Pagnamenta, A.T. orcid.org/0000-0001-7334-0602, Yu, J., Walker, S. et al. (65 more authors) (2024) The impact of inversions across 33,924 families with rare disease from a national genome sequencing project. The American Journal of Human Genetics, 111 (6). pp. 1140-1164. ISSN 0002-9297
Abstract
Detection of structural variants (SVs) is currently biased toward those that alter copy number. The relative contribution of inversions toward genetic disease is unclear. In this study, we analyzed genome sequencing data for 33,924 families with rare disease from the 100,000 Genomes Project. From a database hosting >500 million SVs, we focused on 351 genes where haploinsufficiency is a confirmed disease mechanism and identified 47 ultra-rare rearrangements that included an inversion (24 bp to 36.4 Mb, 20/47 de novo). Validation utilized a number of orthogonal approaches, including retrospective exome analysis. RNA-seq data supported the respective diagnoses for six participants. Phenotypic blending was apparent in four probands. Diagnostic odysseys were a common theme (>50 years for one individual), and targeted analysis for the specific gene had already been performed for 30% of these individuals but with no findings. We provide formal confirmation of a European founder origin for an intragenic MSH2 inversion. For two individuals with complex SVs involving the MECP2 mutational hotspot, ambiguous SV structures were resolved using long-read sequencing, influencing clinical interpretation. A de novo inversion of HOXD11-13 was uncovered in a family with Kantaputra-type mesomelic dysplasia. Lastly, a complex translocation disrupting APC and involving nine rearranged segments confirmed a clinical diagnosis for three family members and resolved a conundrum for a sibling with a single polyp. Overall, inversions play a small but notable role in rare disease, likely explaining the etiology in around 1/750 families across heterogeneous clinical cohorts.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2024 The Author(s). This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
Keywords: | APC; HOXD cluster; MECP2; MSH2; PacBio; RNA-seq; complex rearrangement; founder mutation; genome sequencing; inversion; Humans; Rare Diseases; Male; Female; Chromosome Inversion; Pedigree; Genome, Human; Whole Genome Sequencing; Methyl-CpG-Binding Protein 2; Mutation; Homeodomain Proteins; Middle Aged |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > School of Medicine and Population Health |
Funding Information: | Funder Grant number MEDICAL RESEARCH COUNCIL MR/W01761X/1 |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 28 Jun 2024 13:59 |
Last Modified: | 28 Jun 2024 13:59 |
Status: | Published |
Publisher: | Elsevier BV |
Refereed: | Yes |
Identification Number: | 10.1016/j.ajhg.2024.04.018 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:214063 |