Case Report Open Access
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World J Cardiol. Dec 26, 2017; 9(12): 848-852
Published online Dec 26, 2017. doi: 10.4330/wjc.v9.i12.848
Transposition of the great arteries - a phenotype associated with 16p11.2 duplications?
Zarmiga Karunanithi, Department of Cardiothoracic and Vascular Surgery, Aarhus University Hospital, Aarhus N 8200, Denmark
Else Marie Vestergaard, Department of Clinical Genetics, Aarhus University Hospital, Aarhus N 8200, Denmark
Mette H Lauridsen, Department of Pediatrics and Adolescent Medicine, Aarhus University Hospital, Aarhus N 8200, Denmark
Author contributions: Lauridsen MH conducted the primary research, selected the patients, obtained informed consent from the parents and children, retrieved the blood samples, and communicated the genetic results to the families; Vestergaard EM performed and interpreted the chromosomal microarray analyses; Karunanithi Z collected the patient information from medical records; Karunanithi Z, Vestergaard EM and Lauridsen MH collectively summarized the data and wrote the manuscript.
Supported by The Helga and Peter Kornings Fund.
Institutional review board statement: Permission and approval for this study were obtained from both the Central Denmark Region Committees on Health Ethics (1-10-72-290-13) and the Danish Data Protection Agency (journal number 2007-58-0010).
Informed consent statement: All study participants, or their legal guardian, provided informed written consent prior to study enrollment.
Conflict-of-interest statement: None.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Mette H Lauridsen, MD, Department of Pediatrics and Adolescent Medicine, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, Aarhus N 8200, Denmark. lauridsen.mette@auh.rm.dk
Telephone: +45-61716847 Fax: + 45-78451750
Received: March 23, 2017
Peer-review started: March 24, 2017
First decision: July 17, 2017
Revised: August 28, 2017
Accepted: September 12, 2017
Article in press: September 12, 2017
Published online: December 26, 2017
Processing time: 273 Days and 6.5 Hours

Abstract

Genetic analyses of patients with transposition of the great arteries have identified rare copy number variations, suggesting that they may be significant to the aetiology of the disease. This paper reports the identification of a 16p11.2 microduplication, a variation that has yet to be reported in association with transposition of the great arteries. The 16p11.2 microduplication is associated with autism spectrum disorder and developmental delay, but with highly variable phenotypic effects. Autism and attention deficit disorders are observed more frequently in children with congenital heart disease than in the general population. Neonatal surgery is proposed as a risk factor, but as yet unidentified genetic abnormalities should also be taken into account. Thus, congenital heart abnormalities may constitute a part of the phenotypic spectrum associated with duplications at 16p11.2. We suggest chromosomal microarray be considered part of the diagnostic work-up in patients with transposition of the great arteries.

Key Words: Transposition of the great arteries; Copy number variation; Genetics; 16p11.2; Microduplication

Core tip: Rare copy number variations may be of significance to the aetiology of transposition of the great arteries. This paper reports, for the first time, the finding of a 16p11.2 microduplication in a patient with transposition of the great arteries. Recognizing a possible genetic association to transposition of the great arteries will spur investigations into associated phenotypic effects such as developmental delays, thus allowing for earlier identification and treatment. We recommend that chromosomal microarray be considered part of the diagnostic work-up in patients with transposition of the great arteries.



INTRODUCTION

Structural gene mutations are emerging as important causes of congenital heart diseases[1]. Transposition of the great arteries is a rare, life-threatening form of congenital heart disease. In contrast to some congenital heart defects, such as atrioventricular septal defects and tetralogy of Fallot, simple transposition of the great arteries is rarely associated with syndromes[2].

Although the aetiology of the disease of is currently unknown, rare copy number variations have recently been identified in patients with transposition of the great arteries[1,3-5] (Table 1). To investigate this further, we screened 13 patients with transposition of the great arteries for copy number variations using high-resolution chromosomal microarray analyses. Approximately half of the screened patients had additional congenital heart diseases.

