Advertisement

Pediatric Cardiology

, Volume 34, Issue 7, pp 1687–1694 | Cite as

22q11.2 Deletions in Patients with Conotruncal Defects: Data from 1,610 Consecutive Cases

  • Shabnam Peyvandi
  • Philip J. Lupo
  • Jennifer Garbarini
  • Stacy Woyciechowski
  • Sharon Edman
  • Beverly S. Emanuel
  • Laura E. Mitchell
  • Elizabeth Goldmuntz
Original Article

Abstract

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.

Keywords

Congenital Conotruncal cardiac defects Genes Genetic heart disease 

Notes

Acknowledgments

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.

Supplementary material

246_2013_694_MOESM1_ESM.docx (80 kb)
Supplementary material 1 (DOCX 80 kb)

References

  1. 1.
    Agergaard P, Hebert A, Sørensen KM, Østergaard JR, Olesen C (2011) Can clinical assessment detect 22q11.2 deletions in patients with cardiac malformations?A review. Eur J Med Genet 54:3–8CrossRefPubMedGoogle Scholar
  2. 2.
    Agergaard P, Olesen C, Ostergaard JR, Christiansen M, Sørensen KM (2011) The prevalence of chromosome 22q11.2 deletions in 2,478 children with cardiovascular malformations: a population-based study. Am J Med Genet A 158A(3):498–508CrossRefPubMedGoogle Scholar
  3. 3.
    American Congress of Obstetricians and Gynecologists (ACOG) (2009) ACOG Committee Opinion No. 446: array comparative genomic hybridization in prenatal diagnosis. Obstet Gynecol 114:1161–1163CrossRefGoogle Scholar
  4. 4.
    Anilkumar A, Kappanayil M, Thampi MV, Nampoothiri S, Sundaram KR, Vasudevan DM (2011) Variation in prevalence of chromosome 22q11 deletion in subtypes of conotruncal defect in 254 children. Acta Paediatr 100:e97–e100CrossRefPubMedGoogle Scholar
  5. 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. 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
  7. 7.
    Chow EWC, Ho A, Wei C, Voormolen EHJ, Crawley AP, Bassett AS (2011) Association of schizophrenia in 22q11.2 deletion syndrome and gray matter volumetric deficits in the superior temporal gyrus. Am J Psychiatr 168:522–529PubMedCentralCrossRefPubMedGoogle Scholar
  8. 8.
    De Luca A, Sarkozy A, Consoli F, Ferese R (2010) Familial transposition of the great arteries caused by multiple mutations in laterality genes. Heart 96:673CrossRefPubMedGoogle Scholar
  9. 9.
    Fine SE, Weissman A, Gerdes M, Pinto-Martin J, Zackai EH, McDonald-McGinn DM, Emanuel BS (2005) Autism spectrum disorders and symptoms in children with molecularly confirmed 22q11.2 deletion syndrome. J Autism Dev Disord 35:461–470PubMedCentralCrossRefPubMedGoogle Scholar
  10. 10.
    Friedman J (2008) High-resolution array genomic hybridization in prenatal diagnosis. Wiley online library. Prenat Diagn 29:20–28CrossRefGoogle Scholar
  11. 11.
    Fruhman G, Van den Veyver IB (2010) Applications of array comparative genomic hybridization in obstetrics. Obstet Gynecol Clin North Am 37:71–85CrossRefPubMedGoogle Scholar
  12. 12.
    Goldmuntz E, Clark BJ, Mitchell LE, Jawad AF, Cuneo BF, Reed L, McDonald-McGinn D, Chien P, Feuer J, Zackai EH, Emanuel BS, Driscoll DA (1998) Frequency of 22q11 deletions in patients with conotruncal defects. J Am Coll Cardiol 32:492–498CrossRefPubMedGoogle Scholar
  13. 13.
