22q11.2 Deletions in Patients with Conotruncal Defects: Data from 1,610 Consecutive Cases
The 22q11.2 deletion syndrome is characterized by multiple congenital anomalies including conotruncal cardiac defects. Identifying the patient with a 22q11.2 deletion (22q11del) can be challenging because many extracardiac features become apparent later in life. We sought to better define the cardiac phenotype associated with a 22q11del to help direct genetic testing. 1,610 patients with conotruncal defects were sequentially tested for a 22q11del. The counts and frequencies of primary lesions and cardiac features were tabulated for those with and those without a 22q11del. Logistic regression models investigated cardiac features that predicted deletion status in tetralogy of Fallot (TOF). Deletion frequency varied by primary anatomic phenotype. Regardless of the cardiac diagnosis, a concurrent aortic arch anomaly (AAA) was strongly associated with deletion status [odds ratio (OR), 5.07; 95 % confidence interval (CI), 3.66–7.04]. In the TOF subset, the strongest predictor of deletion status was an AAA (OR, 3.14; 95 % CI 1.87–5.27; p < 0.001), followed by pulmonary valve atresia (OR, 2.03; 95 % CI 1.02–4.02; p = 0.04). Among those with double-outlet right ventricle and transposition of the great arteries, only those with an AAA had a 22q11del. However, 5 % of the patients with an isolated conoventricular ventricular septal defect and normal aortic arch anatomy had a 22q11del, whereas no one with an interrupted aortic arch type A had a 22q11del. A subset of patients with conotruncal defects are at risk for a 22q11del. A concurrent AAA increases the risk regardless of the intracardiac anatomy. These findings help to direct genetic screening for the 22q11.2 deletion syndrome in the cardiac patient.
KeywordsCongenital Conotruncal cardiac defects Genes Genetic heart disease
This study was supported by the National Institutes of Health (grants number-HL062177 and number-HL074731) and by grant number UL1RR024134 from the National Center for Research Resources. The content is solely the responsibility of the authors and does not necessarily represent the official view of the National Center for Research Resources or the National Institutes of Health.
- 5.Botto LD, May K, Fernhoff PM, Correa A, Coleman K, Rasmussen SA, Merritt RK, O’Leary LA, Wong LY, Elixson EM, Mahle WT, Campbell RM (2003) A population-based study of the 22q11.2 deletion: phenotype, incidence, and contribution to major birth defects in the population. Pediatrics 112:101–107CrossRefPubMedGoogle Scholar
- 6.Chhin B, Hatayama M, Bozon D, Ogawa M, Schön P, Tohmonda T, Sassolas F, Aruga J, Valard AG, Chen SC, Bouvagnet P (2007) Elucidation of penetrance variability of a ZIC3 mutation in a family with complex heart defects and functional analysis of ZIC3 mutations in the first zinc finger domain. Hum Mutat 28:563–570CrossRefPubMedGoogle Scholar
- 25.Merscher S, Funke B, Epstein JA, Heyer J, Puech A, Lu MM, Xavier RJ, Demay MB, Russell RG, Factor S, Tokooya K, Jore BS, Lopez M, Pandita RK, Lia M, Carrion D, Xu H, Schorle H, Kobler JB, Scambler P, Wynshaw-Boris A, Skoultchi AI, Morrow BE, Kucherlapati R (2001) TBX1 is responsible for cardiovascular defects in velo-cardio-facial/DiGeorge syndrome. Cell 104:619–629CrossRefPubMedGoogle Scholar
- 38.Volpe P, Marasini M, Caruso G, Marzullo A, Buonadonna AL, Arciprete P, Paolo SD, Volpe G, Gentile M (2003) 22q11 deletions in fetuses with malformations of the outflow tracts or interruption of the aortic arch: impact of additional ultrasound signs. Prenat Diagn 23:752–757CrossRefPubMedGoogle Scholar
- 40.Ziolkowska L, Kawalec W, Turska-Kmiec A, Krajewska-Walasek M, Brzezinska-Rajszys G, Daszkowska J, Maruszewski B, Burczynski P (2008) Chromosome 22q11.2 microdeletion in children with conotruncal heart defects: frequency, associated cardiovascular anomalies, and outcome following cardiac surgery. Eur J Pediatr 167:1135–1140CrossRefPubMedGoogle Scholar