A Novel de Novo WAC Frameshift Variant in DeSanto-Shinawi Syndrome With Temporo-Occipital Epileptiform Activity and Congenital Cardiac Anomalies.

Abstract

DeSanto-Shinawi syndrome (DESSH) is a rare autosomal dominant neurodevelopmental disorder associated with heterozygous pathogenic variants in the WAC gene, most commonly resulting in loss of function. The clinical spectrum of DESSH continues to expand, whereas detailed electroencephalographic descriptions remain limited. We report a 9-year-old male patient presenting with developmental delay, behavioral abnormalities, dysmorphic facial features, epilepsy, and congenital cardiac anomalies. Brain magnetic resonance imaging was normal, while serial electroencephalography demonstrated persistent epileptiform activity involving the bilateral temporo-occipital regions, with left temporo-occipital persistence on follow-up. Whole-exome sequencing identified a novel heterozygous apparently de novo frameshift variant in WAC (NM_016628.5:c.1793delT; p.Met598Serfs*8), which was classified as pathogenic according to ACMG/AMP criteria. The variant is predicted to result in loss of function, supporting haploinsufficiency as the most plausible disease mechanism. This case expands the mutational and clinical spectrum of DESSH and provides additional electroclinical data on epilepsy associated with WAC-related neurodevelopmental disorder. The coexistence of ventricular septal defect and bicuspid aortic valve further supports the multisystemic nature of the syndrome. Our findings highlight the importance of detailed neurological, electroencephalographic, cardiac, and genetic evaluation in patients with suspected DESSH.