Clinical and molecular characterization of Xia–Gibbs syndrome: expanding the phenotypic spectrum in a Brazilian cohort

Xia‒Gibbs syndrome (XGS) is a rare intellectual disability (ID) syndrome caused by de novo AHDC1 pathogenic variants. We characterized clinical and molecular features of 16 Brazilian patients with XGS. Patient data were collected through semistructured interviews with family members, reanalysis of previous health and genetic assessments, and clinical reports from physicians. Genomic variants and their segregation were validated via Sanger sequencing. Statistical analyses were conducted to evaluate genotype‒phenotype associations. Twelve novel AHDC1 causative variants were documented. ID, hypotonia, motor developmental delay, and varied nonspecific facial dysmorphisms were observed in all patients, with speech disorders in 15 of them. Three frequent phenotypes, previously unreported, were identified: hyperphagia/food obsession, genital/gonadal alterations in males, and shortening of the Achilles tendon. Additionally, our data provide statistically significant support for previously reported associations between pathogenic variants in the first half of the AHDC1 coding region and epilepsy and scoliosis. We also propose a novel association between N-terminal mutations and developmental regression. In summary, our findings broaden the clinical phenotype of XGS, with musculoskeletal and genital/gonadal abnormalities highlighting the multisystem involvement in this condition, beyond neurodevelopmental deficits. Comprehensive phenotypic assessments in all identified patients are recommended to accurately identify and associate novel clinical signs with XGS.