Expanding the Neurodevelopmental Spectrum of Xia-Gibbs Syndrome: New Clinical Entities and Novel Variants From a...

Xia-Gibbs syndrome (XGS) is a rare neurodevelopmental disorder caused by heterozygous variants in the AHDC1 gene. While the core phenotype includes developmental delay, hypotonia, and expressive language impairment, the syndrome displays considerable clinical and genetic heterogeneity. Data from non-European populations remain scarce. We report the clinical and molecular findings of five unrelated Turkish patients with XGS diagnosed via whole-exome sequencing (WES). This is a multicenter study, and clinical data were collected from participating centers using standardized forms. All patients carried heterozygous, de novo AHDC1 variants (three frameshift, two nonsense), all of which were classified as pathogenic or likely pathogenic. Three of these, p.(Ala1432Profs13), p.(Val900Glyfs2), and p.(Val704Profs*26), are novel and predicted to cause protein truncation. Nonsense mutations are p.(Arg108*) and p.(Trp638*), which were previously reported as disease-causing. One patient had dual diagnoses with AHDC1 and CDK13 variants, explaining ocular and cardiac anomalies, leading to a particularly severe neurodevelopmental phenotype. This is the largest study reported to date in Turkey on XGS, a rare genetic disorder, further expanding the disease's genotypic and phenotypic spectrum. Recognition of dual diagnoses in a single patient underscores the value of WES in detecting complex genotypes and avoiding misattributed genotype-phenotype associations. As a recently described syndrome, careful evaluation of patients with XGS for atypical phenotypes may provide important contributions to the clinical presentation described in the literature.