Genotype-phenotype study of tuberous sclerosis complex in selected cohort of Malaysian patients with TSC2 mutations

Ismail, Nur Farrah Dila (2015) Genotype-phenotype study of tuberous sclerosis complex in selected cohort of Malaysian patients with TSC2 mutations. Masters thesis, Universiti Sains Malaysia.

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TSC (Tuberous Sclerosis Complex) is an autosomal dominant disorder characterized by a widespread hamartomatous lesion in multiple affected organs. It is a syndrome caused by mutations in either of these two genes, TSC1 and TSC2. Here, mutation analysis as well as genotype-phenotype correlation assessment were done in 37 TSC patients. Thirty-seven patients, diagnosed as a case of TSC (either definite or possible) based on the 2012 clinical diagnostic criteria (Northrup et al, 2013) were included in the studies. TSC clinical manifestations among patients were broad and the most common were skin and brain tumours. Epilepsy was also common and was seen more in male compared to female patients while frequency of mental retardation is low. There is no age, ethnicity and gender preference of TSC manifestations. It is noticeable that familial patients showed less number of clinical features compared to sporadic patients although no difference in the severity of the manifestations was observed. The method of choice used were denaturing high-performance liquid chromatography (DHPLC), direct sequencing, multiplex ligation-dependent probe amplification (MLPA) and Amplicon Sequencing using MiSeq Platform. TSC2 mutations were identified in 22 (73%) of 30 TSC patients while eight (27%) were identified with no mutation. Out of 20 different pathogenic mutations, ten were novel. 30% is nonsense mutations, 25% is missense mutations, 25% is small insertion/deletion causing frameshift mutations, 15% is large deletions and 5% is splice site error mutation. MLPA was suggested as the first line detection method for TSC targeting large duplication and deletion mutations. The second line of mutation detection is Illumina MiSeq Amplicon Sequencing platform for detection of smallmutations. No particular mutations were found to influence severity and/or more number of clinical manifestations. However, polycystic kidney disease was identified in one case with extended deletion from TSC2 to PKD1 while cardiac rhabdomyoma are found more in patients with mutations in exon 33-41 of TSC2 gene. Due to small number of study subjects, the clinical manifestations of the group of patients without identifiable mutation were not much different from the group of patients with identifiable mutations.

Item Type: Thesis (Masters)
Uncontrolled Keywords: Tuberous sclerosis
Subjects: R Medicine > RC Internal medicine
Divisions: Kampus Kesihatan (Health Campus) > Pusat Pengajian Sains Perubatan (School of Medical Sciences) > Thesis
Depositing User: Mr Abdul Hadi Mohammad
Date Deposited: 16 Jul 2018 01:19
Last Modified: 16 Jul 2018 01:19

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