Evaluation of potential modifiers of the cardiac phenotype in the 22q11.2 deletion syndrome.
BACKGROUND
The phenotype associated with deletion of the 22q11.2 chromosomal region is highly variable, yet little is known about the source of this variability. Cardiovascular anomalies, including tetralogy of Fallot, truncus arteriosus, interrupted aortic arch type B, perimembranous ventricular septal defects, and aortic arch anomalies, occur in approximately 75% of individuals with a 22q11.2 deletion.


METHODS
Data from 343 subjects enrolled in a study of the 22q11.2 deletion syndrome were used to evaluate potential modifiers of the cardiac phenotype in this disorder. Subjects with and without cardiac malformations, and subjects with and without aortic arch anomalies were compared with respect to sex and race. In addition, in the subset of subjects from whom a DNA sample was available, genotypes for variants of four genes that are involved in the folate-homocysteine metabolic pathway and that have been implicated as risk factors for other birth defects were compared. Five variants in four genes were genotyped by heteroduplex or restriction digest assays. The chi-square or Fisher's exact test was used to evaluate the association between the cardiac phenotype and each potential modifier.


RESULTS
The cardiac phenotype observed in individuals with a 22q11.2 deletion was not significantly associated with either sex or race. The genetic variants that were evaluated also did not appear to be associated with the cardiovascular phenotype.


CONCLUSIONS
Variation in the cardiac phenotype observed between individuals with a 22q11.2 deletion does not appear to be related to sex, race, or five sequence variants in four folate-related genes that are located outside of the 22q11.2 region.
Goldmuntz
Elizabeth
E
Division of Cardiology, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Driscoll
Deborah A
DA
Emanuel
Beverly S
BS
McDonald-McGinn
Donna
D
Mei
Minghua
M
Zackai
Elaine
E
Mitchell
Laura E
LE
D002648:Child; D004062:DiGeorge Syndrome / Q000150:complications* / Q000453:epidemiology / Q000208:ethnology / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006330:Heart Defects, Congenital / Q000453:epidemiology / Q000208:ethnology / Q000209:etiology* / Q000235:genetics; D006801:Humans; D007206:Individuality; D008297:Male; D010641:Phenotype; D015995:Prevalence; D044469:Racial Groups / Q000706:statistics & numerical data; D012307:Risk Factors; D012737:Sex Factors
J Med Genet. 2005 Jun;42(6):519-22
15937089
J Med Genet. 1997 Oct;34(10):798-804
9350810
Genomics. 1991 May;10(1):201-6
2045103
Genet Test. 1997;1(2):99-108
10464633
Am J Epidemiol. 2000 May 1;151(9):878-84
10791560
Hum Mol Genet. 1996 Dec;5(12):1867-74
8968737
Circulation. 2007 Jun 12;115(23):2995-3014
17519397
Nat Med. 2003 Feb;9(2):173-82
12539040
Clin Chem. 2000 Jul;46(7):907-12
10894832
Am J Hum Genet. 1993 Dec;53(6):1239-49
8250039
Clin Genet. 1998 Jun;53(6):456-9
9712534
Lancet. 1995 Oct 21;346(8982):1070-1
7564788
Pediatrics. 1996 Nov;98(5):911-7
8909485
Am J Obstet Gynecol. 2001 Apr;184(5):806-12; discussion 812-7
11303187
QJM. 1995 Nov;88(11):763-6
8542260
Cleft Palate Craniofac J. 2006 Jul;43(4):435-41
16854201
N Engl J Med. 1992 Dec 24;327(26):1832-5
1307234
Am J Med Genet. 1999 May 21;84(2):151-7
10323741
Hum Mol Genet. 2004 Feb 15;13(4):417-28
14681306
Am J Med Genet. 1996 Mar 15;62(2):179-83
8882400
Clin Perinatol. 2005 Dec;32(4):963-78, ix-x
16325672
Mol Genet Metab. 1999 Aug;67(4):317-23
10444342
Am J Hum Genet. 1997 Sep;61(3):620-9
9326327
Pediatrics. 2003 Jul;112(1 Pt 1):101-7
12837874
Cardiovasc Res. 2001 Aug 1;51(2):251-4
11470464
Nat Genet. 1995 May;10(1):111-3
7647779
Am J Hum Genet. 1995 Jun;56(6):1391-403
7762562
J Am Coll Cardiol. 1998 Aug;32(2):492-8
9708481
J Med Genet. 1993 Oct;30(10):813-7
8230155
Am J Hum Genet. 1995 Jun;56(6):1324-33
7762555
Lancet. 1991 Jul 20;338(8760):131-7
1677062