RT Journal
A1 Vervoort, Lisanne
A1 Dierckxsens, Nicolas
A1 Sousa Santos, Marta
A1 Meynants, Senne
A1 Souche, Erika
A1 Cools, Ruben
A1 Heung, Tracy
A1 Devriendt, Koen
A1 Peeters, Hilde
A1 McDonald-McGinn, Donna M.
A1 Swillen, Ann
A1 Breckpot, Jeroen
A1 Emanuel, Beverly S.
A1 Van Esch, Hilde
A1 Bassett, Anne S.
A1 Vermeesch, Joris R.
T1 Multiple paralogs and recombination mechanisms contribute to the high incidence of 22q11.2 deletion syndrome
JF Genome Research 
JO Genome Research 
YR 2025 
FD April 01 
VO 35 
IS 4 
SP 786 
OP 797 
DO 10.1101/gr.279331.124 
UL http://genome.cshlp.org/content/35/4/786.abstract 
AB 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.