2. CASE REPORT
A 17-year-old female patient was diagnosed as having heart tumor when
she had a routine checkup in a local hospital and transferred to Tam Duc
Heart Hospital was admitted to our hospital. The patient was born at
full term, normal pregnancy and natural delivery, with no family history
of epilepsy. At 5-month-old, the patient started suffering from
convulsion after falling down from a hammock. She was then diagnosed
with generalized epilepsy and prescribed anticonvulsant medication. From
age 2, she experienced partial seizures with eight to ten episodes a
year. Throughout the years, she was treated with anti-epileptic drugs
including sodium valproate and carbamazepine without successful control
of seizures. She stopped studying at age 15 due to intellectual
disability.
Physical examination showed facial angiofibromas over her nose, cheeks
and forehead, intraoral fibromas and hypopigmented skin lesions
(shagreen patch) on different parts of the body (Figure 1). Her
biochemical laboratory test was unremarkable. Echocardiography showed
chordae of tendinae sclerosis (Figure 2). Chordae tendineae sclerosis
and the presence of lipofibroma in midlateral wall of left ventricle
were also demonstrated by cardiac MRI (Figure 2). Cerebral MRI revealed
multiple 5 to 7 mm nodules in the brain cortex and subependymal zone
(Figure 3). Thoracic multi-slide computed tomography (MSCT) showed
multiple 3-5 mm nodules in both lungs (Figure 4) . Renal
angiomyolipomas of 50x50 mm in bilateral kidneys were revealed by
ultrasonography and MSCT (Figure 5). With those characteristic clinical
manifestations, we considered that the patient fulfilled diagnostic
criteria of TSC.
Next generation sequencing of TSC 1 and TSC2 gene was performed on
patient blood sample to confirm the diagnosis of TSC, after obtention of
patient’s parents signed informed consent. Library preparation was
carried out using Trusight Cancer kit (Illumina, United States)
according to the manufacturer’s instructions. Prepared library was
sequenced using Illumina Miniseq platform. Variants (SNPs and indels)
were called using the Genome Analysis ToolKit (GATK) according to
guidelines, and human reference genome hg38.4 Variants
with at least 20X coverage were further analyzed using Alamut Visual
(Interactive Biosoftware). Synonymous variants, intronic variants
outside of the flanking regions, and variants with a minor allelic
frequency (MAF) ≥ 5% in the Genome Aggregation (gnomAD) database were
excluded based on the American College of Medical Genetics and Genomics
(ACMG) recommendations for variant frequency in control
populations.5 The patient was found to carry a novel
heterozygous frameshift mutation c.2626delA, p.Thr876ProfsTer18
(NM_000548.5) in exon 23 of TSC 2 gene. This mutation was
classified as likely pathogenic based on ACMG guidelines. Sanger
sequencing was used to confirm the identified mutation (Figure 6). This
mutation was not identified in normal subjects according to gnomAD, and
was not reported in HGMD, OMIM and Clinvar as associated with TSC.
There is no approved therapy protocol for TSC in Vietnam yet and the
follow-up was not possible since the patient lives in distant region
from our hospital.