3. DISCUSSION
The two tumor suppressor genes TSC 1 and TSC 2 were
identified through their involvement in TSC with more than 1000
mutations localized throughout the genes. TSC 2 mutations
accounted for approximately 70% of all disease-causing mutations and
expressed more severe clinical phenotypes than TSC 1
mutations.3
The novel frameshift mutation found in this study was classified as
likely pathogenic according to ACMG guidelines for variant
classification. It was considered as member of the null variant group
which includes nonsense, frameshift, canonical +/-1 or 2 splice sites,
initiation codon, single or multi-exon deletion mutations. This is the
most prominent disease-causing group found in TSC 2
gene.3 The mutation is located in the tuberin-type
domain and was predicted to result in truncating and structural
modification of the encoded protein. Different mutations were previously
reported for TSC 2 gene.6–13 A novel frameshift
mutation in exon 23 of TSC 2 gene classified as likely pathogenic
was previously reported in Chinese patients suffering
epilepsy.8 Another TSC 2 frameshift mutation was
identified in a Bulgarian patient.10 Cases of
lymphangiomyomatosis (LAM) considered as affecting almost exclusively
young women resulted from mutations in the extreme carboxy-terminus of
tuberin.11 However, the lymphangiomyomatosis phenotype
observed in our patient was not due to mutation in Rap-Gap domain as
previously described. The patient multisystemic impairments and severe
clinical phenotypes were probably associated with the pathogenic variant
identified in TSC 2 gene, but we cannot exclude the role of an
additional unknown factor. Furthermore, the clear association of this
novel mutation with the disease needs to be verified using cell and
animal model for mutant protein function. We were not able to collect
sample from the patient’s family due to refusal to participate.
Therefore, it was not possible to determine whether the mutation was
sporadic or hereditary.
There was currently no available and approved therapy for TSC in
Vietnam. Confirmatory diagnosis for TSC by next-generation sequencing
could contribute to induce awareness of health care personnel and
patient’s family about the disease.