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Clin Genet. 2019 Apr;95(4):496-506. doi: 10.1111/cge.13507.

Deep phenotyping of 14 new patients with IQSEC2 variants, including monozygotic twins of discordant phenotype.

Author information

1
West Midlands Regional Clinical Genetics Service and Birmingham Health Partners, Birmingham Women's and Children's Hospitals NHS Foundation Trust, Birmingham, UK.
2
Medical School, University of Sheffield, Sheffield, UK.
3
West Midlands Regional Genetics Laboratory Birmingham Women's and Children's Hospitals NHS Foundation Trust, Birmingham, UK.
4
Manchester Centre for Genomic Medicine, Manchester University Hospitals NHS Foundation Trust, Manchester, UK.
5
Division of Evolution and Genomic Sciences, School of Biological Sciences, University of Manchester, Manchester, UK.
6
University Hospitals Bristol NHS Foundation Trust, Clinical Genetics, St. Michael's Hospital, Bristol, UK.
7
Wessex Clinical Genetics Service, University Hospitals of Southampton NHS Trust, Southampton, UK.
8
Peninsula Clinical Genetics, Royal Devon and Exeter NHS Trust, Exeter, UK.
9
Sheffield Diagnostic Genetics Service, Sheffield Children's NHS Foundation Trust, Sheffield, UK.
10
South West Thames Regional Genetics Service, St George's University Hospitals NHS Foundation Trust, London, UK.
11
All Wales Medical Genetics Service, Cardiff and Vale University Health Board, Institute of Medical Genetics, University Hospital of Wales, Cardiff, UK.
12
Wellcome Trust Sanger Institute, Cambridge, UK.
13
Sheffield Clinical Genetics Service, Sheffield Children's NHS Foundation Trust, Sheffield, UK.
14
Academic Unit of Child Health, Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK.

Abstract

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.

KEYWORDS:

IQSEC2; epilepsy; intellectual disability; secondary microcephaly; twin discordance

PMID:
30666632
DOI:
10.1111/cge.13507
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