Recalculated CNV penetrance: what it does and does not change for counselling

Abstract

Goh et al. recently reported that most recurrent copy number variants (CNVs) are far less penetrant for intellectual disability (ID) than previously estimated, and recommended that fourteen should no longer be reported. We show that the lower estimates arise mainly from assuming the population prevalence of ID alone, while case counts derive from broad diagnostic referral cohorts in which about half of individuals were referred for other indications. The proposed formula estimates a risk difference rather than penetrance, and cases and controls were selected, assayed and phenotyped differently. Restricting the outcome to ID also leaves the analysis unable to inform risk for autism, epilepsy, psychiatric, cardiac and other phenotypes. We recommend that families receive phenotype-specific absolute risks for carriers alongside background risks, and that reporting decisions be made locus by locus by guideline bodies, considering all relevant phenotypes. The recalculated estimates inform this debate but are not yet sufficient grounds for changing reporting practice.