Multiple paralogs and recombination mechanisms contribute to the high incidence of 22q11.2 deletion syndrome
- Lisanne Vervoort1,
- Nicolas Dierckxsens1,2,
- Marta Sousa Santos1,
- Senne Meynants1,
- Erika Souche1,
- Ruben Cools1,
- Tracy Heung3,
- Koen Devriendt1,
- Hilde Peeters1,
- Donna M. McDonald-McGinn4,5,6,
- Ann Swillen1,
- Jeroen Breckpot1,
- Beverly S. Emanuel4,5,
- Hilde Van Esch1,
- Anne S. Bassett3 and
- Joris R. Vermeesch1
- 1Department of Human Genetics, KU Leuven, Leuven 3000, Belgium;
- 2Genomics and Regulatory Systems Unit & Marine Climate Change Unit, Okinawa Institute of Science and Technology Graduate University, Okinawa 904-0495, Japan;
- 3Clinical Genetics Research Program, Centre for Addiction and Mental Health, Toronto, Ontario M5T 1R8, Canada;
- 4Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA;
- 5Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;
- 6Department of Human Biology and Medical Genetics, Sapienza University, Rome 00185, Italy
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 duplications (SDs) 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 clusters, we combined fiber-FISH optical mapping with whole-genome (ultra-)long-read sequencing or rearrangement-specific long-range PCR on 25 families comprising several different LCR22-mediated rearrangements. We demonstrate that not only different paralogous SDs but also palindromic AT-rich repeats (PATRR) within LCR22s 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 paralogs and PATRRs, which are copy number expanding in the human population, is a likely contributor for the high 22q11.2DS incidence.
Footnotes
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[Supplemental material is available for this article.]
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Article published online before print. Article, supplemental material, and publication date are at https://www.genome.org/cgi/doi/10.1101/gr.279331.124.
- Received March 14, 2024.
- Accepted October 31, 2024.
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