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

Area of Science:

• Genetics
• Neuroscience

Background:

• Pathogenic variants in the IQSEC2 gene are associated with X-linked mental retardation.
• Clinical features are variable, including developmental delays, intellectual disability, seizures, and autistic features.

Observation:

• This study presents five probands (2 males, 3 females) with distinct IQSEC2 variant types identified through exome sequencing.
• All patients exhibited epilepsy, global developmental delays, intellectual disability, and constipation.
• The study observed a spectrum of phenotypic severity influenced by patient sex, variant type, and inheritance patterns.

Findings:

• De novo truncating IQSEC2 variants correlate with severe disease in both sexes.
• Missense variants are associated with milder phenotypes, with males generally exhibiting more severe symptoms than females.
• The first confirmed case of parental mosaicism for IQSEC2 variants is reported, impacting recurrence risk counseling.

Implications:

• These findings establish a clearer genotype-phenotype correlation for IQSEC2 variations.
• Understanding these correlations is crucial for accurate diagnosis, prognosis, and genetic counseling.
• The study highlights the importance of considering sex, variant type, and inheritance in IQSEC2-related disorders.