Table 1 Known genetic associations with transposition of the great arteries.
CytobandRef.
Non-syndromicZIC3Xq26.3Bamford et al[12]
Nodal10q22.1Nomura et al[13]
CFC12q21.1Bamford et al[12]
Smad218q21.1Nomura et al[13]
1p31.1Costain et al[2]
3q25.33-q25.32Costain et al[2]
4q28.3-4q28.2Costain et al[2]
7q21.11Costain et al[2]
8p22Costain et al[2]
12q24.33Costain et al[2]
13q13.1-13q13.2Costain et al[2]
16p12.3-16p13.11Costain et al[2]
16p12.2Costain et al[2]
Xp22.12Costain et al[2]
16p11.2Current paper
SyndromicCHARGEUnolt et al[3]
Deletion 11qJacobsen et al[14]
Deletion 18pDigilio et al[15]
DiGeorge/deletion 22q11Van Mierop et al[16]
Heterotaxy (right isomerism)Marino et al[17]
Marfan syndromeUnolt et al[3]
Noonan syndromeUnolt et al[3]
Trisomy 18Unolt et al[3]
Trisomy 8Unolt et al[3]
Tuberous sclerosisJiang et al[18]
Turner syndromeUnolt et al[3]
VACTERLUnolt et al[3]
Williams syndromeUnolt et al[3]
CASE REPORT

Here, we present the case of a young patient with a genetic mutation that has yet to be reported in association with transposition of the great arteries.

Blood samples were collected from patients and their parents during planned visits. Informed consent to perform chromosomal microarray was obtained. Chromosomal microarray (Agilent Technologies Inc., Santa Clara, CA, United States; 180K CGH for nine patients or 400K CGN + SNP for four patients) was performed on DNA extracted from blood leucocytes as per the manufacturer’s protocol.

In one patient, the chromosomal microarray revealed a 0.5 Mb duplication at chromosome 16p11.2 {arr(hg19) 16p11.2 [(29664529-30198600)] × 3 mat} covering the region involved in chromosome 16p11.2 duplication syndrome (OMIM 614671). This microduplication was subsequently detected in the patient’s 35-year-old Caucasian mother, who was phenotypically unaffected. The mother was without any cardiac symptoms or murmurs and was not interested in further examinations of her heart.

The patient was born at gestational age 40 wk, weighing 3.06 kg and measuring 50 cm in length. The patient’s Apgar score was 9 at one minute and 10 at five minutes. In addition to transposition of the great arteries, a pulmonary valve stenosis and ventricular and atrial septal defects were present. The patient had an arterial switch operation at birth and the Nikaidoh procedure at 7 years of age. Postoperatively, the patient achieved a relatively high level of activity and had no cardiac or respiratory discomfort. At 8 years of age, the patient was diagnosed with attention deficit hyperactive disorder. The patient was followed until the age of 9.5 years.

The 16p11.2 microduplication is associated with autism spectrum disorder and developmental delay, but with highly variable phenotypic effects. This duplication does not always result in severe impairment and may be inherited from a parent with minimal or no clinical features[6]. The 16p11.2 microduplication has not previously been associated with transposition of the great arteries. In the Decipher database, two cases of persistent arterial duct and one case of ventricular septal defect were seen among all patients with a 16p11.2 microduplication[7].

DISCUSSION

Transposition of the great arteries is one of the more severe congenital cardiac defects, but only few studies have investigated the possible aetiology of this defect[1,2]. Two clinical reports have documented a variety of genetic variations associated with transposition of the great arteries[4,5]. On a review of the literature, Unolt et al[3] identified frequent syndromes, such as Turner and Noonan, that were rarely associated with transposition of the great arteries; however, a sporadic association with several other genetic variations is possible (Table 1). Costain et al[2] studied a cohort of patients with transposition of the great arteries (n = 101) and identified 11 different rare copy number variations, none of which were found in the control group (n = 10528)[2]. Osoegawa et al[8] searched for candidate gene loci and sex chromosome aneuploidy among patients with conotruncal cardiac anomalies, of which 194 patients had transposition of the great arteries. They identified a 22q11.22 microdeletion in one patient, an 8p23.2 micro duplication in another patient, and sex chromosome abnormalities (47XYY and 47XXY) in two patients with transposition of the great arteries.

