Mode of inheritance needs to be accounted for in interpreting genotype-phenotype links in monogenic disorders

Introduction A recently published study by Ke et al . utilized whole exome sequencing (WES) to screen genetic variants contributing to premature ovarian insufficiency (POI) in a large cohort of 1,030 patients from China (doi: 10.1038/s41591-022-02194-3). The authors reported that 285 likely pathogenic (LP) and pathogenic (P) variants identified in 79 genes contributed to POI in 242 study subjects, representing 23.5% of the cohort. The majority, 191 patients (∼79%), carried monoallelic (heterozygous) variants. Objective We re-analyzed the contribution of reported genotypes considering the inheritance mode of POI and other inherited conditions linked to 79 genes with reported findings by Ke et al . Methods The disease inheritance modes linked to targeted genes were retrieved from publicly available databases (OMIM, Genomic England PanelApp, PubMed, DOMINO, gnomAD). Genotypes of 242 cases reported by Ke et al. were assessed in the context of known inheritance mode(s) of disorders linked to respective genes. Results Most, 48 of 79 genes were classified as recessive, whereas only 13 genes were dominant. Insufficient data was available for 18 genes to conclusively determine their inheritance mode. Nearly half of 242 cases reported by Ke et al ., 119 women (∼49%), carried heterozygous variants in known autosomal recessive genes and therefore these variants are not contributing to their POI phenotype. Only 68 of women (6.6%) carried biallelic variants in either recessive or dominant genes or monoallelic variants in dominant genes, hence contributing to the diagnostic yield. This is ∼3.5-fold lower than 23.5% claimed in Ke et al . Additional 56 women (5.4%) were reported monoallelic variants in genes with insufficient data to determine the inheritance mode or multiple heterozygous variants in >1 recessive gene, whereby oligogenic contribution to POI cannot be excluded. But when even including these cases, the maximum estimated contributing yield is ∼12%, two times lower than claimed. Conclusion Using WES to screen monogenic causes of POI as part of the diagnostic pipeline will improve patient management strategies, but overestimated diagnostic yield in genetic research can create unrealistic expectations in the POI clinical community, typically non-specialist in genetics. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement ARE is supported by National Institutes of Health of the United States of America grants R01HD078641 and P50HD096723, and CKW by R01HD099487. ML is supported by Estonian Research Agency grant PRG1021. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present work are contained in the manuscript.