Multiple paralogs and recombination mechanisms contribute to the high incidence of 22q11.2 deletion syndrome
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.
Authors
- Nicolas Dierckxsens (ORCID: https://orcid.org/0000-0001-8051-6602)
- Lisanne Vervoort (ORCID: https://orcid.org/0000-0002-0805-8149)
- Jeroen Breckpot (ORCID: https://orcid.org/0000-0002-0734-5154)
- Beverly S. Emanuel (ORCID: https://orcid.org/0000-0002-9207-6955)
- Erika L. Souche (ORCID: https://orcid.org/0000-0001-9184-445X)
- Donna M. McDonald‐McGinn (ORCID: https://orcid.org/0000-0003-4077-250X)
- Tracy Heung (ORCID: https://orcid.org/0000-0003-1860-7292)
- Hilde Van Esch (ORCID: https://orcid.org/0000-0002-9604-5726)
- Koenraad Devriendt (ORCID: https://orcid.org/0000-0002-3651-2548)
- Joris Robert Vermeesch (ORCID: https://orcid.org/0000-0002-3071-1191)
- Ann Swillen (ORCID: https://orcid.org/0000-0003-4258-4537)
- Anne S. Bassett (ORCID: https://orcid.org/0000-0002-0681-7279)
- Hilde Peeters (ORCID: https://orcid.org/0000-0002-7295-3375)
- Senne Meynants
- Marta Sousa Santos (ORCID: https://orcid.org/0000-0002-0974-1724)
- Ruben Cools (ORCID: https://orcid.org/0009-0004-7484-5564)
Institutions
- Children's Hospital of Philadelphia (US)
- Centre for Addiction and Mental Health (CA)
- Okinawa Institute of Science and Technology Graduate University (JP)
- Knowledge Unlatched (Germany) (DE)
- Center for Human Genetics (US)
- University of Pennsylvania (US)
- Sapienza University of Rome (IT)
- KU Leuven (BE)
Publication Details
- Journal
- Genome Research
- Published
- 2024-11-13
- DOI
- https://doi.org/10.1101/gr.279331.124
- Citations
- 3
- Primary Topic
- Congenital heart defects research
- Type
- article
Funders
- Fonds Wetenschappelijk Onderzoek
- KU Leuven
- National Institute of General Medical Sciences