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.