Title | HMZDupFinder: a robust computational approach for detecting intragenic homozygous duplications from exome sequencing data. |
Publication Type | Journal Article |
Year of Publication | 2023 |
Authors | Du, H, Dardas, Z, Jolly, A, Grochowski, CM, Jhangiani, SN, Li, H, Muzny, DM, Fatih, JM, Yesil, G, Elcioglu, NH, Gezdirici, A, Marafi, D, Pehlivan, D, Calame, DG, Carvalho, CMB, Posey, JE, Gambin, T, Coban-Akdemir, Z, Lupski, JR |
Journal | Nucleic Acids Res |
Date Published | 2023 Dec 28 |
ISSN | 1362-4962 |
Abstract | Homozygous duplications contribute to genetic disease by altering gene dosage or disrupting gene regulation and can be more deleterious to organismal biology than heterozygous duplications. Intragenic exonic duplications can result in loss-of-function (LoF) or gain-of-function (GoF) alleles that when homozygosed, i.e. brought to homozygous state at a locus by identity by descent or state, could potentially result in autosomal recessive (AR) rare disease traits. However, the detection and functional interpretation of homozygous duplications from exome sequencing data remains a challenge. We developed a framework algorithm, HMZDupFinder, that is designed to detect exonic homozygous duplications from exome sequencing (ES) data. The HMZDupFinder algorithm can efficiently process large datasets and accurately identifies small intragenic duplications, including those associated with rare disease traits. HMZDupFinder called 965 homozygous duplications with three or less exons from 8,707 ES with a recall rate of 70.9% and a precision of 16.1%. We experimentally confirmed 8/10 rare homozygous duplications. Pathogenicity assessment of these copy number variant alleles allowed clinical genomics contextualization for three homozygous duplications alleles, including two affecting known OMIM disease genes EDAR (MIM# 224900), TNNT1(MIM# 605355), and one variant in a novel candidate disease gene: PAAF1. |
DOI | 10.1093/nar/gkad1223 |
Alternate Journal | Nucleic Acids Res |
PubMed ID | 38153174 |
Grant List | UM1 HG006542 / HG / NHGRI NIH HHS / United States R35 NS105078 / NS / NINDS NIH HHS / United States 2023-0235 / DDCF / Doris Duke Charitable Foundation / United States R01 GM132589 / GM / NIGMS NIH HHS / United States U01 HG011758 / HG / NHGRI NIH HHS / United States |