French Guidelines of the AchroPuce Network for the Interpretation and Reporting of Constitutional Copy Number...

Over the past 15 years, molecular methods for human genome analysis have evolved significantly, becoming integral to routine genetic diagnostics. Among various genomic alterations, copy-number variations (CNVs) are particularly important as sources of both benign and pathogenic variants. Accurate assessment of these variants' clinical implications is critical, especially for rare, non-recurrent CNVs and for susceptibility loci linked to neurodevelopmental disorders (NDDs). To address these challenges, the French AchroPuce CNV Interpretation Working Group proposes a novel classification termed "PIEV," referring to CNVs associated with NDDs characterized by incomplete penetrance and variable expressivity. This category complements the existing five-tier ACMG classification system, supporting genetic professionals in harmonizing practice through standardized French national guidelines, thereby enhancing genetic counseling and clinical interpretation precision. Distinguishing clearly pathogenic variants from those with incomplete penetrance is crucial, and the consistent classification of these CNVs independently of the clinical context is essential. Clinical significance assessments should entail collaboration between biologists and multidisciplinary clinical teams, especially in prenatal diagnostics. The working group maintains an annually reviewed curated list of recurrent neurodevelopmental CNVs with reduced penetrance and provides consensus recommendations with a customized interpretation tool to enhance national consistency in CNVs reporting.