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

Alistair T Pagnamenta, 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, Fiona Lalloo, Adrian Waite, Julie Evans, Zoe Allen, Cristina Perez-Becerril, Rachel Hart, John TaylorTina Bedenham, Emma Clement, Ed Blair, Eleanor Hay, Francesca Forzano, Natalie Canham, Anirban Majumdar, Meriel McEntagart, Nayana Lahiri, Helen Stewart, 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, 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

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)1140-1164
Number of pages25
JournalAmerican Journal of Human Genetics
Volume111
Issue number6
Early online date16 May 2024
DOIs
Publication statusPublished - 6 Jun 2024

Keywords

  • APC
  • HOXD cluster
  • MECP2
  • MSH2
  • PacBio
  • RNA-seq
  • complex rearrangement
  • founder mutation
  • genome sequencing
  • inversion

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