The role of small genetic variants in the aetiology of developmental disorders in South Africa - a whole exome sequencing study

dc.contributor.authorMolatoli, Mhlekazi Cathrine
dc.contributor.supervisorLombard, Zané
dc.date.accessioned2024-12-12T08:00:06Z
dc.date.available2024-12-12T08:00:06Z
dc.date.issued2024
dc.descriptionthesis submitted in fulfillment of the requirements for the degree of Doctor of Philosophy to the School of Pathology, Division of Human Genetics, University of the Witwatersrand, Johannesburg, 2024
dc.description.abstractDevelopmental disorders (DD) are a diverse group of chronic conditions characterized by significant limitations to both mental and physical development. Genetic variants have been identified as the underlying aetiology in about 40-50% of DD cases. Whole exome sequencing (WES) is the recommended first-line genetic test in this group of patients and is associated with diagnostic yields of 16-45%. However, in South Africa and other resource-poor settings, karyotype testing and MLPA analysis (offering low diagnostic rates of 3% and ~9% respectively) are still being utilized for genetic testing. Thus, a higher proportion of patients remain with unexplained DD due to the limitations of these diagnostic tools and limited genetic services. The main challenge facing the clinical implementation of WES in African settings is the complex data analysis and interpretation associated with the large amount of variant data produced. This is especially challenging as African ancestry individuals have been demonstrated to have a high level of genetic diversity resulting in a higher number of novel variants reported compared to European ancestry individuals. This study seeks to investigate whether the clinical utility of WES can be replicated in an African setting. Additionally, we seek to make recommendations for variant filtering and prioritization, thus making the process of WES data analysis for DD patients more efficient. To achieve these, WES was performed in 117 patients with unexplained DD and their 180 unrelated parents. Variant data was filtered and prioritized using two in-house semi-automated pipelines. The first pipeline, prioritized variants overlapping known DD genes, as identified using the G2P-DDG2P bioinformatics analysis tool. The second pipeline identified de novo variants in trio families using the trio-dnm bioinformatics analysis tool. Sanger sequencing was used to validate low-quality prioritized variants prior to in-house interpretation and curation, and all subsequently identified putative disease-causing variants prior to reporting. Of the 117 patients from 115 families analysed, a positive molecular diagnosis was achieved for 29 families, resulting in a diagnostic yield of 25.2% (29/115). Leveraging currently available DD data, our findings demonstrate the diagnostic and clinical utility of WES which resulted in recommendations for improving patient clinical management and surveillance. This study has also developed and made recommendations for variant filtering and prioritization strategies, which can be implemented in both research and diagnostic settings to streamline and aid in the identification of putative disease-causing variants in DD patients
dc.description.sponsorshipH3Africa NIMH/NIH
dc.description.sponsorshipNational Health Laboratory Service Research Trust (NHLSRT):94785
dc.description.sponsorshipFaculty of Health Science Research Council (FRC)
dc.description.sponsorshipThe National Manpower and Development Secretariat (NMDS) Lesotho
dc.description.submitterMM2024
dc.facultyFaculty of Health Sciences
dc.identifierhttps://orcid.org/ 0000-0003-1618-9971
dc.identifier.citationMolatoli, Mhlekazi Cathrine. (2024). The role of small genetic variants in the aetiology of developmental disorders in South Africa - a whole exome sequencing study [PhD thesis, University of the Witwatersrand, Johannesburg]. WireDSpace.
dc.identifier.urihttps://hdl.handle.net/10539/43295
dc.language.isoen
dc.publisherUniversity of the Witwatersrand, Johannesburg
dc.rights© 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.
dc.rights.holderUniversity of the Witwatersrand, Johannesburg
dc.schoolSchool of Pathology
dc.subjectDevelopmental disorders
dc.subjectWhole exome sequencing
dc.subjectSingle nucleotide variants
dc.subjectUCTD
dc.subject.otherSDG-8: Decent work and economic growth
dc.titleThe role of small genetic variants in the aetiology of developmental disorders in South Africa - a whole exome sequencing study
dc.typeDissertation
Files
Original bundle
Now showing 1 - 1 of 1
Loading...
Thumbnail Image
Name:
Molatoli_Role_2024.pdf
Size:
9.53 MB
Format:
Adobe Portable Document Format
License bundle
Now showing 1 - 1 of 1
No Thumbnail Available
Name:
license.txt
Size:
2.43 KB
Format:
Item-specific license agreed upon to submission
Description: