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Title: Genetic investigation of neonatal sclerosing cholangitis
Author: Grammatikopoulos, Tassos
ISNI:       0000 0004 5368 2818
Awarding Body: King's College London
Current Institution: King's College London (University of London)
Date of Award: 2015
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Neonatal sclerosing cholangitis (NSC) is a rare form of severe liver disease, presenting in the newborn period with great similarities to the more common condition of biliary atresia (BA). Both involve inflammation and narrowing of the bile ducts, and lead to liver failure. NSC appears to be common amongst children of consanguineous marriages, suggesting it is inherited as an autosomal recessive trait. Despite the distinct disease phenotype and the suspicion of genetic inheritance no gene variants have so far been identified. The aim of this study is to identify the cause of NSC by mapping the genetic locus and characterising the causative gene within the disease region. We retrospectively identified 39 NSC patients (20 male). Consanguinity was identified in 24, two families having 2 affected siblings in each. Four patients with Kabuki make up syndrome, one of the high GGT cholestasis syndromes, were also included. DNA from 24 (14 male) patients was used for whole genome analysis with the Human CytoSNP-12 v2.1 microarray. Homozygosity Mapper and BeadStudio Genotyping Module were used and large areas of homozygosity in 5 chromosomes were identified with a high number of genes within, making it impractical to filter down to a single causal gene. Whole exome sequencing (WES) was performed in 5 patients initially, but a strong candidate gene was not found. A further 21 patients with a diagnosis of neonatal cholangiopathy underwent WES. Through the latter data analysis, protein truncating mutations in the doublecortin domain containing 2 gene (DCDC2) were identified in seven patients (4 homozygous, 3 heterozygous). DCDC2, a microtubule associated protein has a regulatory role in the ciliary microtubule’s function possibly by affecting Shh and Wnt signalling pathways. These pathways could have an impact on cholangiocyte morphology and development of cholangiopathies. Mutations in DCDC2 were confirmed following Sanger sequencing and liver tissue immunohistochemical and ultrastructure studies. A better understanding of the aetiology and pathogenesis of NSC through this finding will allow improved diagnostics and potentially new treatment options.
Supervisor: Thompson, Richard John ; Mieli-Vergani, Giorgina Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available