Germline mutations of 4567 patients with hereditary breast-ovarian cancer spectrum in Thailand.

Multi-gene panel testing has led to the detection of pathogenic/likely pathogenic (P/LP) variants in many cancer susceptibility genes in patients with breast-ovarian cancer spectrum. However, the clinical and genomic data of Asian populations, including Thai cancer patients, was underrepresented, and the clinical significance of multi-gene panel testing in Thailand remains undetermined. In this study, we collected the clinical and genetic data from 4567 Thai patients with cancer in the hereditary breast-ovarian cancer (HBOC) spectrum who underwent multi-gene panel testing. Six hundred and ten individuals (13.4%) had germline P/LP variants. Detection rates of germline P/LP variants in breast, ovarian, pancreatic, and prostate cancer were 11.8%, 19.8%, 14.0%, and 7.1%, respectively. Non-BRCA gene mutations accounted for 35% of patients with germline P/LP variants. ATM was the most common non-BRCA gene mutation. Four hundred and thirty-two breast cancer patients with germline P/LP variants (80.4%) met the current NCCN genetic testing criteria. The most common indication was early-onset breast cancer. Ten patients harbored double pathogenic variants in this cohort. Our result showed that a significant proportion of non-BRCA P/LP variants were identified in patients with HBOC-related cancers. These findings support the benefit of multi-gene panel testing for inherited cancer susceptibility among Thai HBOC patients. Some modifications of the testing policy may be appropriate for implementation in diverse populations.

Tranexamic Acid as a Successful Therapy in Turner Syndrome With Recurrent Overt Gastrointestinal Bleeding due to Small Intestinal Venous Anomalies.

Small intestinal venous abnormalities are an underrecognized condition as an etiology of overt gastrointestinal (GI) bleeding in patients with Turner syndrome. Evidence-based therapeutic options for these lesions are lacking in the published literature. A 47-year-old woman with Turner syndrome with a 30-year course of recurrent GI bleeding was found to harbor diffuse small intestinal venous ectasias through endoscopic imaging. Achievement of a 21-month clinical remission (elimination of hospitalizations for overt GI bleeding and normalization of hemoglobin concentration) was reached after initiation of tranexamic acid titrated to 2,600 mg daily.

A cost-utility analysis of BRCA1 and BRCA2 testing in high-risk breast cancer patients and family members in Thailand: a cost-effective policy in resource-limited settings.

Background: Screening for germline pathogenic BRCA1 or BRCA2 variants (gBRCA) in high-risk breast cancer patients is known to be cost-effective in high-income countries. Nationwide adoption of genetics testing in high-risk breast cancer population remains poor. Our study aimed to assess gBRCA health economics data in the middle-income country setting of Thailand. Methods: Decision tree and Markov model were utilized to assess cost-utility between the testing vs. no-testing groups from a societal and lifetime perspective and lifetime. We interviewed 264 patients with breast/ovarian cancer and their family members to assess relevant costs and quality of life using EQ-5D-5L. One-way sensitivity, probabilistic sensitivity (Monte Carlo simulation), and budget impact analyses were done to estimate the outcome under Thailand's Universal Health Coverage scheme. Results: The predicted lifetime cost and Quality-adjusted Life Years (QALY) for those with breast cancer were $13,788 and 10.22 in the testing group and $13,702 and 10.07 in the no-testing group. The incremental cost-effectiveness ratio for gBRCA testing in high-risk breast cancer patients was $573/QALY. The lifetime cost for the family members of those with gBRCA was $14,035 (QALY 9.99), while the no-testing family members group was $14,077 (QALY 9.98). Performing gBRCA testing in family members was cost-saving. Conclusion: Cost-utility analysis demonstrated a cost-effective result of gBRCA testing in high-risk breast cancer patients and cost-saving in familial cascade testing. The result was endorsed in the national health benefits package in 2022. Other middle-income countries may observe the cost-effective/cost-saving aspects in common genetic diseases under their national health schemes.

Coronary artery aneurysm in Loeys-Dietz syndrome: a case report.

