Double Mosaicism in Xia-Gibbs Syndrome

Xia-Gibbs Syndrome (XGS; MIM: 615829) is a rare neurodevelopment disorder (NDD) caused by de novo pathogenic variants in the single coding exon of the AT-Hook DNA-Binding Motif-Containing 1 (AHDC1) gene. In this study, we investigate a rare case of double mosaicism in a 10-year-old female with XGS. The proband presented with characteristic clinical findings observed in XGS, including severe developmental delay, hypotonia, seizures, and dysmorphic features. Initial clinical genetic testing reported two adjacent de novo arising variants in AHDC1 (c.1167delG and c.1169delC), each present with an approximately 30%-36% allelic fraction in genomic DNA from a blood sample. In order to establish the haplotype phase of the variants, we performed long-read whole genome sequencing of DNA from an additional blood sample and short-read amplicon sequencing with blood and buccal swab samples. These data indicated that the adjacent variants are in trans on the same parental haplotype, likely originating in the zygote. These findings indicate a rare occurrence of double mosaicism and provide insights into the mechanisms behind somatic mutations influencing early development. The case underscores the importance of advanced molecular techniques in resolving complex genetic events and their impact on clinical presentations in XGS.