Germline variants of uncertain significance, their frequency, and clinico-pathological features in a cohort of Sri Lankan patients with hereditary breast cancer.

BACKGROUND: Next-Generation Sequencing (NGS)-based testing in cancer patients has led to increased detection of variants of uncertain significance (VUS). VUS are genetic variants whose impact on protein function is unknown. VUS pose a challenge to clinicians and patients due to uncertainty regarding their cancer predisposition risk. Paucity of data exists on the pattern of VUS in under-represented populations. This study describes the frequency of germline VUS and clinico-pathological features in Sri Lankan hereditary breast cancer patients. METHODS: Data of 72 hereditary breast cancer patients who underwent NGS-based testing between January 2015 and December 2021 were maintained prospectively in a database and analyzed retrospectively. Data were subjected to bioinformatics analysis and variants were classified according to international guidelines. RESULTS: Germline variants were detected in 33/72(45.8%) patients, comprising 16(48.5%) pathogenic/likely pathogenic variants and 17(51.5%) VUS. Distribution of VUS in breast cancer predisposing genes were :APC:1(5.8%), ATM:2(11.7%), BRCA1:1(5.8%), BRCA2:5(29.4%), BRIP1:1(5.8%), CDKN2A:1(5.8%), CHEK2:2(11.7%), FANC1:1(5.8%), MET:1(5.8%), STK11:1(5.8%), NF2:1(5.8%). Mean age at cancer diagnosis in patients with VUS was 51.2 years. Most common tumour histopathology was ductal carcinoma 11(78.6%). 50% of tumours in patients having VUS in BRCA1/2 genes were hormone receptor negative. 73.3% patients had family history of breast cancer. CONCLUSIONS: A significant portion of patients had a germline VUS. Highest frequency was in BRCA2 gene. Majority had family history of breast cancer. This highlights the need to undertake functional genomic studies to determine the biological effects of VUS and identify potentially clinically actionable variants that would be useful for decision-making and patient management.

The first genetically authenticated case of Leber hereditary optic neuropathy in Sri Lanka: a case report and review of the literature.

INTRODUCTION: Leber hereditary optic neuropathy is a genetic disease of mitochondrial inheritance characterized by bilateral irreversible vision loss, predominantly affecting males. We report the first genetically authenticated Sri Lankan case of Leber hereditary optic neuropathy, illustrating its characteristic features of male predominance and variable penetrance. CASE PRESENTATION: A 15-year-old previously healthy Sri Lankan boy presented with painless progressive vision loss in his right eye, followed by vision loss in his left eye within 3 months. There was no history of drug or toxin exposure, or a family history of vision loss. His parents were nonconsanguineous. On examination, he could only perceive light. Funduscopy revealed bilateral optic atrophy. Routine hematological and biochemical blood tests, including inflammatory markers, were normal. Cranial magnetic resonance imaging was unremarkable. Optical coherence tomography, and the clinical presentation, suggested a diagnosis of Leber hereditary optic neuropathy, which was confirmed by detection of m.14484T > C pathogenic variant in the MT-ND6 gene through targeted genetic analysis for the three common pathogenic variants in mitochondrial deoxyribonucleic acid. He was homoplasmic for the variant, and his asymptomatic mother and two female siblings were also found to be harboring the variant with homoplasmy. CONCLUSIONS: This case report is intended to increase awareness of Leber hereditary optic neuropathy, and highlights the need to consider this rare diagnosis in the appropriate clinical context. It also illustrates the phenomena of incomplete penetrance and male predominance, and suggests the possibility of an X-linked gene governing Leber hereditary optic neuropathy disease expression, which warrants further investigation.

Multi-system Klebsiella sepsis: A tale of destruction form lung to eye.

Klebsiella pneumoniae, found in the gastrointestinal flora is a causative agent of hospital-acquired infections. Although isolated organ infections are common, reports of multi-system involvement are rare. We report on a susceptible patient presenting with disseminated Klebsiella infection with concurrent multi-organ disease involving the lung, liver, prostate and eye. He recovered after prolonged therapy but suffered from permanent sequalae. Early diagnosis and aggressive therapy is facilitated by awareness and a high degree of suspicion in at-risk patient groups.

Tuberculosis presenting as arthritis of the ankle: A case report.

Tuberculosis presenting as monoarticular involvement in immunocompetent patients is rare. Here, we report a Sri Lankan patient presenting with ankle swelling due to tuberculosis with no other extrapulmonary or pulmonary involvement. Magnetic resonance imaging showed destruction of articular cartilage of the ankle joint with chronic inflammation of the subtalar joint. The diagnosis was confirmed by synovial tissue culture which was positive for Mycobacterium tuberculosis. The patient recovered uneventfully with anti-tuberculosis treatment. Therefore, a high degree of suspicion is necessary to diagnose extrapulmonary tuberculosis when patients are presenting with atypical monoarthritis.

Descriptive analysis of glomerulonephritis by histological type and their progression among adults in a tertiary care center in Sri Lanka.

Prevalence of different glomerulonephritides and their clinical course vary geographically. Our objectives are to assess the prevalence of different histological types of glomerulonephritis (GN) based on the light microscopic histology and to assess their progression according to histological type. A retrospective cross-sectional study was carried out among adult patients (>18 years) with a histological diagnosis of GN at the University Professorial Unit over a period of six months. Information including demographic data, renal biopsy findings, and progression of the disease through serum creatinine (SCr) level were collected through existing clinic records of consenting patients. Data were analyzed by Statistical Package for the Social Sciences. There were 109 patients (females = 90) with a mean age of 40.32 ± 15.24 years. The most common histological type was focal segmental glomerulosclerosis (FSGS) in 27 (24.8%) followed by minimal change disease in 25 (22.9%), mesangioproliferative glomerulonephritis (MesPGN) in 18 (16.5%), membranoproliferative glomerulonephritis in six (5.5%), membranous glomerulonephritis in three patients (2.8%), and crescentic GN in one patient (0.9%). There was a statistically significant rise in SCr level at seven years from the initial presentation in the histological types; FSGS [P = 0.04; 95% confidence interval (CI) = 0.06-1.0] and MesPGN (P = 0.03; 95% CI = 0.3-0.9). Focal segmental glomerulosclerosis was the most common histology type in the population studied. There was a statistically significant progression of FSGS and MesPGN.