Dissertation/Thesis Abstract

Biallelic and Multiallelic Copy Number Variants and Their Association with Obstructive Congenital Heart Defects
by Levy, Joseph, Ph.D., University of Arkansas for Medical Sciences, 2020, 208; 27962982
Abstract (Summary)

Introduction: Congenital heart defects (CHDs) are the most prevalent birth defects and obstructive heart defects (OHDs) represent approximately one third of these damaging abnormalities. There is evidence to suggest OHDs are driven by complex interrelationships between environmental factors and genetic variants, but less than half of CHDs occur due to a recognized causal factor. Many associations between non-syndromic CHDs and copy number variants (CNVs) have been reported.

Objectives: The objectives of this dissertation were to identify CNVs and multiallelic CNV risk factors for non-syndromic obstructive CHDs.

Methods: DNA derived from case infants with obstructive heart defects (n = 687) and control infants (n = 976) received through the CDC-funded National Birth Defects Prevention Study (NBDPS) from participating collection sites in Arkansas, Georgia, California, Texas and Iowa. All samples were genotyped using an Illumina® Infinium Omni5Exome-4 BeadChip in the Hobbs Birth Defects Genomics Laboratory as part of an NIH-funded Genome Wide Association Study. CNVs were identified using PennCNV and QuantiSNP and analyzed using case-control statistical methods. A rare variant annotation pipeline was assembled for the prioritization of rare CNV risk factors. Potential multiallelic CNVs were selected and tested using case-control statistical methods.

Results: A totally of 570 case and 828 control infants were passed quality control metrics and were included in the analysis. We identified 2 common duplications associated with CHD risk in 10q11.22 (OR = 4.31, P-Value = 0.016) and 22q13.2 (OR = 3.46, P-Value = 0.024). The rare variant annotation pipeline identified 50 potential CNV risk factors for OHD. Two or more rare CNV risk factors were identified in 1q21.3, 7q11.23, 7q22.1, 11q13.1, 16p11.2, 17p13.2, 19q13.2, 19p13.12, 19q13.33, and 22q11.21. Seven TADs disproportionately impacted by either deletions or duplications in the case population were detected (Benjamini-Hochberg p < 0.05). Our analysis did not identify any potential multiallelic CNV risk factors for non-syndromic CHD in the study population.

Conclusions: The results demonstrate the significant role both common and rare CNVs play in CHD risk. Enrichment of CNVs in specific TADs in our case population provides initial evidence for TAD disruption by CNVs as a potential risk factor for non-syndromic CHD.

Indexing (document details)
Advisor: Hobbs, Charlotte A
Commitee: MacLeod, Stewart L, Cleves, Mario A, Nookaew, Intawat, McGehee, Robert E
School: University of Arkansas for Medical Sciences
Department: Interdisciplinary Biomedical Sciences
School Location: United States -- Arkansas
Source: DAI-B 81/11(E), Dissertation Abstracts International
Source Type: DISSERTATION
Subjects: Genetics, Bioinformatics
Keywords: Bioinformatics, Congenital heart defect, Copy number variation, Genetics, Obstructive heart defect
Publication Number: 27962982
ISBN: 9798643197799
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