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.
Abstract
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.
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