ADNP-Related Neurodevelopmental Disorder: The First Turkish Case Series with Novel Variants and Reduced Intrafamilial...

Background/Objectives: Helsmoortel-Van der Aa syndrome (HVDAS), or ADNP syndrome, is a neurodevelopmental disorder characterized by cognitive deficits, dysmorphic features, and multisystem involvement. While typically arising de novo, familial cases with variable penetrance remain exceptionally rare. No cases have been reported from Türkiye to date. This study aims to define the first Turkish case series and provide compelling evidence for familial inheritance with variable penetrance/expressivity. Methods: We clinically and molecularly evaluated six Turkish subjects from four unrelated families presenting varying degrees of clinical display such as developmental delay, intellectual disability, or autism spectrum disorder. Next-generation clinical exome sequencing was performed, followed by Sanger sequencing for variant validation and parental segregation analysis. Results: Four distinct heterozygous truncating/frameshift variants were identified (three of them were novel) across the cohort, all falling within the CpG hypomethylating epigenetic group. Notably, a familial cluster (three individuals) shared the c.2815_2816del p.(Ile939Serfs*4) variant. Within this family, striking intrafamilial variability and reduced penetrance were observed: the 2.5-year-old proband displayed a severe phenotype with epilepsy and brain abnormalities, his 17-year-old sister showed a remarkably mild phenotype, and their 47-year-old father was almost entirely asymptomatic. Additionally, prolonged umbilical cord retention complicated by infection was identified as a novel clinical finding in two unrelated probands. Conclusions: This study presents the first Turkish case series of ADNP syndrome, expanding its global mutation spectrum with novel variants. Our findings provide robust evidence for familial transmission with reduced penetrance, emphasizing the necessity of family-based genetic counseling and parental testing, even when evaluating apparently asymptomatic individuals.