Treffer: A De Novo Loss-of-Function NCKAP1 Variant in a Boy with Neurodevelopmental Delay and Congenital Heart Defect.

Background: Neurodevelopmental disorders (NDDs), such as autism spectrum disorder (ASD), intellectual disability (ID), and global developmental delay (GDD), frequently have underlying genetic causes. NCKAP1, a gene essential for actin cytoskeleton remodeling and neuronal development, has recently gained recognition as a promising candidate gene in NDDs. While not yet linked to a defined Mendelian disorder, damaging NCKAP1 variants have been identified in individuals with NDDs. NCKAP1 is also expressed in cardiac tissue, with emerging evidence supporting its potential involvement in cardiac development. Here, we present a case of a patient with neurodevelopmental delay and congenital heart disease (CHD) harboring a novel damaging NCKAP1 variant. Methods: Comprehensive clinical evaluations and trio exome sequencing (proband and parents) were conducted on a patient with complex cardiac and neurodevelopmental phenotypes. Results: We identified a de novo heterozygous frameshift variant in NCKAP1, NM_205842.3:c.2956_2959del p.(Ser986Hisfs*34), predicted to result in loss of function through nonsense-mediated mRNA decay. The patient's clinical features included neonatally diagnosed and surgically repaired infradiaphragmatic total anomalous pulmonary venous return (TAPVR), intellectual disability, speech delay, and autistic traits. His NDD phenotypes and variant type align well with previously described NCKAP1-associated NDD, while the cardiac anomaly adds evidence to the gene's expanding phenotypic spectrum. This represents the fourth reported case linking NCKAP1 variants to CHD and/or neurodevelopmental delay. Conclusions: This case strengthens the growing recognition of NCKAP1 in both neurodevelopment and cardiac formation. It highlights the importance of genetic testing for individuals with overlapping developmental and cardiac conditions. Further research is warranted to elucidate the role of NCKAP1 in cardiac development and its contribution to CHD. [ABSTRACT FROM AUTHOR]

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