Familial clustering of nonalcoholic fatty liver disease in first-degree relatives of adults with lean nonalcoholic fatty liver disease.

BACKGROUND AND AIMS: The heritability of nonalcoholic fatty liver disease (NAFLD) in lean individuals is undetermined. This familial aggregation study aimed to evaluate familial linkage for NAFLD and the risk of NAFLD among first-degree relatives of probands with lean NAFLD. METHODS: This study prospectively recruited cohorts of probands with lean NAFLD, probands with obese NAFLD, and lean probands with non-NAFLD and their respective first-degree relatives. A total of 257 participants were evaluated for liver steatosis, defined by the controlled attenuation parameter ≥288 dB/m2 , metabolic characteristics, and the PNPLA3, TM6SF2, and MBOAT7 polymorphisms. RESULTS: The prevalence of NAFLD in first-degree relatives of lean NAFLD probands (39.9%) was similar to that in the obese NAFLD group (36.9%) and was significantly higher than in lean persons without NAFLD (19.1%). First-degree relatives of probands with NAFLD who were male, and had central obesity, hypertriglyceridaemia, insulin resistance, and the PNPLA3 rs738409C>G allele had a significantly higher prevalence of NAFLD. After multivariable adjustment for gender, metabolic characteristics, and the PNPLA3 rs738409C>G allele, first-degree relatives of probands with lean NAFLD (odds ratio [OR], 5.13; 95% CI, 1.77-14.86) and obese NAFLD (OR, 3.20; 95% CI, 1.14-8.99) exhibited an increased risk of NAFLD compared with those of lean controls without NAFLD. CONCLUSIONS: Our well-phenotype cohorts revealed familial clustering of NAFLD and higher risks of NAFLD in first-degree relatives of probands with lean or obese NAFLD. The findings encourage clinicians caring for NAFLD patients to be more vigilant for NAFLD in their family members.

How do we translate gaps and unmet needs of blood management for thalassemia into a collaborative implementation framework?

BACKGROUND AND OBJECTIVE: The mainstay of management for thalassemia is regular blood transfusions. However, gaps and unmet needs of blood services for thalassemia are still not clearly identified and addressed in Thailand, a country prevalent with thalassemia. What can be a collaborative implementation framework that helps advance practices and policies relating to blood management for thalassemia? METHODS: The first Blood & Beyond Roundtable Discussion was held in July 2022 to gather the current situation, gaps, and unmet needs of blood services for thalassemia from multidisciplinary experts and thalassemic patients. The Implementation Guide as suggested by the Centre for Effective Services was applied as a tool to consolidate information from the discussions and construct the collaborative implementation framework. RESULTS: The National Blood Center and hospitals in Thailand followed the missions specified in the National Blood Policy and the standard guidelines to ensure the best practice of blood management for thalassemia. However, there were six gaps and unmet needs identified from the discussions. After all discussion points were mapped onto the framework, an implementation plan comprised of five specific activities became clear and actionable. CONCLUSION: Without the complete information from both experts and patients, the implementation plan would not have been successfully constructed. The method that we employed to translate all information into the framework can be adapted by other countries to develop their own specific framework efficiently.

Single-Tube Screen for Rapid Detection of Repeat Expansions in Seven Common Spinocerebellar Ataxias.

BACKGROUND: The autosomal dominantly inherited and genetically heterogeneous spinocerebellar ataxias (SCAs) exhibit highly similar clinical presentations. Many are caused by repeat expansions, of which at least 8 involve CAG repeats. Repeat expansion detection is the only method to confirm disease status in symptomatic individuals. We present a novel strategy to simultaneously screen for the presence of CAG repeat expansion in the genes responsible for SCAs 1, 2, 3, 6, 7, 12, and dentatorubral-pallidoluysian atrophy using a simplified single-tube assay. METHODS: The method employs differentially labeled locus-specific primers and a common triplet-primed primer. Amplified products from each locus are distinguished by a combination of the product size and the fluorophore tag. The upper size limit of the normal allele range was used as the cutoff for distinguishing normal from potentially affected samples, with repeat expansion detected by presence of electrophoretic peaks extending beyond the cutoff. RESULTS: Blinded evaluation of the assay on 60 genotype-known DNA samples correctly detected repeat expansion in the expected SCA repeat locus for all 31 DNA samples. CONCLUSIONS: In principle, this strategy can be applied to the simultaneous screening of any group of disease genes sharing the same repetitive units and/or their reverse complement.

Sleep Disorder: An Overlooked Manifestation of Glucose Transporter Type-1 Deficiency Syndrome.

