Impact of Incomplete Penetrance Copy Number Variants on Neurodevelopmental Disorders

Abstract

Neurodevelopmental disorders (NDDs) encompass a broad range of conditions characterized by cognitive, behavioral, and motor impairments, often with complex genetic causes. Copy number variations (CNVs) have emerged as significant contributors to NDDs, but those with incomplete penetrance pose challenges in clinical interpretation and genetic counseling. This study investigates the role of incomplete penetrance CNVs located on chromosomes 15, 16, and 22 in individuals diagnosed with NDDs. Using a retrospective cross-sectional approach, we analyzed a cohort of 163 patients from the Genetics Service of the Faculty of Medicine of the University of Porto, focusing on pathogenic (P) or likely pathogenic (LP) CNVs detected via array-based comparative genomic hybridization (aCGH) and single nucleotide polymorphism (SNP) microarray. Our findings revealed clinical manifestations with significant variability, even among individuals carrying the same CNV. Variants in regions such as 15q11q13, 16p11.2, and 22q11.2 were associated with a wide spectrum of phenotypic outcomes, from mild cognitive impairment to severe neuropsychiatric and neurodevelopmental disorders. The conducted research highlights the need to integrate high-resolution genomic analyses with comprehensive clinical assessments to increase diagnostic accuracy and improve patient management. Further research is needed to elucidate the modifying factors that contribute to the variable expressivity of these CNVs, which could facilitate genetic counseling and personalized therapeutic approaches of these individuals.