UC San Diego

Aicardi Syndrome is a rare female-specific neurodevelopmental disorder that severely affects the intellectual capabilities and the development of the central nervous system of patients. Although the exact genetic cause of Aicardi Syndrome is yet unknown, based on the skewed X-inactivation patterns, absence of familial recurrences, and the often multifocal symptoms observed among Aicardi patients, This study aims at testing the hypothesis that Aicardi Syndrome is caused by postzygotic de novo somatic mosaic variants on the X chromosome. Bioinformatic workflows that integrate various sequencing data processing tools, machine-learning-based mosaicism prediction tools, and variant filtering and annotation scripts were deployed to identify, filter, and annotate the somatic mosaic single-nucleotide variants from the whole-genome sequencing data of the Aicardi patients. 162 passed and unique de novo somatic mosaic variants on the X chromosome were identified from 18 Aicardi patients. The somatic mosaic variants on the X chromosome from Aicardi patients are significantly more damaging than those identified from the control individuals. Seventeen recurrent genes that have variants within or near them in more than one Aicardi patient have been identified, and in particular, the PAK3 gene could be a possible gene candidate for the Aicardi Syndrome due to its recurrence among AIC patients and relevance to the symptoms of Aicardi Syndrome. Still, more Aicardi patients, sequencing data with higher read depth, and Aicardi-enriched tissues are required to more confidently discover the gene candidates to solve the elusive etiology of Aicardi Syndrome.