TY - JOUR
T1 - Exploring penetrance of clinically relevant variants in over 800,000 humans from the Genome Aggregation Database
AU - Gudmundsson, Sanna
AU - Singer-Berk, Moriel
AU - Genome Aggregation Database Consortium
AU - Stenton, Sarah L.
AU - Goodrich, Julia K.
AU - Wilson, Michael W.
AU - Einson, Jonah
AU - Watts, Nicholas A.
AU - Lappalainen, Tuuli
AU - Rehm, Heidi L.
AU - MacArthur, Daniel G.
AU - O’Donnell-Luria , Anne
AU - Zhao, Xuefang
AU - Yolken, Robert
AU - Yohannes, Mary T.
AU - Xavier, Ramnik J.
AU - Witzgall, Lauren
AU - Wilson, James G.
AU - Whiffin, Nicola
AU - Whelan, Christopher
AU - Wessman, Maija
AU - Weisburd, Ben
AU - Weersma, Rinse K.
AU - Watkins, Hugh
AU - Ware, James S.
AU - Wang, Qingbo
AU - Wang, Lily
AU - Wang, Arcturus
AU - Walker, Mark
AU - Wade, Gordon
AU - Vittal, Christopher
AU - Vilella, Elisabet
AU - Vermeire, Severine
AU - Vawter, Marquis
AU - Vartiainen, Erkki
AU - Tusie-Luna, Teresa
AU - Turner, Dan
AU - Tuomi, Tiinamaija
AU - Tsuang, Ming
AU - Tolonen, Charlotte
AU - Tibbetts, Kathleen
AU - Tiao, Grace
AU - Teo, Yik Ying
AU - Taylor, Kent D.
AU - Tarasova, Yekaterina
AU - Talkowski, Michael E.
AU - Tai, E. Shyong
AU - Suvisaari, Jaana
AU - Sullivan, Patrick F.
AU - Stitziel, Nathan O.
AU - Stevens, Christine
AU - Posthuma, Danielle
AU - Ophoff, Roel
AU - Dupuis, Josée
AU - Chowdhury, Rajiv
N1 - Publisher Copyright:
© The Author(s) 2025.
PY - 2025/10/31
Y1 - 2025/10/31
N2 - Incomplete penetrance, or absence of disease phenotype in an individual with a disease-associated variant, is a major challenge in variant interpretation. Studying individuals with apparent incomplete penetrance can shed light on underlying drivers of altered phenotype penetrance. Here, we investigate clinically relevant variants from ClinVar in 807,162 individuals from the Genome Aggregation Database (gnomAD), demonstrating improved representation in gnomAD version 4. We then conduct a comprehensive case-by-case assessment of 734 predicted loss of function variants in 77 genes associated with severe, early-onset, highly penetrant haploinsufficient disease. Here, we identify explanations for the presumed lack of disease manifestation in 701 of 734 variants (95%). Individuals with unexplained lack of disease manifestation in this set of disorders are rare, underscoring the need and power of deep case-by-case assessment presented here to minimize false assignments of disease risk, particularly in unaffected individuals with higher rates of secondary properties that result in rescue.
AB - Incomplete penetrance, or absence of disease phenotype in an individual with a disease-associated variant, is a major challenge in variant interpretation. Studying individuals with apparent incomplete penetrance can shed light on underlying drivers of altered phenotype penetrance. Here, we investigate clinically relevant variants from ClinVar in 807,162 individuals from the Genome Aggregation Database (gnomAD), demonstrating improved representation in gnomAD version 4. We then conduct a comprehensive case-by-case assessment of 734 predicted loss of function variants in 77 genes associated with severe, early-onset, highly penetrant haploinsufficient disease. Here, we identify explanations for the presumed lack of disease manifestation in 701 of 734 variants (95%). Individuals with unexplained lack of disease manifestation in this set of disorders are rare, underscoring the need and power of deep case-by-case assessment presented here to minimize false assignments of disease risk, particularly in unaffected individuals with higher rates of secondary properties that result in rescue.
UR - https://www.scopus.com/pages/publications/105020652699
U2 - 10.1038/s41467-025-61698-x
DO - 10.1038/s41467-025-61698-x
M3 - Article
C2 - 41173899
AN - SCOPUS:105020652699
SN - 2041-1723
VL - 16
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 9623
ER -