IQSEC2 mutation update and review of the female‐specific phenotype spectrum including intellectual disability and epilepsy

• Published in: Human mutation Vol. 40; no. 1; pp. 5 - 24
• Main Authors: Shoubridge, Cheryl, Harvey, Robert J., Dudding‐Byth, Tracy
• Format: Journal Article
• Language: English
• Published: United States Hindawi Limited 01-01-2019
• Subjects: affected females; Epilepsy; Epilepsy - genetics; escape X‐inactivation; Female; Females; Genetic Association Studies; Guanine Nucleotide Exchange Factors - chemistry; Guanine Nucleotide Exchange Factors - genetics; Heredity; Humans; Intellectual disabilities; intellectual disability; Intellectual Disability - genetics; IQSEC2; Mutation - genetics; Phenotype; Phenotypes; Seizures; X Chromosomes; affected females; seizures; IQSEC2; escape X-inactivation; intellectual disability
• ISSN: 1059-7794; 1098-1004
• DOI: 10.1002/humu.23670

The IQSEC2‐ related disorders represent a spectrum of X‐chromosome phenotypes with intellectual disability (ID) as the cardinal feature. Here, we review the increasing number of reported families and isolated cases have been reported with a variety of different pathogenic variants. The spectrum of clinical features is expanding with early‐onset seizures as a frequent comorbidity in both affected male and female patients. There is a growing number of female patients with de novo loss‐of‐function variants in IQSEC2 have a more severe phenotype than the heterozygous state would predict, particularly if IQSEC2 is thought to escape X‐inactivation. Interestingly, these findings highlight that the classical understanding of X‐linked inheritance does not readily explain the emergence of these affected females, warranting further investigations into the underlying mechanisms.
IQSEC2‐ related disorders represent a spectrum of X‐chromosome phenotypes of intellectual disability, more recently expanding with early‐onset seizures as a frequent comorbidity in both affected male and female patients. There is a growing number of female patients with de novo loss‐of‐function variants in IQSEC2 have a more severe phenotype than the heterozygous state would predict, particularly if IQSEC2 is thought to escape X‐inactivation. The classical understanding of X‐linked inheritance does not readily explain the emergence of these affected females.