dupG15p.Ala1347Glyfs*401098 MEE (19 mo)ASD, macrocephaly(42)
P41Mild-mod IDSeizures (3 years) absence and fallsSpeaks sentences, writes first name, counts to 15 at 11 years. Mild autistic behaviour.(29)
c.4401del15p.Gly1468Alafs*27P42Mod-severe IDNoneShort sentences at 11 years. Attention deficit/hyperactivity(29)
c.4419_4420insC15p.Ser1474Glnfs*P6DD, Severe to profound IDAbsence, complexAutism, hypotonia. First words at 7 years. Ataxic gait, stereotypies, bouts of laughter, self-injurious behaviour.(34)
Twin sister of P6P7DD, Mild IDNoAutism, first words 11.5 mo. Ataxic gait
  • ASD, autistic spectrum disorder; DD, developmental delay; EE, epileptic encephalopathy; GTCS, generalised tonic–clonic seizures; IS, infantile spasms; SGE, symptomatic generalised epilepsy.

  • Del, deletion; dup, duplication. Numbers (alone) in brackets indicate number of affected individuals.

  • Nucleotide numbering reflects cDNA numbering with +1 corresponding to the A of the ATG translation initiation codon in the reference sequence for IQSEC2 (GenBank: NM_001111125.2).