Adibah, Sahmat (2018) Demographic and molecular genetic studies of neural tube defects in a cohort of Malaysian patients / Adibah Sahmat. Masters thesis, University of Malaya.
Abstract
Neural tube defects (NTDs) are among the most common birth defect which occur at a range of 0.5 – 10 or more in 1000 live births worldwide. According to our data from the Department of Patient Information University of Malaya Medical Centre (UMMC) between the years 2003 until 2016, there were 86 cases with spina bifida (1.33-6.4 per 1000 live births), 19 cases of anencephaly (0.38 per 1000 live births) and no report of craniorachischisis. Ethnicity of the patients was a factor of the incident whereby the highest numbers were Malays for both spina bifida and anencephaly. Most of the patients belonged to in mothers below 35 years of age. Additionally, males dominate the occurrence of spina bifida meanwhile almost equal number of male and female for anencephaly. For spina bifida cases, the highest number of diagnoses reported was lumbar myelomeningocele. Furthermore, 32.84% of patients were found to be mobile and 36.07% of patients received formal education. To date, the most studied human spina bifida risk variant is the MTHFR C677T (rs1801133). However, this variant was not well replicated in many populations across the world, indicating that the variant is not likely to be a major contributor of NTDs globally. Therefore, the candidate genes for screening NTDs worldwide has remained elusive. We screened for the potential genetic cause of spina bifida in 40 reported spina bifida risk genes in our patient cohort using Whole Exome Sequencing (WES) datasets. We managed to identify 10 non-synonymous variants in MTHFR, ALDH1L1, MTRR, SARDH, XPD, CUBN and BRCA1 genes with potential pathogenic effects. The identified variants might be the risk factor for spina bifida in patients individually, but do not represent as common variants within the cohort. We also screened the potential spina bifida candidate genes using Whole-Exome Sequencing (WES) in three representative patients (triad study); (1) syndromic spina bifida aperta, (2) non-syndromic spina bifida aperta and (3) non-syndromic spina bifida occulta. Although our patient cohort is small, the power of the study is enhanced as it is iv a triad study involving the proband and his/her parents. Case (1) involves a patient born with spina bifida aperta (myelomeningocele-type) with variant Turner syndrome. No likely candidate variant was identified for Patient 1. Case (2) is a non-syndromic spina bifida aperta. WES revealed six candidate variants but only SEC63 (rs17854547) variant was chosen as the potential candidate variant by taking into account the literature surrounding the SEC family of genes and NTDs. The variant is considered uncommon but was predicted to be non-deleterious when subjected to the bioinformatics analysis. Case (3) is a patient born with spina bifida occulta (lipomyelomeningocele-type). WES identified a novel and deleterious variant in the ZIC2 gene as the candidate variant for Patient 3. In summary, all variants found on their own might not be the spina bifida genetic risk factor. The act of these variants in combination with other events might be the possible causative factor(s). In the future, screening of these variants in large scale genome-wide association study is needed to confirm the variants as common genetic risk factors for spina bifida.
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