Glucose transporter type-1 deficiency syndrome (Glut1 DS) is a rare disorder with various manifestations. Early diagnosis is crucial because treatment with the ketogenic diet can lead to clinical improvement. Here, we report the cases of two siblings with Glut1 DS and one of them presented with sleep disorder which is a rare and atypical manifestation of Glut1 DS. Patient 1 was a 3.5-year-old boy who presented with paroxysmal loss of tone and weakness of the whole body with unresponsiveness after waking up. He also had excessive daytime sleepiness, insomnia, and restless sleep. His other clinical findings included focal seizures, paroxysmal exercise-induced dyskinesia (PED), ataxia, mild global developmental delay, and hyperactivity. Patient 2 was a 5.5-year-old boy who presented with drug-resistant focal epilepsy, global developmental delay, paroxysmal dystonia, and ataxia. A novel heterozygous nonsense variant of SLC2A1, c.1177G > T (p.Glu393*), classified as a pathogenic variant, was identified in both patients, but not in their parents' blood. After treatment with the modified Atkins diet, their neurological functions significantly improved. In conclusion, we reported two siblings with variable phenotypes of Glut1 DS with a novel nonsense mutation. Although sleep disorder and daytime somnolence were the nonclassical manifestations of Glut1 DS, the diagnostic evaluation of possible Glut1 DS in patients presented with daytime sleepiness, particularly in cases with the cooccurrence of seizures or movement disorders should be considered.

Association study identifies genetic determinants and non-genetic factors on steady-state plasma and therapeutic outcome of galantamine in mixed dementia.

PURPOSE: This study aimed to evaluate the influence of genetic polymorphisms of drug-metabolizing enzyme genes, transporter gene, pathological gene (APOE), and non-genetic factors on therapeutic outcomes as well as steady-state plasma concentrations (Cpss) of galantamine in Thai patients with mixed dementia. METHODS: Fifty-one Thai patients with mixed dementia who received galantamine for at least 6 months were recruited. CYP2D6, CYP3A5, and ABCB1 polymorphisms were detected by TaqMan® Genotyping Assay. UGT1A1 and APOE polymorphism was detected by direct Sanger sequencing technique and restriction fragment length polymorphism technique. Cpss of galantamine was measured by ultra-performance liquid chromatography. Associations of genetic and non-genetic factors with Cpss and clinical outcomes (change in cognitive function as measured by the Thai Mental State Examination (ΔTMSE) scores) were determined by using univariate and multivariate analysis. RESULTS: The multivariate regression model revealed that patients who carried one or more detrimental allelic variant (CYP2D6, CYP3A5, and UGT1A1) showed a tendency toward a higher galantamine adjusted Cpss (B = 34.559, 95% CI = 0.741-68.377, p value = 0.045). Logistic regression analysis also revealed CYP2D6*10 carriers were significantly associated with higher ΔTMSE (B = 5.227, 95% CI = 2.395-8.060, p value = 0.001). UGT1A1 mutant alleles and non-genetic factors including concomitant use of statin drugs and higher education level can attenuate therapeutic outcomes of galantamine. CONCLUSION: Pharmacokinetic-related genes including CYP2D6*10 and UGT1A1 mutant alleles were significantly associated with galantamine adjusted Cpss and cognitive function. Determination of Cpss and genotype could be an adjunct examination to provide further explanation in interindividual variability of galantamine therapeutic outcome.

Effect of gene polymorphisms in ADAM33, TGFß1, VEGFA, and PLAUR on asthma in Thai population.

BACKGROUND: Most of the asthma susceptibility genes have demonstrated moderate effect. Gene-gene interaction may play a role in asthma. OBJECTIVE: To investigate the genetic and gene-gene interaction effects of single nucleotide polymorphisms (SNPs) in the ADAM33, TGFß1, VEGFA, and PLAUR genes on asthma in Thai population. METHODS: Two hundred and fifty control and 250 asthmatic Thai subjects were recruited. Asthma was diagnosed based on symptoms and spirometry assessments using criteria outlined by the American Thoracic Society. Degrees of asthma severity were determined according to guidelines provided by the Global Initiative for Asthma. Asthmatic subjects were subcategorized into the low-severity (n = 106) and high-severity (n = 144) groups. Eleven SNPs in four genes were genotyped, including ADAM33 SNPs (rs528557/S2, rs598418, rs44707/ST+4), TGFß1 SNPs (rs2241715, rs11466345), VEGFA SNPs (rs833069, rs3025010), and PLAUR SNPs (rs344781, rs344787, rs2239374, rs2239372). Association analyses between SNPs and asthma, and tests for gene-gene interaction were performed. RESULTS: The ADAM33 rs528557/S2 SNP was found to be associated with asthma according to the additive and dominant models. Comparison between the low-severity group and controls showed the VEGFA rs833069 SNP to be significantly associated with the low-severity group. No gene-gene interactions were observed in this study. CONCLUSIONS: The ADAM33 rs528557/S2 and the VEGFA rs833069 SNPs were associated with Thai asthmatics, as well as with other populations worldwide. Further studies are warranted to investigate the use these SNPs as biomarkers for establishing early diagnosis or for predicting future risk of asthma.

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.