We are the first to document the presence of a 16p 11.2 microduplication in a patient with transposition of the great arteries. Deletions and duplications of the recurrent 600 base pair region on chromosome 16p11.2 are frequent findings in patients with autism spectrum disorders and the concomitant finding of congenital heart disease may be an incidental finding not caused by the microduplication[9]. It is, however, well known that congenital abnormalities can occur in the context of recurrent duplications associated with susceptibility to intellectual disability.

Autism and attention deficit disorders are observed more frequently in children with congenital heart disease than in the general population[10]. Neonatal surgery is proposed as a risk factor[11], but as yet unidentified genetic abnormalities should also be taken into account.

Thus, congenital heart abnormalities may constitute a part of the phenotypic spectrum associated with duplications at 16p11.2. We suggest chromosomal microarray be considered part of the diagnostic work-up in patients with transposition of the great arteries.

In conclusion, rare copy number variations may be of significance to the aetiology of transposition of the great arteries. This paper reports, for the first time, the finding of a 16p11.2 microduplication in a patient with transposition of the great arteries. Recognizing a possible genetic association to transposition of the great arteries will spur investigations into associated phenotypic effects such as developmental delays, thus allowing for earlier identification and treatment. We therefore recommend that chromosomal microarray be considered part of the diagnostic work-up in patients with transposition of the great arteries.

ARTICLE HIGHLIGHTS
Case characteristics

Young patient diagnosed with transposition of the great arteries and a 16p11.2 microduplication.

Clinical diagnosis

The child deteriorated after birth, when the arterial duct closed. Echocardiography revealed transposition of the great arteries, pulmonary valve stenosis and ventricular and atrial septal defects. Around school age the child was diagnosed with attention deficit disorder.

Differential diagnosis

Regarding deterioration after birth, differential diagnoses are: Neonatal sepsis, metabolic disease, and other cyanotic heart defects. Neonatal surgery is a risk factor for attention deficit disorder.

Laboratory diagnosis

Chromosomal microarray revealed the 0.5 Mb chromosomal duplication at chromosome 16p11.2.

Imaging diagnosis

The congenital heart diseases were diagnosed using echocardiography.

Treatment

The transposition of the great arteries was treated with an arterial switch operation at birth and the Nikaidoh procedure at the age of 7 years.

Related reports

Transposition of the great arteries is rarely associated with genetic variations. Transposition of the great arteries have once before been associated with a 16p13.11 duplication (Ref. [19]). The authors are the first to report the 16p11.2 microduplication in association with transposition of the great arteries.

Term explanation

Copy number variation: A structural variation in the DNA that results in the cell having an abnormal number of copies of one or more sections of the DNA.

Experiences and lessons

The case document that copy number variations may be of significance in transposition of the great arteries and chromosomal microarray should be considered part of the diagnostic work-up in these patients.

ACKNOWLEDGMENTS

We thank professor Vibeke Hjortdal at the Department of Cardiothoracic and Vascular Surgery, Aarhus University Hospital, Denmark, and Rikke Christensen and Ida Vogel, both at the Department of Clinical Genetics, Aarhus University Hospital, Denmark for help with initiating the study, collecting blood samples, analysing data, and helping prepare the manuscript. We thank research nurse Vibeke Laursen at the Department of Cardiothoracic and Vascular surgery for colleting blood samples and secretary Jette Breiner at the Department of Cardiothoracic and Vascular surgery for administrating bills and translating patient information.