Background: Loeys-Dietz syndrome (LDS) is a connective tissue disorder that commonly presents with vascular abnormalities. Owing to the rarity and severity of the condition, consensus guidelines for aortic surgery thresholds vary. In addition, evaluation of coronary arteries in patients with LDS (either routinely or before aortic root surgery) remain undefined. In this case report, we discuss a patient with LDS who found to have an ectatic aortic root and a coronary artery aneurysm and discuss guidelines for evaluation and management in this patient population. Case summary: A 48-year-old woman was incidentally found to have a 45 mm ectatic aortic root during evaluation for a neck mass. As part of pre-operative evaluation for aortic root replacement, left heart catheterization revealed a left main coronary artery aneurysm. Family history revealed aortic aneurysms, sudden cardiac death, and tall height. Physical examination was notable for pectus excavatum and elongated limbs. Workup for inflammatory aetiologies of aortic root dilation was negative. Genetic testing revealed a heterozygous pathogenic TGBF3 variant, consistent with LDS Type 5. She subsequently underwent two-vessel coronary artery bypass, excision of her left main coronary artery aneurysm, and ascending aortic replacement. Discussion: In this case, we describe a patient with LDS who was noted to have a coronary artery aneurysm, a rare finding in the initial presentation of disease. In addition, we examine guidelines regarding evaluation of management of aortic root disease and coronary aneurysms.

Etiology of Dementia in Thai Patients.

INTRODUCTION: Molecular imaging has been developed and validated in Thai patients, comprising a portion of patients in the dementia registry. This should provide a more accurate diagnosis of the etiology of dementia, which was the focus of this study. METHODS: This was a multicenter dementia study. The baseline characteristics, main presenting symptoms, and results of investigations and cognitive tests of the patients were electronically collected in the registry. Functional imaging and/or molecular imaging were performed in patients with an equivocal diagnosis of the causes of dementia, especially in atypical dementia or young onset dementia (YOD). RESULTS: There were 454 patients in the study. The mean age of the patients was 78 years, with 60% female. Functional imaging and/or molecular imaging were performed in 57 patients (57/454 patients, 13%). The most common cause of dementia was Alzheimer's disease (AD; 50%), followed by vascular dementia (VAD; 24%), dementia with Lewy bodies (6%), Parkinson's disease dementia (6%), frontotemporal dementia (FTD; 2.6%), progressive supranuclear palsy (2%), multiple system atrophy (0.8%), and corticobasal syndrome (0.4%). YOD accounted for 17% (77/454 patients), with a mean age of 58 years. The causes of YOD were early onset amnestic AD (44%), VAD (16%), behavioral variant FTD (8%), posterior cortical atrophy (6.5%), and logopenic variant primary progressive aphasia (5.2%). CONCLUSION: AD was the most common cause of dementia in Thai patients and the distribution of other types of dementia and main presenting symptoms were similar to previous reports in Western patients; however, the proportion of YOD was higher.

Identification of novel mutation in RANKL by whole-exome sequencing in a Thai family with osteopetrosis; a case report and review of RANKL osteopetrosis.

BACKGROUND: Osteopetrosis is a rare form of skeletal dysplasia characterized by increased bone density that leads to bone marrow failure, compressive neuropathy, and skeletal dysmorphism. Molecular diagnosis is essential as it guides treatment and prognosis. We report Thai siblings with an ultra-rare form of osteopetrosis. METHODS: The older brother and the younger sister presented with chronic mandibular osteomyelitis in their 20s. Since childhood, they had visual impairment, pathological fracture, and skeletal dysmorphism. Quadruplet whole-exome sequencing was performed and confirmed with Sanger sequencing. Novel mutation in TNFSF11 (RANKL) c.842T>G, p.Phe281Cys was identified in a homozygous state in both siblings. RESULTS: Surgical debridement, antibiotic, and hyperbaric oxygen therapy were used and discontinued over a 6-month period with normalization of C-reactive protein. Hematopoietic stem cell transplantation candidacy was excluded by molecular diagnosis. CONCLUSION: We report a novel mutation in an ultra-rare form of osteopetrosis. Our siblings manifested with a milder phenotype in comparison with nine cases previously published.

Thai patients who fulfilled NCCN criteria for breast/ovarian cancer genetic assessment demonstrated high prevalence of germline mutations in cancer susceptibility genes: implication to Asian population testing.

