Dataset Information

Enhanced maternal origin of the 22q11.2 deletion in velocardiofacial and DiGeorge syndromes.

ABSTRACT: Velocardiofacial and DiGeorge syndromes, also known as 22q11.2 deletion syndrome (22q11DS), are congenital-anomaly disorders caused by a de novo hemizygous 22q11.2 deletion mediated by meiotic nonallelic homologous recombination events between low-copy repeats, also known as segmental duplications. Although previous studies exist, each was of small size, and it remains to be determined whether there are parent-of-origin biases for the de novo 22q11.2 deletion. To address this question, we genotyped a total of 389 DNA samples from 22q11DS-affected families. A total of 219 (56%) individuals with 22q11DS had maternal origin and 170 (44%) had paternal origin of the de novo deletion, which represents a statistically significant bias for maternal origin (p = 0.0151). Combined with many smaller, previous studies, 465 (57%) individuals had maternal origin and 345 (43%) had paternal origin, amounting to a ratio of 1.35 or a 35% increase in maternal compared to paternal origin (p = 0.000028). Among 1,892 probands with the de novo 22q11.2 deletion, the average maternal age at time of conception was 29.5, and this is similar to data for the general population in individual countries. Of interest, the female recombination rate in the 22q11.2 region was about 1.6-1.7 times greater than that for males, suggesting that for this region in the genome, enhanced meiotic recombination rates, as well as other as-of-yet undefined 22q11.2-specific features, could be responsible for the observed excess in maternal origin.

SUBMITTER: Delio M

PROVIDER: S-EPMC3591861 | biostudies-literature | 2013 Mar

REPOSITORIES: biostudies-literature

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Enhanced maternal origin of the 22q11.2 deletion in velocardiofacial and DiGeorge syndromes.

Delio Maria M Guo Tingwei T McDonald-McGinn Donna M DM Zackai Elaine E Herman Sean S Kaminetzky Mark M Higgins Anne Marie AM Coleman Karlene K Chow Carolyn C Jalbrzikowski Maria M Bearden Carrie E CE Bailey Alice A Vangkilde Anders A Olsen Line L Olesen Charlotte C Skovby Flemming F Werge Thomas M TM Templin Ludivine L Busa Tiffany T Philip Nicole N Swillen Ann A Vermeesch Joris R JR Devriendt Koen K Schneider Maude M Dahoun Sophie S Eliez Stephan S Schoch Kelly K Hooper Stephen R SR Shashi Vandana V Samanich Joy J Marion Robert R van Amelsvoort Therese T Boot Erik E Klaassen Petra P Duijff Sasja N SN Vorstman Jacob J Yuen Tracy T Silversides Candice C Chow Eva E Bassett Anne A Frisch Amos A Weizman Abraham A Gothelf Doron D Niarchou Maria M van den Bree Marianne M Owen Michael J MJ Suñer Damian Heine DH Andreo Jordi Rosell JR Armando Marco M Vicari Stefano S Digilio Maria Cristina MC Auton Adam A Kates Wendy R WR Wang Tao T Shprintzen Robert J RJ Emanuel Beverly S BS Morrow Bernice E BE

American journal of human genetics 20130228 3

Velocardiofacial and DiGeorge syndromes, also known as 22q11.2 deletion syndrome (22q11DS), are congenital-anomaly disorders caused by a de novo hemizygous 22q11.2 deletion mediated by meiotic nonallelic homologous recombination events between low-copy repeats, also known as segmental duplications. Although previous studies exist, each was of small size, and it remains to be determined whether there are parent-of-origin biases for the de novo 22q11.2 deletion. To address this question, we genoty ...[more]

PMID: 23453669

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Project description: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.

Dataset Information

Enhanced maternal origin of the 22q11.2 deletion in velocardiofacial and DiGeorge syndromes.

Publications

Enhanced maternal origin of the 22q11.2 deletion in velocardiofacial and DiGeorge syndromes.

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