Footnotes

Manuscript source: Unsolicited Manuscript

Specialty type: Cardiac and cardiovascular systems

Country of origin: Denmark

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P- Reviewer: Gong KZ, Weber HS S- Editor: Kong JX L- Editor: A E- Editor: Lu YJ

References
1.  Erdogan F, Larsen LA, Zhang L, Tümer Z, Tommerup N, Chen W, Jacobsen JR, Schubert M, Jurkatis J, Tzschach A. High frequency of submicroscopic genomic aberrations detected by tiling path array comparative genome hybridisation in patients with isolated congenital heart disease. J Med Genet. 2008;45:704-709.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 96]  [Cited by in F6Publishing: 105]  [Article Influence: 6.6]  [Reference Citation Analysis (0)]
2.  Costain G, Lionel AC, Ogura L, Marshall CR, Scherer SW, Silversides CK, Bassett AS. Genome-wide rare copy number variations contribute to genetic risk for transposition of the great arteries. Int J Cardiol. 2016;204:115-121.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 20]  [Cited by in F6Publishing: 21]  [Article Influence: 2.3]  [Reference Citation Analysis (0)]
3.  Unolt M, Putotto C, Silvestri LM, Marino D, Scarabotti A, Valerio Massaccesi, Caiaro A, Versacci P, Marino B. Transposition of great arteries: new insights into the pathogenesis. Front Pediatr. 2013;1:11.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 73]  [Cited by in F6Publishing: 64]  [Article Influence: 5.8]  [Reference Citation Analysis (0)]
4.  van Bon BWM, Koolen DA, Pfundt R, van der Burgt I, De Leeuw N, de Vries BBA.  Transposition of the great vessels in a patient with a 2.9 Mb interstitial deletion of 9q31.1 encompassing the inversin gene: Clinical report and review. USA: Wiley Subscription Services, Inc., A Wiley Company; 2008; .  [PubMed]  [DOI]  [Cited in This Article: ]
5.  Costain G, Roche SL, Scherer SW, Silversides CK, Bassett AS. Rare copy number variations in an adult with transposition of the great arteries emphasize the importance of updated genetic assessments in syndromic congenital cardiac disease. Int J Cardiol. 2016;203:516-518.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 9]  [Cited by in F6Publishing: 10]  [Article Influence: 1.1]  [Reference Citation Analysis (0)]
6.  Fernandez BA, Roberts W, Chung B, Weksberg R, Meyn S, Szatmari P, Joseph-George AM, Mackay S, Whitten K, Noble B. Phenotypic spectrum associated with de novo and inherited deletions and duplications at 16p11.2 in individuals ascertained for diagnosis of autism spectrum disorder. J Med Genet. 2010;47:195-203.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 183]  [Cited by in F6Publishing: 191]  [Article Influence: 12.7]  [Reference Citation Analysis (0)]
7.  Firth HV, Richards SM, Bevan AP, Clayton S, Corpas M, Rajan D, Vooren S Van, Moreau Y, Pettett RM, Carter NP. DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans Using Ensembl Resources. 2009;.  [PubMed]  [DOI]  [Cited in This Article: ]
8.  Osoegawa K, Iovannisci DM, Lin B, Parodi C, Schultz K, Shaw GM, Lammer EJ. Identification of novel candidate gene loci and increased sex chromosome aneuploidy among infants with conotruncal heart defects. Am J Med Genet A. 2014;164A:397-406.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 18]  [Cited by in F6Publishing: 20]  [Article Influence: 1.8]  [Reference Citation Analysis (0)]
9.  Steinman KJ, Spence SJ, Ramocki MB, Proud MB, Kessler SK, Marco EJ, Green Snyder L, D’Angelo D, Chen Q, Chung WK. 16p11.2 deletion and duplication: Characterizing neurologic phenotypes in a large clinically ascertained cohort. Am J Med Genet A. 2016;170:2943-2955.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 100]  [Cited by in F6Publishing: 103]  [Article Influence: 12.9]  [Reference Citation Analysis (0)]