    Goldmuntz E, Bamford R, Karkera JD, Cruz dela J, Roessler E, Muenke M (2002) CFC1 mutations in patients with transposition of the great arteries and double-outlet right ventricle. Am J Hum Genet 70:776–780PubMedCentralCrossRefPubMedGoogle Scholar
  14. 14.
    Jerome LA, Papaioannou VE (2001) DiGeorge syndrome phenotype in mice mutant for the T-box gene, Tbx1. Nat Genet 27:286–291CrossRefPubMedGoogle Scholar
  15. 15.
    Kyburz A, Bauersfeld U, Schinzel A, Riegel M, Hug M, Tomaske M, Valsangiacomo Büchel ER (2008) The fate of children with microdeletion 22q11.2 syndrome and congenital heart defect: clinical course and cardiac outcome. Pediatr Cardiol 29:76–83CrossRefPubMedGoogle Scholar
  16. 16.
    Lichtenbelt KD, Knoers NVAM, Schuring-Blom GH (2011) From karyotyping to array-CGH in prenatal diagnosis. Cytogenet Genome Res 135:241–250CrossRefPubMedGoogle Scholar
  17. 17.
    Lindsay EA, Botta A, Jurecic V, Carattini-Rivera S, Cheah YC, Rosenblatt HM, Bradley A, Baldini A (1999) Congenital heart disease in mice deficient for the DiGeorge syndrome region. Nature 401:379–383PubMedGoogle Scholar
  18. 18.
    Mahle WT, Crisalli J, Coleman K, Campbell RM, Tam VKH, Vincent RN, Kanter KR (2003) Deletion of chromosome 22q11.2 and outcome in patients with pulmonary atresia and ventricular septal defect. Ann Thorac Surg 76:567–571CrossRefPubMedGoogle Scholar
  19. 19.
    Maya I, Davidov B, Gershovitz L, Zalzstein Y, Taub E, Coppinger J, Shaffer LG, Shohat M (2010) Diagnostic utility of array-based comparative genomic hybridization (aCGH) in a prenatal setting. Prenat Diagn 30:1131–1137CrossRefPubMedGoogle Scholar
  20. 20.
    McDonald-McGinn DM, Zackai EH (2008) Genetic counseling for the 22q11.2 deletion. Dev Disabil Res Rev 14:69–74CrossRefPubMedGoogle Scholar
  21. 21.
    McElhinney DB, Bernard J, Clark I, Weinberg PM, Kenton ML, McDonald-McGinn D, Driscoll DA, Zackai EH, Goldmuntz E (2001) Association of chromosome 22q11 deletion with isolated anomalies of aortic arch laterality and branching. J Am Coll Cardiol 37:2114–2119CrossRefPubMedGoogle Scholar
  22. 22.
    McElhinney DB, McDonald-McGinn D, Zackai EH, Goldmuntz E (2001) Cardiovascular anomalies in patients diagnosed with a chromosome 22q11 deletion beyond 6 months of age. Pediatrics 108:104CrossRefGoogle Scholar
  23. 23.
    McElhinney DB, Driscoll DA, Emanuel BS, Goldmuntz E (2003) Chromosome 22q11 deletion in patients with truncus arteriosus. Pediatr Cardiol 24:569–573CrossRefPubMedGoogle Scholar
  24. 24.
    McElhinney DB, Driscoll DA, Levin ER, Jawad AF, Emanuel BS, Goldmuntz E (2003) Chromosome 22q11 deletion in patients with ventricular septal defect: frequency and associated cardiovascular anomalies. Pediatrics 112:472–476CrossRefGoogle Scholar
  25. 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
  26. 26.
    Momma K (2007) Cardiovascular anomalies associated with chromosome 22q11.2 deletion. Int J Cardiol 114:147–149CrossRefPubMedGoogle Scholar
  27. 27.
    Momma K (2010) Cardiovascular anomalies associated with chromosome 22q11.2 deletion syndrome. Am J Cardiol 105:1617–1624CrossRefPubMedGoogle Scholar
  28. 28.
    Momma K, Kondo C, Matsuoka R (1996) Tetralogy of fallot with pulmonary atresia associated with chromosome 22q11 deletion. JAC 27:198–202CrossRefGoogle Scholar
