Pathogenic loss-of-function variants in IQSEC2 in females with intellectual disability and other comorbidities.
| cDNA | Ex | Protein | Dom | Family | DD/ID | Seizures | Behavioural/Psychiatric/Physical features | Ref |
|---|---|---|---|---|---|---|---|---|
| c.55_151delinsAT | 1 | p.Ala19Ilefs*32 | — | P1 | Mild ID | None | Speech deficits—pronunciation, syntax issues at 6.5 years. Tantrums, anxiety | (29) |
| c.83_85del | 1 | p.Asp28del | CC | 108286 | Rett like | None | Loss of language. Regression stabilization, gait abnormalities | (30) |
| c.273_282del | 1 | p.Asp91Lysfs*112 | — | P7 | Rett like | Regression stabilization, gait abnormalities, stereotypic hand movements, inappropriate laughing/screaming spells. Partial or loss of spoken language. | (31) | |
| c.566C>A | 1 | p.(S189*) | — | Fin2 | Severe-profound ID | Generalised seizures (18 mo) | Limited speech, low-set large ears, asymmetric facial features, mild hypertrichosis, mild ASD. | This report |
| c.804delC | 3 | p.Tyr269Thrfs*3 | — | 48 | Seizures | Limited phenotype reported. | (32) | |
| c.854del | 3 | p.Pro285Leufs*21 | — | P11 | Severe ID | Seizures (12 mo) tonic–clonic | Says words at 16 years. Limb rigidity, walking instability. | (29) |
| c.928G>T | 3 | p.Glu310* | — | P16 | Mild-mod DD | FE | No ASD or other features. Nonverbal at 3 years. | (33) |
| c.1556_1599delACCT | 5 | p.Tyr519Trpfs*87 | — | P10 | DD, Severe to profound ID | None | Hypotonia, first word at 2 years, stereotypies, and dysmorphic features. | (34) |
| c.1591C>T | 5 | p.Arg531* | — | P3 | DD, Severe to profound ID | Tonic–clonic, absence | Autism, first words at 11 mo, hypotonia, stereotypies, ataxic gait | (34) |
| c.1744_1763del | 5 | p.Arg582Cysfs*9 | — | P16 | Mild DD | Focal epilepsy (17 mo) | 50–60 words at 3 years. Autistic behaviour, hypertonia. | (29) |
| c.1983_1999del | 5 | p.Leu662Glnfs*25 | — | P17 | Global DD | Focal epilepsy (11 mo) | Babbling at 16 mo Hypertonia. | (29) |
| c.2052_2053delCG | 5 | p.Cys684* | — | 47 | Seizures | Limited phenotype reported. | (32) | |
| c.2078delG | 5 | p.Gly693Valfs*29 | P18 | Mod global DD | None | Nonverbal at 2.8 years. Self-injurious behaviour, hypotonia | (29) | |
| c.2203C>T | 5 | p.Gln735* | — | T17563 | Mild ID | SGE (5 years)—regression with nonconvulsive SE. Absence to tonic–clonic and myoclonic seizures, drop attacks. Offset at 38 years. | (35) | |
| c.2272C>T | 5 | p.Arg758* | — | P19 | Severe ID | Multifocal epilepsy (23 mo) | 3 words at 11.3 years. Self-injurious behaviours. | (29) |
| P20 | Mod ID | Seizures (9 years 4 mo) GTCS, focal, atypical absences | Speaks sentences, reasoning difficulties | |||||
| c.2317C>T | 6 | p.Gln773* | Sec7 | P6 | Global DD | Seizures (18 mo) | Hypotonic, strabismus, dysmorphic face | (36) |
| P23 | Mod ID | Seizures (14 years), GTCS, absences | Few words at 43 years. ASD (13 years) aggressive. | (29) | ||||
| c.2317_2332del | 6 | p.Gln773Glyfs*25 | Sec7 | P24 | Seizures (6 years) | Sentences at 11.3 years | (29) | |
| c.2679_2680insA | 8 | p.Asp894fs*10 | Sec7 | K2 | DD, Mod-severe ID | Epilepsy | 4 affected sisters, nonverbal (2), language delay (1), aggressive when young and ASD traits (2) | (37) |
| c.2776C>T | 9 | p.Arg926* | Sec7 | P3 | Severe ID Rett like | EE | ASD (balance & hand stereotypies), pain sensitivity & aggressive. Speech delay, regression at 2 years. Now nonverbal | (38) |
| P26 | Profound ID | LGS (23 mo) | Nonverbal at 11.3 years. Autistic behaviour, truncal hypotonia, strabismus. | (29) | ||||
| 9 | p.Tyr933* | Sec7 | M2189 | Global DD Mod ID | ASD, sleep disturbances, behavioural aspects, oral motor dyspraxia, strabismus. Marked speech delay, nonverbal at 14 years. | (39) | ||
| c.2854C>T | 9 | p.Gln952* | PH | P27 | Severe ID | EE (12 years), absences, GTCS | Nonverbal at 16 years. Autistic behaviour, dystonia, tremor, ataxia. | (29) |
| c.2911C>T | 10 | p.Arg971* | PH | P8 | DD, Severe to profound ID | Seizures | No ASD. Stereotypies and dysmorphic features. | (34) |
| P11 | DD, Severe to profound ID | Seizures | Autism, first word at 2.3–3 years, stereotypies and dysmorphic features, ataxic gait | (34) | ||||
| c.3079delC | 11 | p.Leu1027Serfs*75 | PH | P29 | Mod-severe ID | None | 10 words at 8 years | (29) |
| c.3163C>T | 12 | p.Arg1055* | PH | Pat19 | Severe ID | Epilepsy | Borderline macrocephaly, skewed X-inactivation (97:3) | (40) |
| P31 | Mod-severe ID | Seizures (5 years 8 mo) GTCS, focal dyscognitive | 3 word sentences, and 20 words at 8 years. Autistic behaviour, Global hypotonia, aggression, hyperactivity. | (29) | ||||
| c.3278C>A | 13 | p.Ser1093* | — | P36 | Severe ID | None | Few words, rare sentences at 13 years. | (29) |
| c.3322C>T | 13 | p.Gln1108* | — | KO | EE | (41) | ||
| c.3433C>T | 13 | p.Arg1145* | — | P39 | Severe ID | Focal epilepsy (11 mo) focal, tonic, tonic–clonic | Nonverbal at 11 years. Autistic behaviour. | (29) |
| c.3457del | 14 | p.Arg1153Glyfs*244 | — | P40 | Severe ID | IS (7 mo) spasms, focal, absence, tonic, myoclonic jerks | Nonverbal at 20 years. Autistic behaviour, truncal hypotonia. MRI mild atrophy and cerebral white matter hyperintensities. | (29) |
| c.4039dupG | 15 | p.Ala1347Glyfs*40 | — | 1098 M | EE (19 mo) | ASD, macrocephaly | (42) | |
| P41 | Mild-mod ID | Seizures (3 years) absence and falls | Speaks sentences, writes first name, counts to 15 at 11 years. Mild autistic behaviour. | (29) | ||||
| c.4401del | 15 | p.Gly1468Alafs*27 | — | P42 | Mod-severe ID | None | Short sentences at 11 years. Attention deficit/hyperactivity | (29) |
| c.4419_4420insC | 15 | p.Ser1474Glnfs* | — | P6 | DD, Severe to profound ID | Absence, complex | Autism, hypotonia. First words at 7 years. Ataxic gait, stereotypies, bouts of laughter, self-injurious behaviour. | (34) |
| Twin sister of P6 | P7 | DD, Mild ID | No | Autism, 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).