10.  Bean Jaworski JL, Flynn T, Burnham N, Chittams JL, Sammarco T, Gerdes M, Bernbaum JC, Clancy RR, Solot CB, Zackai EH. Rates of autism and potential risk factors in children with congenital heart defects. Congenit Heart Dis. 2017;12:421-429.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 28]  [Cited by in F6Publishing: 27]  [Article Influence: 3.9]  [Reference Citation Analysis (0)]
11.  Yamada DC, Porter AA, Conway JL, LeBlanc JC, Shea SE, Hancock-Friesen CL, Warren AE. Early repair of congenital heart disease associated with increased rate of attention deficit hyperactivity disorder symptoms. Can J Cardiol. 2013;29:1623-1628.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 20]  [Cited by in F6Publishing: 18]  [Article Influence: 1.6]  [Reference Citation Analysis (0)]
12.  Bamford RN, Roessler E, Burdine RD, Saplakoğlu U, dela Cruz J, Splitt M, Goodship JA, Towbin J, Bowers P, Ferrero GB. Loss-of-function mutations in the EGF-CFC gene CFC1 are associated with human left-right laterality defects. Nat Genet. 2000;26:365-369.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 257]  [Cited by in F6Publishing: 271]  [Article Influence: 11.3]  [Reference Citation Analysis (0)]
13.  Nomura M, Li E. Smad2 role in mesoderm formation, left-right patterning and craniofacial development. Nature. 1998;393:786-790.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 479]  [Cited by in F6Publishing: 460]  [Article Influence: 17.7]  [Reference Citation Analysis (0)]
14.  Jacobsen P, Hauge M, Henningsen K, Hobolth N, Mikkelsen M, Philip J. An (11;21) translocation in four generations with chromosome 11 abnormalities in the offspring. A clinical, cytogenetical, and gene marker study. Hum Hered. 1973;23:568-585.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 156]  [Cited by in F6Publishing: 163]  [Article Influence: 3.2]  [Reference Citation Analysis (0)]
15.  Digilio MC, Marino B, Giannotti A, Di Donato R, Dallapiccola B. Heterotaxy with left atrial isomerism in a patient with deletion 18p. Am J Med Genet. 2000;94:198-200.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in F6Publishing: 1]  [Reference Citation Analysis (0)]
16.  Van Mierop LH, Kutsche LM. Cardiovascular anomalies in DiGeorge syndrome and importance of neural crest as a possible pathogenetic factor. Am J Cardiol. 1986;58:133-137.  [PubMed]  [DOI]  [Cited in This Article: ]
17.  Marino B, Capolino R, Digilio MC, Di Donato R. Transposition of the great arteries in asplenia and polysplenia phenotypes. Am J Med Genet. 2002;110:292-294.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 26]  [Cited by in F6Publishing: 28]  [Article Influence: 1.3]  [Reference Citation Analysis (0)]
18.  Jiang ZY, Pircova A, Sekarski N, Hack I, Laurini R, Janzer R, Payot M. Transposition of the great arteries, pulmonary atresia, and multiple ventricular septal defects associated with multiple cardiac rhabdomyomas in a case of tuberous sclerosis. Pediatr Cardiol. 2000;21:165-169.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 8]  [Cited by in F6Publishing: 10]  [Article Influence: 0.4]  [Reference Citation Analysis (0)]
19.  Nagamani SC, Erez A, Bader P, Lalani SR, Scott DA, Scaglia F, Plon SE, Tsai CH, Reimschisel T, Roeder E. Phenotypic manifestations of copy number variation in chromosome 16p13.11. Eur J Hum Genet. 2011;19:280-286.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 76]  [Cited by in F6Publishing: 90]  [Article Influence: 6.4]  [Reference Citation Analysis (0)]