  29. 29.
    Momma K, Matsuoka R, Takao A (1999) Aortic arch anomalies associated with chromosome 22q11 deletion (CATCH 22). Pediatr Cardiol 20:97–102CrossRefPubMedGoogle Scholar
  30. 30.
    Moss E, Batshaw M, Solot C, Gerdes M, Mcdonald-Mcginn D, Driscoll D, Emanuel B, Zackai E, Wang P (1999) Psychoeducational profile of the 22q11.2 microdeletion: a complex pattern. J Pediatr 134:193–198CrossRefPubMedGoogle Scholar
  31. 31.
    Obler D, Juraszek AL, Smoot LB, Natowicz MR (2008) Double-outlet right ventricle: aetiologies and associations. J Med Genet 45:481–497CrossRefPubMedGoogle Scholar
  32. 32.
    Park IS, Ko JK, Kim YH, Yoo HW, Seo EJ, Choi JY, Gil HY, Kim SJ (2007) Cardiovascular anomalies in patients with chromosome 22q11.2 deletion: a Korean multicenter study. Int J Cardiol 114:230–235CrossRefPubMedGoogle Scholar
  33. 33.
    Philip N, Bassett A (2011) Cognitive, behavioural, and psychiatric phenotype in 22q11.2 deletion syndrome. Behav Genet 41:403–412PubMedCentralCrossRefPubMedGoogle Scholar
  34. 34.
    Rauch R, Rauch A, Koch A, Zink S, Kaulitz R, Girisch M, Singer H, Hofbeck M (2004) Laterality of the aortic arch and anomalies of the subclavian artery: reliable indicators for 22q11.2 deletion syndromes? Eur J Pediatr 163:642–645PubMedGoogle Scholar
  35. 35.
    Ryan A, Goodship J, Wilson D (1997) Spectrum of clinical features associated with interstitial chromosome 22q11 deletions: a European collaborative study. J Med Genet 34:798PubMedCentralCrossRefPubMedGoogle Scholar
  36. 36.
    Savage MS, Mourad MJ, Wapner RJ (2011) Evolving applications of microarray analysis in prenatal diagnosis. Curr Opin Obstet Gynecol 23:103–108PubMedCentralCrossRefPubMedGoogle Scholar
  37. 37.
    Simsic JM, Coleman K, Maher KO, Cuadrado A, Kirshbom PM (2009) Do neonates with genetic abnormalities have an increased morbidity and mortality following cardiac surgery? Congenit Heart Dis 4:160–165CrossRefPubMedGoogle Scholar
  38. 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
  39. 39.
    Vorstman JAS, Jalali GR, Rappaport EF, Hacker AM, Scott C, Emanuel BS (2006) MLPA: a rapid, reliable, and sensitive method for detection and analysis of abnormalities of 22q. Hum Mutat 27:814–821PubMedCentralCrossRefPubMedGoogle Scholar
  40. 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

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Shabnam Peyvandi
    • 1
  • Philip J. Lupo
    • 2
  • Jennifer Garbarini
    • 1
  • Stacy Woyciechowski
    • 1
  • Sharon Edman
    • 1
  • Beverly S. Emanuel
    • 3
  • Laura E. Mitchell
    • 4
  • Elizabeth Goldmuntz
    • 1
  1. 1.Division of Pediatric Cardiology, The Children’s Hospital of Philadelphia, Department of Pediatrics at the Perelman School of MedicineThe University of PennsylvaniaPhiladelphiaUSA
  2. 2.Department of PediatricsBaylor College of MedicineHoustonUSA
  3. 3.Division of Human Genetics, The Children’s Hospital of Philadelphia, Department of Pediatrics at the Perelman School of MedicineThe University of PennsylvaniaPhiladelphiaUSA
  4. 4.Human Genetics Center, Department of Epidemiology, Human Genetics and Environmental SciencesThe University of Texas School of Public HealthHoustonUSA

Personalised recommendations