Abstract
PurposeVariants in IQSEC2, escaping X inactivation, cause X-linked intellectual disability with frequent epilepsy in males and females. We aimed to investigate sex-specific differences.MethodsWe collected the data of 37 unpublished patients (18 males and 19 females) with IQSEC2 pathogenic variants and 5 individuals with variants of unknown significance and reviewed published variants. We compared variant types and phenotypes in males and females and performed an analysis of IQSEC2 isoforms.ResultsIQSEC2 pathogenic variants mainly led to premature truncation and were scattered throughout the longest brain-specific isoform, encoding the synaptic IQSEC2/BRAG1 protein. Variants occurred de novo in females but were either de novo (2/3) or inherited (1/3) in males, with missense variants being predominantly inherited. Developmental delay and intellectual disability were overall more severe in males than in females. Likewise, seizures were more frequently observed and intractable, and started earlier in males than in females. No correlation was observed between the age at seizure onset and severity of intellectual disability or resistance to antiepileptic treatments.ConclusionThis study provides a comprehensive overview of IQSEC2-related encephalopathy in males and females, and suggests that an accurate dosage of IQSEC2 at the synapse is crucial during normal brain development.
Highlights
This study provides a comprehensive overview of IQSEC2-related encephalopathy in males and females, and suggests that an accurate dosage of IQSEC2 at the synapse is crucial during normal brain development
Pathogenic variants on chromosome X represent an important cause of neurodevelopmental disorders, where expression usually depends on the sex of the individual.[1]
We collected the data from 37 unpublished patients (18 males and 19 females) with IQSEC2 pathogenic variants, 5 individuals (4 males and 1 female) with variants previously reported without clinical data, and 5 novel patients (3 males and 2 females) with variants of unclear significance (VUS) from 45 unrelated families (Table 1): one splice-site variant
Summary
Pathogenic variants on chromosome X represent an important cause of neurodevelopmental disorders, where expression usually depends on the sex of the individual.[1] X-linked conditions are often restricted to males, or more severe in males than in females, because males have a single copy of the X chromosome while females have two copies.[2] EFNB1-related craniofrontonasal syndrome and PCDH19-related femalelimited epilepsy, two X-linked disorders where heterozygous females are affected and hemizygous males are spared, constitute the only exceptions to this rule known so far.[3,4] Yet, increasing evidence shows that variants on chromosome X account for a significant proportion of affected females and that some X-linked disorders affect males and females almost . Compensation of gene dosage in females is achieved for most genes on the X chromosome by epigenetic silencing of one X chromosome. This process, known as X chromosome inactivation (XCI), usually occurs randomly from one cell to another at an early stage of embryonic development. 15–20% of genes escape XCI and are expressed from both X alleles in females.[7,8] Escapee genes differ from one mammalian species to the other and both their function and link with human disorders are still largely unknown.[9,10]
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