BACKGROUND: Germline genetic mutation plays a significant role in breast cancer susceptibility. The strength of such predisposition varies among ethnic groups across the globe, and clinical data from Asian population to develop a strategic approach to who should undergo a genetic test are lacking. METHODS: We performed a multigene test with next generation sequencing in Thai patients whose clinical history fulfilled NCCN criteria for breast/ovarian cancer genetic assessment, consists of 306 breast cancer patients, 62 ovarian cancer patients, 14 pancreatic cancer patients and 7 prostate cancer patients. Genetic test result and clinical history were then checked with each NCCN criteria to determined detection rate for each indication. RESULTS: There were 83 pathogenic/likely pathogenic (P/LP) variants identified in 104 patients, 44 of these P/LP variants were novel. We reported a high rate of germline P/LP variants in breast cancer (24%), ovarian cancer (37%), pancreatic cancer (14%), and prostate cancer (29%). Germline P/LP variants in BRCA1 and BRCA2 accounted for 80% of P/LP variants found in breast cancer and 57% of P/LP variants found in ovarian cancer. The detection rate of patients who fulfilled NCCN 2019 guideline for genetic/familial high-risk assessment of breast and ovarian cancers was 22-40%. CONCLUSION: Overall, the data from this study strongly support the consideration of multigene panel test as a diagnostic tool for patients with inherited cancer susceptibility in Thailand and Asian population. Implementation of the NCCN guideline is applicable, some modification may be needed to be more suitable for Asian population.

C9orf72 Hexanucleotide Repeat in Huntington-Like Patients: Systematic Review and Meta-Analysis.

Introduction: Patients with Huntington-Like disorders (HLD) comprise a variety of allelic disorders sharing a Huntington phenotype. The hexanucleotide repeat expansion of the C9orf72 gene could explain part of the HLD etiology. We aimed to conduct a systematic review and meta-analysis looking for the frequency of the hexanucleotide repeat expansion of the C9orf72 gene in HLD patients. Methods: The protocol was registered on the International Prospective Register of Systematic Reviews database (PROSPERO) (registration number: CRD42018105465). The search was carried out in Medline, Scopus, Web of Science, and Embase in April 2018, and updated in July 2020. Observational studies reporting patients with HLD carrying the hexanucleotide repeat expansion in the C9orf72 gene were selected and reviewed; this process was duplicated. The cutoff threshold for considering the hexanucleotide expansion as a pathogenic variant was equal to or >30 G4C2 repeats. Cases with intermediate alleles with 20-29 repeat are also analyzed. Pooled frequency and 95% CI were calculated using random-effects models. Results: Nine out of 219 studies were selected, reporting 1,123 affected individuals with HLD. Among them, 18 individuals carried C9orf72 expansion, representing 1% (95% CI: 0-2%, I 2 = 0%) of the pooled frequency. Seven selected studies came from European centers, one was reported at a US center, and one came from a South-African center. We identified five individuals carrying intermediate alleles representing 3% (95% CI: 0-14%, I 2 = 78.5%). Conclusions: The frequency of C9orf72 unstable hexanucleotide repeat expansion in HLD patients is very low. Further studies with more accurate clinical data and from different ethnic backgrounds are needed to confirm this observation.

Factors influencing the National License Examination step 1 score in preclinical medical students.

The National License Examination step 1 (NLE1), which tests basic medical sciences knowledge in Thailand, is considered to be tough and stressful for medical students due to the large amount of content. This study aimed to determine factors influencing the NLE1 score (NLE1S). The NLE1S, academic achievement, and class attendance were obtained officially. Other factors, including study habits, were obtained via a questionnaire, with 81.97% (241/294) being returned. Students were divided into four groups according to the central passing score and Z-score of the NLE1S, including the fail (<52%; n = 13), low-pass (52 to <70%; n = 121), high-pass (70 to <80%; n = 89), and excellent (≥80%; n = 18) groups. Men had higher NLE1S (P < 0.001) and comprehensive examination scores (P < 0.001) than women. Students with high motivation to study medicine had higher NLE1S. Daily preparation time (h/day) was lower, but stress was higher, in the fail group. In the excellent group, internet for academic use and achievement of study targets were higher; internet for nonacademic use, instance of absence, and stress were lower; and check-in time was earlier. The NLE1S had strong positive correlations with the comprehensive examination score and academic achievement during preclinical studies. By setting the NLE1S as a dependent variable in multivariate regression analyses, models of significant interactions were observed by setting behavioral factors, the comprehensive examination score, and academic achievement during a regular class as independent variables. Thus exhibiting good study habits and showing good academic performance throughout preclinical studies should be encouraged among students to achieve a good NLE1S.