Multiple paralogues and recombination mechanisms contribute to the high incidence of 22q11.2 Deletion Syndrome
- Lisanne Vervoort1,
- Nicolas Dierckxsens2,
- Marta Sousa Santos1,
- Senne Meynants1,
- Erika Souche1,
- Ruben Cools1,
- Tracy Heung3,
- Koen Devriendt1,
- Hilde Peeters1,
- Donna McDonald-McGinn4,
- Ann Swillen1,
- Jeroen Breckpot1,
- Beverly S. Emanuel5,
- Hilde Van Esch1,
- Anne S. Bassett3 and
- Joris R. Vermeesch1,6
- 1 KU Leuven;
- 2 KU Leuven, Okinawa Institute of Science and Technology;
- 3 Centre for Addiction and Mental Health;
- 4 Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Sapienza University;
- 5 Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania
Abstract
The 22q11.2 deletion syndrome (22q11.2DS) is the most common microdeletion disorder. Why the incidence of 22q11.2DS is much greater than that of other genomic disorders remains unknown. Short read sequencing cannot resolve the complex segmental duplicon structure to provide direct confirmation of the hypothesis that the rearrangements are caused by nonallelic homologous recombination between the low copy repeats on Chromosome 22 (LCR22s). To enable haplotype-specific assembly and rearrangement mapping in LCR22 regions, we combined fiber-FISH optical mapping with whole genome (ultra-)long read sequencing or rearrangement-specific long-range PCR on 24 duos (22q11.2DS patient and parent-of-origin) comprising several different LCR22-mediated rearrangements. Unexpectedly, we demonstrate that not only different paralogous segmental duplicon but also palindromic AT-rich repeats (PATRR) are driving 22q11.2 rearrangements. In addition, we show the existence of two different inversion polymorphisms preceding rearrangement, and somatic mosaicism. The existence of different recombination sites and mechanisms in paralogues and PATRRs which are copy number expanding in the human population are a likely explanation for the high 22q11.2DS incidence.
- Received March 14, 2024.
- Accepted October 31, 2024.
- Published by Cold Spring Harbor Laboratory Press
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