RESUMO
PURPOSE: Many copy number variants (CNVs) are reported to cause a variety of neurodevelopmental disabilities including intellectual disability, developmental delay, autism and other phenotypes with incomplete penetrance, so not all individuals with a pathogenic CNV are affected. Penetrance estimates vary between studies. A systematic review was conducted to clarify CNV penetrance for 83 recurrent CNVs. METHODS: A systematic review using PRISMA guidelines (PROSPERO #CRD42021253955) was conducted to identify penetrance estimates for CNVs associated with neurodevelopment. Pooled analysis was performed using forest plots. The Ottawa Risk of Bias Assessment facilitated evaluation. RESULTS: Fifteen studies were reviewed in detail with nine affected cohorts pooled and compared against the gnomAD v4.0 CNV control cohort of 269,885 individuals. Several CNVs previously associated with non-statistically significant penetrance estimates now exhibit statistically significant differences, contributing to emerging evidence for their pathogenicity (15q24 duplication [A-D breakpoints], 15q24.2q24.5 deletion and duplication (FBXO22), 17q11.2 duplication (NF1), 17q21.31 duplication (KANSL1) and 22q11.2 distal duplication). Additionally, evidence is presented for the benign nature of some CNVs (15q11.2 duplication (NIPA1) and 2q13 proximal duplication (NPHP1)). CONCLUSION: This is a large-scale systematic review of CNVs associated with neurodevelopment. A synopsis analysing penetrance and pathogenicity is provided for each of the 83 recurrent CNVs.
