Demographic and molecular genetic studies of neural tube defects in a cohort of Malaysian patients / Adibah Sahmat
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...
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my.um.stud.114532021-01-05T00:32:21Z Demographic and molecular genetic studies of neural tube defects in a cohort of Malaysian patients / Adibah Sahmat Adibah, Sahmat R Medicine (General) 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. 2018 Thesis NonPeerReviewed application/pdf http://studentsrepo.um.edu.my/11453/4/adibah.pdf 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. http://studentsrepo.um.edu.my/11453/ |
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R Medicine (General) Adibah, Sahmat Demographic and molecular genetic studies of neural tube defects in a cohort of Malaysian patients / Adibah Sahmat |
description |
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. |
format |
Thesis |
author |
Adibah, Sahmat |
author_facet |
Adibah, Sahmat |
author_sort |
Adibah, Sahmat |
title |
Demographic and molecular genetic studies of neural tube defects in a cohort of Malaysian patients / Adibah Sahmat |
title_short |
Demographic and molecular genetic studies of neural tube defects in a cohort of Malaysian patients / Adibah Sahmat |
title_full |
Demographic and molecular genetic studies of neural tube defects in a cohort of Malaysian patients / Adibah Sahmat |
title_fullStr |
Demographic and molecular genetic studies of neural tube defects in a cohort of Malaysian patients / Adibah Sahmat |
title_full_unstemmed |
Demographic and molecular genetic studies of neural tube defects in a cohort of Malaysian patients / Adibah Sahmat |
title_sort |
demographic and molecular genetic studies of neural tube defects in a cohort of malaysian patients / adibah sahmat |
publishDate |
2018 |
url |
http://studentsrepo.um.edu.my/11453/4/adibah.pdf http://studentsrepo.um.edu.my/11453/ |
_version_ |
1738506486325182464 |
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13.209306 |