Year: 2026
Type: preprint
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.
Source: medRxiv
Institutions: King's College London, South London and Maudsley NHS Foundation Trust, National Institute for Health and Care Research, NIHR Maudsley Biomedical Research Centre, Guy's Hospital, St Thomas' Hospital, Guy's and St Thomas' NHS Foundation Trust, University Medical Center Hamburg-Eppendorf, University of Bonn, University Hospital Bonn, Aarhus University, Centre National de la Recherche Scientifique, Inserm, Institut Pasteur, Université Paris Cité, Gènes, synapses et cognition, NeuroDiderot, McGill University, Max Planck Institute of Psychiatry, Institut für Psychiatrische Phänomik und Genomik, Ludwig-Maximilians-Universität München, Cardiff and Vale University Health Board, Aarhus University Hospital, Amsterdam Public Health, Amsterdam University Medical Centers, Vrije Universiteit Amsterdam, Karolinska Institutet, Cardiff University
Language: English
Topic: Genomics and Rare Diseases
Subfield: Genetics
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7221675567