Pediatric Cardiology

, Volume 39, Issue 5, pp 924–940 | Cite as

Identification of De Novo and Rare Inherited Copy Number Variants in Children with Syndromic Congenital Heart Defects

  • Ibtessam R. Hussein
  • Rima S. Bader
  • Adeel G. Chaudhary
  • Randa Bassiouni
  • Maha Alquaiti
  • Fai Ashgan
  • Hans-Juergen Schulten
  • Mohammad H. Al Qahtani
Original Article


Congenital heart defects (CHDs) are the most common birth defects in neonatal life. CHDs could be presented as isolated defects or associated with developmental delay (DD) and/or other congenital malformations. A small proportion of cardiac defects are caused by chromosomal abnormalities or single gene defects; however, in a large proportion of cases no genetic diagnosis could be achieved by clinical examination and conventional genetic analysis. The development of genome wide array-Comparative Genomic Hybridization technique (array-CGH) allowed for the detection of cryptic chromosomal imbalances and pathogenic copy number variants (CNVs) not detected by conventional techniques. We investigated 94 patients having CHDs associated with other malformations and/or DD. Clinical examination and Echocardiography was done to all patients to evaluate the type of CHD. To investigate for genome defects we applied high-density array-CGH 2 × 400K (41 patients) and CGH/SNP microarray 2 × 400K (Agilent) for 53 patients. Confirmation of results was done using Fluorescent in situ hybridization (FISH) or qPCR techniques in certain cases. Chromosomal abnormalities such as trisomy 18, 13, 21, microdeletions: del22q11.2, del7q11.23, del18 (p11.32; p11.21), tetrasomy 18p, trisomy 9p, del11q24-q25, add 15p, add(18)(q21.3), and der 9, 15 (q34.2; q11.2) were detected in 21/94 patients (22%) using both conventional cytogenetics methods and array-CGH technique. Cryptic chromosomal anomalies and pathogenic variants were detected in 15/73 (20.5%) cases. CNVs were observed in a large proportion of the studied samples (27/56) (48%). Clustering of variants was observed in chromosome 1p36, 1p21.1, 2q37, 3q29, 5p15, 7p22.3, 8p23, 11p15.5, 14q11.2, 15q11.2, 16p13.3, 16p11.2, 18p11, 21q22, and 22q11.2. CGH/SNP array could detect loss of heterozygosity (LOH) in different chromosomal loci in 10/25 patients. Array-CGH technique allowed for detection of cryptic chromosomal imbalances that could not be detected by conventional cytogenetics methods. CHDs associated with DD/congenital malformations presented with a relatively high rate of cryptic chromosomal abnormalities. Clustering of CNVs in certain genome loci needs further analysis to identify candidate genes that may provide clues for understanding the molecular pathway of cardiac development.


Congenital heart defects Array-CGH Copy number variants Syndromic CHDs Chromosomal aberrations 



The authors would like to thank the King Abdulaziz City for Science and Technology (KACST), King Abdulaziz University, for funding this study as part of the project No. P-L-11-0556. We thank Assoc. Prof. M. Abu-Elmagd for helping in editing and improving the quality of the figures. We also thank all the patients and their families who participated in this study for donating their blood samples.


The study was part of a project funded by King Abdulaziz City for Science and Technology (KACST), KSA, Project No. (P-L-11-0556). The research team declares that the copyrights are reserved to the KACST and that all views, scientific findings, conclusions, and recommendations mentioned in the study represent the sole opinion of the research team and do not in any way reflect KACST views.

Compliance with Ethical Standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethics Approval

The work was part of the KACST large project (P-L-11-0556) approved by the CEGMR Ethical committee under the Code # 016-CEGMR-ETH. The Ethical committee License # at KACST: HA-02-J-003.

Informed Consent

An informed consent to participate in this study was obtained from patients, or their parents or legal guardians.


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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Centre of Excellence in Genomic Medicine Research (CEGMR), King Fahd Medical Research CentreKing Abdulaziz UniversityJeddahKingdom of Saudi Arabia
  2. 2.Pediatric Cardiology DepartmentKing Abdulaziz University HospitalJeddahKingdom of Saudi Arabia
  3. 3.Faculty of Medical SciencesKing Abdulaziz UniversityJeddahKingdom of Saudi Arabia
  4. 4.Children HospitalMinistry of HealthTa’ifKingdom of Saudi Arabia

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