Browsing by Author "Nomaru, Hiroko"
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Item Deletion size analysis of 1680 22q11.2DS subjects identifies a new recombination hotspot on chromosome 22q11.2(2018) Guo, Tingwei; Diacou, Alexander; Nomaru, Hiroko; McDonald-McGinn, Donna M.; Hestand, Matthew; Demaerel, Wolfram; Zhang, Liangtian; Zhao, Yingjie; Ujueta, Francisco; Shan, Jidong; Montagna, Cristina; Zheng, Deyou; Crowley, Terrence B.; Kushan-Wells, Leila; Bearden, Carrie E.; Kates, Wendy R.; Gothelf, Doron; Schneider, Maude; Eliez, Stephan; Breckpot, Jeroen; Swillen, Ann; Vorstman, Jacob; Zackai, Elaine; Benavides, Felipe; Repetto, Gabriela; Emanuel, Beverly S.; Bassett, Anne S.; Vermeesch, Joris R.; Marshall, Christian R.; Morrow, Bernice E.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 LCR22Aþ, resulting in LCR22Aþ-B or LCR22Aþ-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-LCR22Aþregion with a breakpoint in LCR22Aþ. Another six had a typical de novo LCR22A-D deletion on one allele and inherited the LCR22A-Aþduplication from the other parent thus appearing on microarrays to have a nested deletion. LCR22Aþmaps to an evolutionary breakpoint between mice and humans and appears to serve as a local hotspot for chromosome rearrangements on 22q11.2.Item Genome-Wide Association Study to Find Modifiers for Tetralogy of Fallot in the 22q11.2 Deletion Syndrome Identifies Variants in the GPR98 Locus on 5q14.3(Lippincott Williams & Wilkins, 2017) Guo, Tingwei; Repetto, Gabriela; McDonald, Donna; Chung, Jonathan; Nomaru, Hiroko; Campbell, Christopher; Blonska, Anna; Bassett, Anne; Chow, Eva; Mlynarski, Elisabeth; Swillen, Ann; Vermeesch, Joris; Devriendt, Koen; Gothelf, Doron; Carmel, Miri; Michaelovsky, Elena; Schneider, Maude; Eliez, Stephan; Antonarakis, Stylianos; Coleman, Karlene; Tomita, Aoy; Mitchell, Michael; Digilio, Cristina; Dallapiccola, Bruno; Marino, Bruno; Philip, Nicole; Busa, Tiffany; Kushan, Leila; Bearden, Carrie; Piotrowicz, Małgorzata; Hawuła, Wanda; Roberts, Amy; Tassone, Flora; Simon, Tony; van Duin, Esther; van Amelsvoort, Thérèse; Kates, Wendy; Zackai, Elaine; Johnston, Richard; Cutler, David; Agopian, A; Goldmuntz, Elizabeth; Mitchell, Laura; Wang, Tao; Emanuel, Beverly; Morrow, Bernice; the International 22q11.2 Consortium/Brain and Behavior ConsortiumBACKGROUND: The 22q11.2 deletion syndrome (22q11.2DS; DiGeorge syndrome/velocardiofacial syndrome) occurs in 1 of 4000 live births, and 60% to 70% of affected individuals have congenital heart disease, ranging from mild to severe. In our cohort of 1472 subjects with 22q11.2DS, a total of 62% (n=906) have congenital heart disease and 36% (n=326) of these have tetralogy of Fallot (TOF), comprising the largest subset of severe congenital heart disease in the cohort. METHODS AND RESULTS: To identify common genetic variants associated with TOF in individuals with 22q11.2DS, we performed a genome-wide association study using Affymetrix 6.0 array and imputed genotype data. In our cohort, TOF was significantly associated with a genotyped single-nucleotide polymorphism (rs12519770, P=2.98×10-8) in an intron of the adhesion GPR98 (G-protein-coupled receptor V1) gene on chromosome 5q14.3. There was also suggestive evidence of association between TOF and several additional single-nucleotide polymorphisms in this region. Some genome-wide significant loci in introns or noncoding regions could affect regulation of genes nearby or at a distance. On the basis of this possibility, we examined existing Hi-C chromatin conformation data to identify genes that might be under shared transcriptional regulation within the region on 5q14.3. There are 6 genes in a topologically associated domain of chromatin with GPR98, including MEF2C (Myocyte-specific enhancer factor 2C). MEF2C is the only gene that is known to affect heart development in mammals and might be of interest with respect to 22q11.2DS. CONCLUSIONS: In conclusion, common variants may contribute to TOF in 22q11.2DS and may function in cardiac outflow tract development.