Vania, Ashira2024-11-082024-11-082024Vania, Ashira. (2024). Genetic characterisation of epidermolysis bullosa in South African patients [Master’s dissertation, University of the Witwatersrand, Johannesburg]. WireDSpace.https://hdl.handle.net/10539/42290A Research Report (in the format of a “submissible” paper) submitted to the Faculty of Health Sciences in partial fulfillment of the requirements for the degree of Master in Medicine, in Medical Genetics , School of Pathology, University of the Witwatersrand, Johannesburg, 2024Background: Epidermolysis bullosa (EB) is a clinically and genetically heterogeneous inherited skin condition, characterised by the formation of blistering skin lesions in response to minimal abrasive skin trauma, with variable additional clinical complications. EB is divided into four subtypes based on histological characteristics: simplex EB (EBS), junctional EB (JEB), dystrophic EB (DEB) and Kindler syndrome (KS). EB is diagnosed on the basis of family history, and clinical signs and symptoms, in conjunction with histological examination, immunofluorescence mapping and transmission electron microscopy to determine subtype. Where available, molecular genetic testing can identify the causative genetic pathogenic variant/s. There is little recently published research on EB and its genetic aetiology in South African cohorts. The aim of this study was to design a multigene EB panel to investigate the pathogenic genetic variant/s responsible for EB in a group of South African patients, thereby providing information for targeted symptomatic treatment, medical surveillance, and to allow for more accurate genetic counselling and future reproductive options. Methods: Thirteen South African patients with clinically-diagnosed EB were recruited from the genetic clinic in four local State hospitals in Gauteng, South Africa. They were phenotypically characterised in terms of family history of the disorder, clinical features, and histological subtype. Whole exome sequencing was performed and a virtual panel of 11 of the commonly implicated EB-associated genes to screen for pathogenic variants. Genetic variants detected were analysed and classified according to American College of Medical Genetics and Genomics guidelines. Results: The 13 patients all had similar clinical characteristics of generalised skin blistering from birth. Skin biopsy with histopathology examination was available for 7/13 (54%). Histological and electron microscopy investigations correlated with molecular findings in only three cases. A genetic result that either confirmed the clinical diagnosis or supported the clinical diagnosis of EB was found in over half of the study cohort (8/12 (67%)). Three recurring variants were identified; COL7A1 (c.3265C>T), LAMB3 (c.958_1034dup) and LAMB3 (c.1034_1035insGGG; previously unreported). Of the eight patients with a confirmed/supported genetic diagnosis, 50% had JEB and 13% had EBS Conclusion: Of the 13 clinically diagnosed EB patients, 8/13 (67%) could be genetically characterised and three parents had confirmed carrier status; allowing for accurate genetic counselling, in terms of inheritance and recurrence risk information. JEB was seen in a higher frequency and EBS in a lower frequency than would be expected, reflecting a possible ascertainment bias. This study validates the clinical utility of an EB multigene panel for South African patients with EB, with particular focus on COL7A1 and LAMB3en© 2024 University of the Witwatersrand, Johannesburg. All rights reserved. The copyright in this work vests in the University of the Witwatersrand, Johannesburg. No part of this work may be reproduced or transmitted in any form or by any means, without the prior written permission of University of the Witwatersrand, Johannesburg.Epidermolysis bullosaSouth AfricanMolecular characterisationUCTDSDG-3: Good health and well-beingDissertationUniversity of the Witwatersrand, Johannesburg