TY - JOUR
T1 - Copy-number variation of the glucose transporter gene SLC2A3 and congenital heart defects in the 22q11.2 deletion syndrome
AU - Mlynarski, Elisabeth E.
AU - Sheridan, Molly B.
AU - Xie, Michael
AU - Guo, Tingwei
AU - Racedo, Silvia E.
AU - McDonald-Mcginn, Donna M.
AU - Gai, Xiaowu
AU - Chow, Eva W.C.
AU - Vorstman, Jacob
AU - Swillen, Ann
AU - Devriendt, Koen
AU - Breckpot, Jeroen
AU - Digilio, Maria Cristina
AU - Marino, Bruno
AU - Dallapiccola, Bruno
AU - Philip, Nicole
AU - Simon, Tony J.
AU - Roberts, Amy E.
AU - Piotrowicz, Małgorzata
AU - Bearden, Carrie E.
AU - Eliez, Stephan
AU - Gothelf, Doron
AU - Coleman, Karlene
AU - Kates, Wendy R.
AU - Devoto, Marcella
AU - Zackai, Elaine
AU - Heine-Suñer, Damian
AU - Shaikh, Tamim H.
AU - Bassett, Anne S.
AU - Goldmuntz, Elizabeth
AU - Morrow, Bernice E.
AU - Emanuel, Beverly S.
N1 - Publisher Copyright:
© 2015 by The American Society of Human Genetics. All rights reserved.
PY - 2015/5/7
Y1 - 2015/5/7
N2 - The 22q11.2 deletion syndrome (22q11DS; velocardiofacial/DiGeorge syndrome; VCFS/DGS) is the most common microdeletion syndrome and the phenotypic presentation is highly variable. Approximately 65% of individuals with 22q11DS have a congenital heart defect (CHD), mostly of the conotruncal type, and/or an aortic arch defect. The etiology of this phenotypic variability is not currently known. We hypothesized that copy-number variants (CNVs) outside the 22q11.2 deleted region might increase the risk of being born with a CHD in this sensitized population. Genotyping with Affymetrix SNP Array 6.0 was performed on two groups of subjects with 22q11DS separated by time of ascertainment and processing. CNV analysis was completed on a total of 949 subjects (cohort 1, n = 562; cohort 2, n = 387), 603 with CHDs (cohort 1, n = 363; cohort 2, n = 240) and 346 with normal cardiac anatomy (cohort 1, n = 199; cohort 2, n = 147). Our analysis revealed that a duplication of SLC2A3 was the most frequent CNV identified in the first cohort. It was present in 18 subjects with CHDs and 1 subject without (p = 3.12 × 10-3, two-tailed Fisher's exact test). In the second cohort, the SLC2A3 duplication was also significantly enriched in subjects with CHDs (p = 3.30 × 10-2, two-tailed Fisher's exact test). The SLC2A3 duplication was the most frequent CNV detected and the only significant finding in our combined analysis (p = 2.68 × 10-4, two-tailed Fisher's exact test), indicating that the SLC2A3 duplication might serve as a genetic modifier of CHDs and/or aortic arch anomalies in individuals with 22q11DS.
AB - The 22q11.2 deletion syndrome (22q11DS; velocardiofacial/DiGeorge syndrome; VCFS/DGS) is the most common microdeletion syndrome and the phenotypic presentation is highly variable. Approximately 65% of individuals with 22q11DS have a congenital heart defect (CHD), mostly of the conotruncal type, and/or an aortic arch defect. The etiology of this phenotypic variability is not currently known. We hypothesized that copy-number variants (CNVs) outside the 22q11.2 deleted region might increase the risk of being born with a CHD in this sensitized population. Genotyping with Affymetrix SNP Array 6.0 was performed on two groups of subjects with 22q11DS separated by time of ascertainment and processing. CNV analysis was completed on a total of 949 subjects (cohort 1, n = 562; cohort 2, n = 387), 603 with CHDs (cohort 1, n = 363; cohort 2, n = 240) and 346 with normal cardiac anatomy (cohort 1, n = 199; cohort 2, n = 147). Our analysis revealed that a duplication of SLC2A3 was the most frequent CNV identified in the first cohort. It was present in 18 subjects with CHDs and 1 subject without (p = 3.12 × 10-3, two-tailed Fisher's exact test). In the second cohort, the SLC2A3 duplication was also significantly enriched in subjects with CHDs (p = 3.30 × 10-2, two-tailed Fisher's exact test). The SLC2A3 duplication was the most frequent CNV detected and the only significant finding in our combined analysis (p = 2.68 × 10-4, two-tailed Fisher's exact test), indicating that the SLC2A3 duplication might serve as a genetic modifier of CHDs and/or aortic arch anomalies in individuals with 22q11DS.
UR - http://www.scopus.com/inward/record.url?scp=84929282777&partnerID=8YFLogxK
U2 - 10.1016/j.ajhg.2015.03.007
DO - 10.1016/j.ajhg.2015.03.007
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C2 - 25892112
AN - SCOPUS:84929282777
SN - 0002-9297
VL - 96
SP - 753
EP - 764
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 5
ER -