Systematic evaluation of incomplete penetrance in 4,325 rare disease families reveals divergent transcriptional networks in CHD8 pathology
Abstract
INTRODUCTIONDespite 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 METHODSWe 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.
RESULTSWe 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.
DISCUSSIONThis 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.
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BibTeX
@misc{singh2026systematic,
title = {{Systematic evaluation of incomplete penetrance in 4,325 rare disease families reveals divergent transcriptional networks in CHD8 pathology}},
author = {M. Singh and S. L. Stenton and E. Groopman and M. Singer-Berk and J. Ma and S. Choufani and E. O'Heir and S. DiTroia and I. Osei-Owusu and L. Pais and G. Lemire and M. O'Leary and C. Austin-Tse and C. A. Genetti and K. N. Anderson and M. H. Wojcik and A. H. Beggs and J. E. Neil and A. Lai and C. A. Walsh and J. A. Jurgens and B. J. Barry and E. C. Engle and S. Donkervoort and C. G. Bonnemann and E. Argilli and E. H. Sherr and P. Kipkemoi and Z. Bruwer and K. A. Donald and V. Straub and A. Topf and S. M. White and T. Y. Tan and L. Gallacher and P. Arts and M. R. Jackson and T. T. Ha and C. P. Barnett and A. B. Byrne and H. S. Scott and V. S. Ganesh and H. L. Rehm and R Weksberg},
howpublished = {medRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.05.26364218},
url = {https://www.medrxiv.org/content/10.64898/2026.10.05.26364218v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Systematic evaluation of incomplete penetrance in 4,325 rare disease families reveals divergent transcriptional networks in CHD8 pathology
AU - M. Singh
AU - S. L. Stenton
AU - E. Groopman
AU - M. Singer-Berk
AU - J. Ma
AU - S. Choufani
AU - E. O'Heir
AU - S. DiTroia
AU - I. Osei-Owusu
AU - L. Pais
AU - G. Lemire
AU - M. O'Leary
AU - C. Austin-Tse
AU - C. A. Genetti
AU - K. N. Anderson
AU - M. H. Wojcik
AU - A. H. Beggs
AU - J. E. Neil
AU - A. Lai
AU - C. A. Walsh
AU - J. A. Jurgens
AU - B. J. Barry
AU - E. C. Engle
AU - S. Donkervoort
AU - C. G. Bonnemann
AU - E. Argilli
AU - E. H. Sherr
AU - P. Kipkemoi
AU - Z. Bruwer
AU - K. A. Donald
AU - V. Straub
AU - A. Topf
AU - S. M. White
AU - T. Y. Tan
AU - L. Gallacher
AU - P. Arts
AU - M. R. Jackson
AU - T. T. Ha
AU - C. P. Barnett
AU - A. B. Byrne
AU - H. S. Scott
AU - V. S. Ganesh
AU - H. L. Rehm
AU - R Weksberg
PY - 2026
DA - 2026/10/05
PB - medRxiv
DO - 10.64898/2026.10.05.26364218
UR - https://www.medrxiv.org/content/10.64898/2026.10.05.26364218v1
AB - INTRODUCTIONDespite 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 METHODSWe 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. RESULTSWe 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. DISCUSSIONThis 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.
ER -