Systematic evaluation of incomplete penetrance in 4,325 rare disease families reveals divergent transcriptional networks in CHD8 pathology
Year: 2026
Type: preprint
Study design: Observational Study
Abstract: INTRODUCTION Despite major advances in genomic sequencing and analytical pipelines for rare disorders, more than 50% of affected individuals remain without a molecular diagnosis. One challenge is the interpretation of inherited variants exhibiting incomplete penetrance (IP). MATERIALS AND METHODS We developed a pipeline to systematically investigate inherited variants as the cause of rare disease in 4,325 families, consisting of affected probands and unaffected parents, from the Broad Center for Mendelian Genomics, part of the GREGoR Consortium. As a proof-of-concept of further omics follow-up, epigenomic and transcriptomic analyses were performed in one family harboring an inherited disease-causing frameshift variant in CHD8 . RESULTS We identified 81 families where the affected proband harbored a putative disease-causing variant inherited from a reportedly unaffected parent. Clinical re-evaluation identified 30 families in which an inherited variant was considered diagnostic, including six previously missed diagnoses. In this cohort, inherited IP variants account for 1.6% of the diagnosed cases, with an overall diagnostic yield of 0.4% in the cohort. Methylation analysis of the CHD8 family confirmed a positive CHD8 clinical episignature in the male proband, but also in the reportedly unaffected mother. Transcriptomic analysis showed that despite similar CHD8 haploinsufficiency, the proband and mother displayed divergent downstream transcriptional effects. DISCUSSION This study highlights the importance of considering parentally inherited IP variants in rare disease, with at least 1 in 60 diagnostic variants inherited from a reportedly unaffected parent, and demonstrates the potential of integrating omics evaluation to improve variant interpretation.
Source: medRxiv
Authors: Mugdha Singh, Sarah L. Stenton, Emily Groopman, Moriel Singer-Berk, Jialan Ma, Sanaa Choufani, Emily O’Heir, Stephanie DiTroia, Ikeoluwa Osei-Owusu, Lynn Pais, Gabrielle Lemire, Melanie O’Leary, Christina Austin-Tse, Casie A. Genetti, Katherine N. Anderson, Monica H. Wojcik, Alan H. Beggs, Jennifer E. Neil, Abbe Lai, Christopher A. Walsh, Julie A. Jurgens, Brenda J. Barry, Elizabeth C. Engle, Sandra Donkervoort, Carsten G. Bönnemann, Emanuela Argilli, Elliott H. Sherr, Patricia Kipkemoi, Zandre Bruwer, Kirsten A. Donald, Volker Straub, Ana Topf, Susan M. White, Tiong Yang Tan, Lyndon Gallacher, Peers Arts, Matilda R. Jackson, Thuong T. Ha, Christopher P. Barnett, Alicia B. Byrne, Hamish S. Scott, Vijay S. Ganesh, Heidi L. Rehm, Rosanna Weksberg, Anne O’Donnell-Luria, Sanna Gudmundsson
Institutions: Broad Institute, Boston Children's Hospital, Harvard University, Massachusetts General Hospital, Manton Center for Orphan Disease Research, Hospital for Sick Children, Howard Hughes Medical Institute, National Institutes of Health, National Institute of Neurological Disorders and Stroke, University of California, San Francisco, Kenya Medical Research Institute, Aga Khan University Nairobi, KEMRI-Wellcome Trust Research Programme, University of Cape Town, Red Cross War Memorial Children's Hospital, Groote Schuur Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle University, The University of Melbourne, Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Maastricht University Medical Centre, South Australia Pathology, Centre for Cancer Biology, Adelaide University, The University of Adelaide, Women's and Children's Hospital, Mass General Brigham, Karolinska University Hospital, Karolinska Institutet
Language: English
Topic: Genomics and Rare Diseases
Subfield: Genetics
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7220945258