Refining the 22q11.2 deletion breakpoints in DiGeorge syndrome by aCGH

Abstract

Hemizygous deletions of the chromosome 22q11.2 region result in the 22q11.2 deletion syndrome also referred to as DiGeorge, Velocardiofacial or Shprintzen syndromes. The phenotype is variable but commonly includes conotruncal cardiac defects, palatal abnormalities, learning and behavioral problems, immune deficiency, and facial anomalies. Four distinct highly homologous blocks of low copy number repeat sequences (LCRs) flank the deletion region. Mispairing of LCRs during meiosis with unequal meiotic exchange is assumed to cause the recurrent and consistent deletions. The proximal LCR is reportedly located at 22q11.2 from 17.037 to 17.083 Mb while the distal LCR is located from 19.835 to 19.880 Mb. Although the chromosome breakpoints are thought to localize to the LCRs, the positions of the breakpoints have been investigated in only a few individuals. Therefore, we used high resolution oligonucleotide-based 244K microarray comparative genomic hybridization (aCGH) to resolve the breakpoints in a cohort of 20 subjects with known 22q11.2 deletions. We also investigated copy number variation (CNV) in the rest of the genome. The 22q11.2 breaks occurred on either side of the LCR in our subjects, although more commonly on the distal side of the reported proximal LCR. The proximal breakpoints in our subjects spanned the region from 17.036 to 17.398 Mb. This region includes the genes DGCR6 (DiGeorge syndrome critical region protein 6) and PRODH (proline dehydrogenase 1), along with three open reading frames that may encode proteins of unknown function. The distal breakpoints spanned the region from 19.788 to 20.122 Mb. This region includes the genes GGT2 (gamma-glutamyltransferase-like protein 2), HIC2 (hypermethylated in cancer 2), and multiple transcripts of unknown function. The genes in these two breakpoint regions are variably hemizygous depending on the location of the breakpoints. Our 20 subjects had 254 CNVs throughout the genome, 94 duplications and 160 deletions, ranging in size from 1 kb to 2.4 Mb. The presence or absence of genes at the breakpoints depending on the size of the deletion plus variation in the rest of the genome due to CNVs likely contribute to the variable phenotype associated with the 22q11.2 deletion or DiGeorge syndrome.

Identification of Copy Number Variants on Human Chromosome 22 in Patients with a Variety of Clinical Findings

“…The deleted sizes of LCR22A-D in cases 2-9 fall into 2 subcategories, 2.57 or 2.80 Mb ( table 1 ), consistent with our previous observation in 20 individuals containing LCR22A-D deletions [Bittel et al, 2009]. These LCR22A-D deletions share the same distal breakpoints at LCR22D, but vary slightly at the proximal breakpoints within LCR22A spanning an ϳ 498-kb region encompassing PRODH, USP18, GGT3P, TSSK2, GSC2 , and multiple members of the DiGeorge syndrome critical region genes, including DGCR6 (online suppl.…”

A French multicenter study of over 700 patients with 22q11 deletions diagnosed using FISH or aCGH

“…In all cases other than patient 15, the deletion involved the LCR22-A. All of these deletions overlapped with the proximal variable region described by Bittel et al 41 (chr22: 18 656 078-19 018 178). In contrast, the distal breakpoint was more variable; in view of our small series, no conclusions could be reached.…”

A patient with a de novo distal 22q11.2 microdeletion and anxiety disorder

“…Four distal low copy repeats (LCR) were identified and were designated as LCR-E to LCR-H [Shaikh et al, 2007]. These LCRs appeared to be located at 22q11.2 from 20.654 to 23.215 Mb (NCBI Build 36), whereas the proximal LCRs (LCR-A to LCR-D) that are included in the common $3 Mb region, are reportedly located from 17.310 to 20.241 Mb [Jalali et al, 2008;Bittel et al, 2009]. Saitta et al [2004] and Coppinger et al [2009] suggested that LCRs on 22q11.2 mediate non-allelic homologous recombination resulting in rearrangements of 22q.…”