The impact of inversions across 33,924 families with rare disease from a national genome sequencing project

• DOI: 10.1016/j.ajhg.2024.04.018
• Publication Date: 2024-05-21T15:05:45Z
• Authors: Alistair T. Pagna...; Jing Yu; Susan Walker; Alexandra J. Noble; Jenny Lord; Prasun Dutta; Mona Hashim; Carme Camps; Hannah Green; Smrithi Devaiah; Lina Nashef; Jason Parr; Carl Fratter; Rana Ibnouf Hussein; Sarah J. Lindsay; Fiona Lalloo; Benito Banos-Pinero; David Evans; Lucy Mallin; Adrian Waite; Julie Evans; Andrew Newman; Zoe Allen; Cristina Perez-Be...; Gavin Ryan; Rachel Hart; John Taylor; Tina Bedenham; Emma Clement; Ed Blair; Eleanor Hay; Francesca Forzano; Jenny Higgs; Natalie Canham; Anirban Majumdar; Meriel McEntagart; Nayana Lahiri; Helen Stewart; Sarah Smithson; Eduardo Calpena; Adam Jackson; Siddharth Banka; Hannah Titheradge; Ruth McGowan; Julia Rankin; Charles Shaw-Smith; D. Gareth Evans; George J. Burghel; Miriam J. Smith; Emily Anderson; Rajesh Madhu; Helen Firth; Sian Ellard; Paul Brennan; Claire Anderson; Doug Taupin; Mark T. Rogers; Jackie A. Cook; Miranda Durkie; James E. East; Darren Fowler; Louise Wilson; Rebecca Igbokwe; Alice Gardham; Ian Tomlinson; Diana Baralle; Holm H. Uhlig; Jenny C. Taylor
• Keywords: Male; *Chromosome Inversion/genetics; DYSPLASIA KANTAPUTRA TYPE; Methyl-CpG-Binding Protein 2/genetics; 610; STRUCTURAL VARIANTS; Article; inversion; 03 medical and health sciences; *Rare Diseases/genetics; Humans; PARACENTRIC INVERSION; Mecp2; PacBio; 0303 health sciences; Genome; Whole Genome Sequencing; MESOMELIC DYSPLASIA; MUTATIONS; LYNCH SYNDROME; REARRANGEMENTS; Middle Aged; GENE; Pedigree; Apc; Msh2; APC; MECP2; MSH2; genome sequencing; complex rearrangement; Mutation; founder mutation; Female; Homeodomain Proteins/genetics; RNA-seq; GENOMICS; Human; HOXD cluster

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.