Open AccessAtypical chromosome 22q11.2 deletions are complex rearrangements and have different mechanistic origins
Author(s) -
Lisanne Vervoort,
Wolfram Demaerel,
Laura Yissel Rengifo,
Adrian Odrzywolski,
Elfi Vergaelen,
Matthew S. Hestand,
Jeroen Breckpot,
Koen Devriendt,
Ann Swillen,
Donna M. McDonaldMcGinn,
Ania Fiksinski,
Janneke Zinkstok,
Bernice E. Morrow,
Tracy Heung,
Jacob Vorstman,
Anne S. Bassett,
Eva W.C. Chow,
Vandana Shashi,
Joris Robert Vermeesch
Publication year - 2019
Publication title -
human molecular genetics online/human molecular genetics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.811
H-Index - 276
eISSN - 1460-2083
pISSN - 0964-6906
DOI - 10.1093/hmg/ddz166
Subject(s) - biology , genetics , breakpoint , non allelic homologous recombination , homologous chromosome , homologous recombination , chromosomal inversion , allele , chromosome , chromosome 22 , genome , recombination , gene , genetic recombination , karyotype
The majority (99%) of individuals with 22q11.2 deletion syndrome (22q11.2DS) have a deletion that is caused by non-allelic homologous recombination between two of four low copy repeat clusters on chromosome 22q11.2 (LCR22s). However, in a small subset of patients, atypical deletions are observed with at least one deletion breakpoint within unique sequence between the LCR22s. The position of the chromosome breakpoints and the mechanisms driving those atypical deletions remain poorly studied. Our large-scale, whole genome sequencing study of >1500 subjects with 22q11.2DS identified six unrelated individuals with atypical deletions of different types. Using a combination of whole genome sequencing data and fiber-fluorescence in situ hybridization, we mapped the rearranged alleles in these subjects. In four of them, the distal breakpoints mapped within one of the LCR22s and we found that the deletions likely occurred by replication-based mechanisms. Interestingly, in two of them, an inversion probably preceded inter-chromosomal 'allelic' homologous recombination between differently oriented LCR22-D alleles. Inversion associated allelic homologous recombination (AHR) may well be a common mechanism driving (atypical) deletions on 22q11.2.