Multiple paralogs and recombination mechanisms contribute to the high incidence of 22q11.2 deletion syndrome.
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| Format: | Artículo científico |
| Language: | en |
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Genome research
2025
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| author | Vervoort, Lisanne Dierckxsens, Nicolas Sousa Santos, Marta Meynants, Senne Souche, Erika Cools, Ruben Heung, Tracy Devriendt, Koen Peeters, Hilde McDonald-McGinn, Donna M Swillen, Ann Breckpot, Jeroen Emanuel, Beverly S Van Esch, Hilde Bassett, Anne S Vermeesch, Joris R |
| author_facet | Vervoort, Lisanne Dierckxsens, Nicolas Sousa Santos, Marta Meynants, Senne Souche, Erika Cools, Ruben Heung, Tracy Devriendt, Koen Peeters, Hilde McDonald-McGinn, Donna M Swillen, Ann Breckpot, Jeroen Emanuel, Beverly S Van Esch, Hilde Bassett, Anne S Vermeesch, Joris R Vervoort, Lisanne Dierckxsens, Nicolas Sousa Santos, Marta Meynants, Senne Souche, Erika Cools, Ruben Heung, Tracy Devriendt, Koen Peeters, Hilde McDonald-McGinn, Donna M Swillen, Ann Breckpot, Jeroen Emanuel, Beverly S Van Esch, Hilde Bassett, Anne S Vermeesch, Joris R |
| collection | PubMed - marine biology |
| contents | Multiple paralogs and recombination mechanisms contribute to the high incidence of 22q11.2 deletion syndrome. Vervoort, Lisanne Dierckxsens, Nicolas Sousa Santos, Marta Meynants, Senne Souche, Erika Cools, Ruben Heung, Tracy Devriendt, Koen Peeters, Hilde McDonald-McGinn, Donna M Swillen, Ann Breckpot, Jeroen Emanuel, Beverly S Van Esch, Hilde Bassett, Anne S Vermeesch, Joris R Humans DiGeorge Syndrome Chromosomes, Human, Pair 22 Segmental Duplications, Genomic Recombination, Genetic Homologous Recombination Incidence Haplotypes Male In Situ Hybridization, Fluorescence Female 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. |
| format | Artículo científico |
| id | pubmed_39537358 |
| institution | PubMed |
| language | en |
| publishDate | 2025 |
| publisher | Genome research |
| record_format | pubmed |
| spellingShingle | Multiple paralogs and recombination mechanisms contribute to the high incidence of 22q11.2 deletion syndrome. Vervoort, Lisanne Dierckxsens, Nicolas Sousa Santos, Marta Meynants, Senne Souche, Erika Cools, Ruben Heung, Tracy Devriendt, Koen Peeters, Hilde McDonald-McGinn, Donna M Swillen, Ann Breckpot, Jeroen Emanuel, Beverly S Van Esch, Hilde Bassett, Anne S Vermeesch, Joris R Humans DiGeorge Syndrome Chromosomes, Human, Pair 22 Segmental Duplications, Genomic Recombination, Genetic Homologous Recombination Incidence Haplotypes Male In Situ Hybridization, Fluorescence Female Multiple paralogs and recombination mechanisms contribute to the high incidence of 22q11.2 deletion syndrome. Vervoort, Lisanne Dierckxsens, Nicolas Sousa Santos, Marta Meynants, Senne Souche, Erika Cools, Ruben Heung, Tracy Devriendt, Koen Peeters, Hilde McDonald-McGinn, Donna M Swillen, Ann Breckpot, Jeroen Emanuel, Beverly S Van Esch, Hilde Bassett, Anne S Vermeesch, Joris R Humans DiGeorge Syndrome Chromosomes, Human, Pair 22 Segmental Duplications, Genomic Recombination, Genetic Homologous Recombination Incidence Haplotypes Male In Situ Hybridization, Fluorescence Female 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. |
| title | Multiple paralogs and recombination mechanisms contribute to the high incidence of 22q11.2 deletion syndrome. |
| topic | Humans DiGeorge Syndrome Chromosomes, Human, Pair 22 Segmental Duplications, Genomic Recombination, Genetic Homologous Recombination Incidence Haplotypes Male In Situ Hybridization, Fluorescence Female |
| url | https://pubmed.ncbi.nlm.nih.gov/39537358/ |