Congenital Heart Malformations in Sub-Saharan Africa and Asia.
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Date
2018-06-01
Authors
Kruszka, P.
Berger, S.
Hong, S.K.
Tanpaiboon, P.
Ekure, E.N.
Muenke, M.
Journal Title
Journal ISSN
Volume Title
Publisher
Wiley Periodicals, Inc.
Abstract
Congenital heart disease is the most common birth defect, affecting
approximately 1% of all newborns. There have been multiple large
studies genotyping humans with structural CHD in resource rich countries
and very little study in developing nations. In this study, we focus
on the genomic analysis of individuals with CHD in resource poor
countries in Sub-Saharan African and Asia. Genomic evaluation of non-
European individuals offers the opportunity to investigate genetic
causes in different genetic backgrounds and different environmental
backgrounds such as vitamin A deficiency which is endemic in Sub-
Saharan Africa and parts of Asia and lower obesity rates. Clinical examination
and echocardiography were used to diagnose patients with both syndromic and isolated CHD. Exome sequencing, assembly, genotyping,
and annotation were performed on probands and their parents (trios)
by the National Intramural Sequencing Center (NISC). DNA variant list
manipulation was performed using perl scripts developed by our group
and significant findings were confirmed with Sanger sequencing. Copy
number variations were evaluated using both the Illumina HumanExome
BeadChip-12v1_A (Illumina Inc. San Diego, CA) and the XHMM
(eXome-Hidden Markov Model) software, which recovers information
on CNVs from targeted exome sequence data. Selected variants are
being evaluated functionally in the mouse model and zebrafish model.
124 probands have completed the pipeline including 111 parentoffspring
trios and 13 probands with one parent. Currently, 60 more
trios are in analysis pipeline. Probands included 83 (67%) from Sub-
Saharan Africa and 41 (33%) from Asia. Tetralogy of fallot (TOF) was
the most common CHD in our cohort occurring in 29 probands (23%),
followed by ventricular septal defects in 27 (22%), and then pulmonary
stenosis in 13 (10%). Large copy number variations were found in 19
probands (15%) with 22q11.2 deletion syndrome being most common
(6%). Syndromic single gene disorders were found 11 probands (9%)
with RASopathy variants found in 8 patients (6%). Three probands had
pathogenic variants in genes known to cause cardiomyopathies
(ACTC1, ACTN2, DSP). Novel candidate genes were chosen using a
strict criterion to minimize false positive: present in two unrelated families
(including families found in Genematcher and other databases),
genes not known to be associated with CHD, variants not present in
the ExAC database, and CADD scores greater than 15. Sixteen genes
met this criteria and zebrafish evaluation is currently underway to validate
pathogenicity. We have initiated the largest CHD study in a non-
European cohort using next generation sequencing project to search
for novel genetic associations with CHD. With 2/3 of next generation
sequencing complete on our cohort, we are now finding novel genes
that explain the CHD phenotype. Similar to European populations, we
found that CHD in diverse populations is enriched with genes associated
with genetic syndromes in which CHD comprises a major part of
the phenotype. More interesting is our new gene discovery that will
increase our understanding of the genetic basis of CHD. Additionally,
we are conducting mouse model experiments on unique vitamin A
pathway variants from our cohort that will contribute to our unde
rstanding of gene-environmental interactions.
Description
Keywords
Congenital heart malformations , genetics , Sub-Saharan Africa , Asia , exome sequencing , congenital heart disease
Citation
P Kruszka, S Berger, SK Hong, P Tanpaiboon, EN Ekure, M. Muenke. Congenital Heart Malformations in Sub-Saharan Africa and Asia. (2018), 38th Annual David W. Smith Workshop on Malformations and Morphogenesis: Abstracts of the 2017 Annual Meeting. Am J Med Genet, 176(6):1523-1523.