Paediatrics- Conference Papers

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Browsing Paediatrics- Conference Papers by Subject "exome sequencing"

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    Congenital Heart Malformations in Sub-Saharan Africa and Asia.
    (Wiley Periodicals, Inc., 2018-06-01) Kruszka, P.; Berger, S.; Hong, S.K.; Tanpaiboon, P.; Ekure, E.N.; Muenke, M.
    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.