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Title: Genetics of congenital heart disease
Author: Khetyar, Maher
ISNI:       0000 0004 7427 1276
Awarding Body: St George's, University of London
Current Institution: St George's, University of London
Date of Award: 2017
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Congenital Heart Disease (CHD) is the leading non-infectious cause of death among children less than one year. CHD is genetically heterogeneous, but analysis of large multi-generational families has led to the identification of a number of genes for CHD. In this project I investigated the molecular genetic basis of CHD in a large Kuwaiti family with clinically diagnosed truncus arteriosus. Using a homozygosity mapping approach I identified a region of interest on chromosome 8p21. I proceeded to sequence candidate genes in this region. One of the novel genes identified was predicted to be the human homolog of mouse Nkx2.6, a gene encoding a homeobox transcription factor expressed in the sinus venosa and the myocardium of the outflow tract in the developing mouse heart. Sanger sequencing identified a Phel51Leu mutation which segregated with disease in the family. Next I investigated whether mutations in Nkx2.6, or the related gene Nkx2.5, were a common cause of type I truncus arteriosus in 12 unrelated individuals. However I found no mutations, suggesting the pattern of inheritance in this phenotype is likely to be complex and potentially multifactorial. Finally I investigated the molecular genetic basis of another congenital heart defect known as Patent Ductus Arteriosus (PDA) in a multigenerational Kuwaiti family with six affected members. A condition known as Char Syndrome is characterized by a combination of major features one of which is PDA and can be caused by mutations in the TFAP2B gene which encodes the Transcription Factor AP-2 Beta. I therefore hypothesised that mutations in TFAP2B may also be responsible for PDA in the Kuwaiti family. I identified a predicted splice site variant in this gene that segregated with disease status. A full clinical history and physical examination confirmed that no affected members of this family have any of the remaining features of Char Syndrome suggesting that mutations in TFAP2B can also cause isolated PDA.
Supervisor: Syrris, Petros ; Cater, Nick ; Jamshidi, Yalda Sponsor: Not available
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available