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Hum Mol Genet. 2018 Apr 1;27(7):1150-1163. doi: 10.1093/hmg/ddy028.

Deletion size analysis of 1680 22q11.2DS subjects identifies a new recombination hotspot on chromosome 22q11.2.

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Department of Genetics, Albert Einstein College of Medicine, Bronx, NY, USA.
Division of Human Genetics, Children's Hospital of Philadelphia and Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA.
Center for Human Genetics, Katholieke University Leuven (KULeuven), Leuven, Belgium.
Department of Neurology, Albert Einstein College of Medicine, Bronx, NY, USA.
Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY, USA.
Department of Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience and Human Behavior, University of California at Los Angeles, Los Angeles, CA, USA.
Department of Psychiatry and Behavioral Sciences, and Program in Neuroscience, SUNY Upstate Medical University, Syracuse, NY, USA.
Sackler Faculty of Medicine and Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel.
Felsenstein Medical Research Center, Sackler Faculty of Medicine, Tel Aviv University, Petah Tikva, Israel.
Developmental Imaging and Psychopathology Lab, University of Geneva School of Medicine, Geneva, Switzerland.
Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands.
Center for Genetics and Genomics, Facultad de Medicina, Clinica Alemana Universidad del Desarrollo, Santiago, Chile.
Center for Addiction and Mental Health, Toronto General Hospital and the University of Toronto, Toronto, Canada.
Department of Pediatric Laboratory Medicine and Laboratory of Medicine and Pathobiology, The Hospital for Sick Children and University of Toronto, Toronto, Canada.


Recurrent, de novo, meiotic non-allelic homologous recombination events between low copy repeats, termed LCR22s, leads to the 22q11.2 deletion syndrome (22q11.2DS; velo-cardio-facial syndrome/DiGeorge syndrome). Although most 22q11.2DS patients have a similar sized 3 million base pair (Mb), LCR22A-D deletion, some have nested LCR22A-B or LCR22A-C deletions. Our goal is to identify additional recurrent 22q11.2 deletions associated with 22q11.2DS, serving as recombination hotspots for meiotic chromosomal rearrangements. Here, using data from Affymetrix 6.0 microarrays on 1680 22q11.2DS subjects, we identified what appeared to be a nested proximal 22q11.2 deletion in 38 (2.3%) of them. Using molecular and haplotype analyses from 14 subjects and their parent(s) with available DNA, we found essentially three types of scenarios to explain this observation. In eight subjects, the proximal breakpoints occurred in a small sized 12 kb LCR distal to LCR22A, referred to LCR22A+, resulting in LCR22A+-B or LCR22A+-D deletions. Six of these eight subjects had a nested 22q11.2 deletion that occurred during meiosis in a parent carrying a benign 0.2 Mb duplication of the LCR22A-LCR22A+ region with a breakpoint in LCR22A+. Another six had a typical de novo LCR22A-D deletion on one allele and inherited the LCR22A-A+ duplication from the other parent thus appearing on microarrays to have a nested deletion. LCR22A+ maps to an evolutionary breakpoint between mice and humans and appears to serve as a local hotspot for chromosome rearrangements on 22q11.2.

[Available on 2019-04-01]
[Indexed for MEDLINE]

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