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Deep phenotyping of 14 new patients with IQSEC2 variants, including monozygotic twins of discordant phenotype
Author(s) -
Radley Jessica A.,
O'Sullivan Rory B.G.,
Turton Sarah E.,
Cox Helen,
Vogt Julie,
Morton Jenny,
Jones Elizabeth,
Smithson Sarah,
Lachlan Katherine,
Rankin Julia,
ClaytonSmith Jill,
Willoughby Josh,
Elmslie Frances F.,
Sansbury Francis H.,
Cooper Nicola,
Balasubramanian Meena
Publication year - 2019
Publication title -
clinical genetics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.543
H-Index - 102
eISSN - 1399-0004
pISSN - 0009-9163
DOI - 10.1111/cge.13507
Subject(s) - microcephaly , macrocephaly , hypotonia , intellectual disability , autism spectrum disorder , rett syndrome , medicine , epilepsy , autism , monozygotic twin , pediatrics , ataxia , scoliosis , developmental disorder , phenotype , neurodevelopmental disorder , exome sequencing , genetics , biology , psychiatry , gene
Whole‐exome sequencing has established IQSEC2 as a neurodevelopmental disability gene. The IQSEC2 variant phenotype includes developmental delay, intellectual disability, epilepsy, hypotonia, autism, developmental regression, microcephaly and stereotypies but is yet to be fully described. Presented here are 14 new patients with IQSEC2 variants. In addition to the established features, we observed: gait ataxia in 7 of 9 (77.8%), drooling in 9 of 14 (64.2%), early feeding difficulties in 7 of 14 (50%), structural brain abnormalities in 6 of 13 (46.2%), brachycephaly in 5 of 14 (35.7%), and scoliosis and paroxysms of laughter each in 4 of 14 (28.6%). We suggest that these are features of the IQSEC2 ‐related disorder. Gastrostomy requirement, plagiocephaly, strabismus and cortical blindness, each seen in 2 of 14 (14.3%), may also be associated. Shared facial features were noted in 8 of 14 patients, and shared hair patterning was identified in 5 of 14 patients. This study further delineates the IQSEC2 phenotypic spectrum and supports the notion of an emerging IQSEC2 syndrome. We draw parallels between the IQSEC2 ‐related disorder and the Angelman‐/Rett‐/Pitt‐Hopkins syndrome group of conditions and recommend the addition of IQSEC2 to epilepsy and developmental delay gene panels. We observed discordant phenotypes in monozygotic twins and apparent gonadal mosaicism, which has implications for recurrence risk counselling in the IQSEC2 ‐related disorder.