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Genotype-phenotype correlation: Inheritance and variant-type infer pathogenicity in IQSEC2 gene.

Authors
  • Barrie, Elizabeth S1
  • Cottrell, Catherine E2
  • Gastier-Foster, Julie2
  • Hickey, Scott E3
  • Patel, Anup D4
  • Santoro, Stephanie L3
  • Alfaro, Maria P5
  • 1 The Institute for Genomic Medicine at Nationwide Children's Hospital, USA.
  • 2 The Institute for Genomic Medicine at Nationwide Children's Hospital, USA; The Ohio State University College of Medicine, Department of Pathology, USA; The Ohio State University College of Medicine, Department of Pediatrics, USA.
  • 3 The Ohio State University College of Medicine, Department of Pediatrics, USA; Division of Genetic and Genomic Medicine, Nationwide Children's Hospital, USA.
  • 4 The Ohio State University College of Medicine, Department of Pediatrics, USA; Department of Neurology, Nationwide Children's Hospital, Columbus, OH, USA.
  • 5 The Institute for Genomic Medicine at Nationwide Children's Hospital, USA; The Ohio State University College of Medicine, Department of Pathology, USA; The Ohio State University College of Medicine, Department of Pediatrics, USA. Electronic address: [email protected]
Type
Published Article
Journal
European journal of medical genetics
Publication Date
Mar 01, 2020
Volume
63
Issue
3
Pages
103735–103735
Identifiers
DOI: 10.1016/j.ejmg.2019.103735
PMID: 31415821
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Pathogenic variants in the IQSEC2 gene including nonsense, frameshift, splice-alterations, deletions, and missense changes have been identified in individuals with X-linked mental retardation. Although highly variable, clinical features may include hypotonia, moderate to severe delayed psychomotor development, intellectual disability, speech deficits, refractory seizures, autistic features, and stereotypical movements. Females with de novo variants have been described with classical features. In contrast, the phenotype in carrier females identified through an affected male may range from asymptomatic to mild intellectual disability. We present male (N = 2) and female (N = 3) probands ascertained via diagnostic exome sequencing with distinct variant types in the IQSEC2 gene encompassing a spectrum of phenotypic severity with patient sex, variant type and inheritance hypothesized to drive disease penetrance and expressivity. All of these patients demonstrated epilepsy, global developmental delays, intellectual disability, and constipation. Our data support that de novo, truncating variants correlate with severe disease in both female and male patients harboring an IQSEC2 alteration. Missense variants in male and female patients may account for a milder disease overall, with more severe symptoms in males than females. We also present the first confirmed case of parental mosaicism, which has implications regarding counseling for recurrence risk. These data further delineate a genotype-phenotype correlation of IQSEC2 variation. Copyright © 2019 Elsevier Masson SAS. All rights reserved.

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