Molecular and clinical characterization of Thai patients with achromatopsia: identification of three novel disease-associated variants in the CNGA3 and CNGB3 genes.

PURPOSE: Achromatopsia (ACHM) is an autosomal recessive cone disorder characterized by pendular nystagmus, photophobia, reduced visual acuity, and partial or total absence of color vision. Mutations in six genes (CNGA3, CNGB3, GNAT2, PDE6C, PDE6H, and ATF6) have been reported in ACHM. There is no information on these disease-associated genes in Thai population. This study aimed to investigate the molecular and clinical characteristics in Thai patients with ACHM. METHODS: Seven unrelated Thai patients with ACHM were recruited. Detailed ophthalmologic examination was performed. Polymerase chain reaction (PCR)-coupled single-strand conformation polymorphism (SSCP) screening followed by Sanger sequencing was used to identify sequence variants in all exons and splice junctions of three genes (CNGA3, CNGB3, and GNAT2). The pathogenicity of the detected variants was interpreted. Segregation analysis was performed to determine variant sharing in available family members. RESULTS: Four patients displayed different SSCP migration patterns. Sequence analysis revealed a reported pathogenic and a novel disease-associated variant in the CNGA3 gene. For the CNGB3 gene, we found two novel disease-associated variants and a reported variant of uncertain significance (VUS). Segregation analysis confirmed that the variants identified in each patient were present in the heterozygous state in their corresponding family members, which was consistent with an autosomal recessive mode of inheritance. CONCLUSIONS: This study demonstrated the first molecular and clinical characterization of ACHM in Thai patients. The identification of disease-associated genes in a specific population leads to a personalized gene therapy benefiting those affected patients.

Incidence and risk factors of vascular dementia in Thai stroke patients.

BACKGROUND: Besides disability in stroke survivors, vascular cognitive impairment (VCI) can prevent these patients from living independently. The purpose of this study is to look for the incidence and risk factors of vascular dementia in Thai patients with stroke. METHODS: Adults patients with ischemic stroke were prospectively included. Cognitive assessment was performed at 3-6 months after stroke onset. Montreal Cognitive Assessment (MOCA)- Thai version was used to evaluate cognitive function, with the cutoff point of 24/25 of MOCA to define cognitive impairment/normal cognition. Vascular mild cognitive impairment (VMCI) and vascular dementia (VAD) were diagnosed in those with cognitive impairment. Epidemiologic data, Apolipoprotein E (ApoE) status, and stroke characteristics were compared between patients with and without VAD. RESULTS: There were 180 patients with the mean age of 65 years. Median time after stroke onset to have cognitive assessment was 6 months. Ninety patients (50%) had VMCI. VAD was diagnosed in 49 patients (27%). Mean Thai version of mental state examination (TMSE) and MOCA scores in patients with VAD were 20 and 12, respectively. Multivariate analysis showed that older age (OR 4.994, 95%CI 1.602-15.565, p-value = 0.006), lower education (OR 10.306, 95%CI 3.162-33.586, p-value < 0.001), history of stroke (OR 4.959, 95%CI 1.036-23.741, p-value = 0.045) and moderate to severe cerebral white matter lesions (OR 5.555, 95%CI 1.710-18.041, p-value = 0.004) were associated with VAD. ApoE 4 allele was found in 25% of the patients, but the presence did not show any association with the increased risk of VAD. CONCLUSIONS: VAD occurred in 27% of the stroke patients. Older age, low education level, history of stroke, and the presence of moderate to severe white matter lesions were associated with the increased risk of VAD.

Skewed X chromosome inactivation in girls and female adolescents with autoimmune thyroid disease.

OBJECTIVE: Skewed X chromosome inactivation (XCI) was associated with female predominance in adult autoimmune thyroid disease (ATD). In normal females, skewed XCI is increased with age. Whether early-onset skewed XCI is associated with childhood ATD remains unknown. This study aimed to determine XCI skewing in paediatric ATD. DESIGN, PATIENTS AND MEASUREMENTS: Ninety-one female ATD patients, aged 3-20 years and 57 age-matched, female controls were enrolled. XCI was analysed by enzymatic digestion of DNA with methylation-sensitive enzymes followed by PCR of the polymorphic CAG repeat in the androgen receptor gene. Skewed XCI was defined as having 80% or greater of the cells preferentially inactivated on the same X chromosome. XCI pattern of the enrolled patients and parental origin of the skewed XCI were determined. RESULTS: After exclusion of samples with homozygous CAG repeats, skewed XCI was analysed in 83 patients (57 Graves' disease and 26 Hashimoto thyroiditis) and 52 controls. There was an increased frequency of skewed XCI in ATD patients as compared with the controls (23% vs 8%, P = 0.022). Patients with Hashimoto thyroiditis had greater frequency of skewed XCI than patients with Graves' disease (38% vs 16%, P = 0.023). There were no differences in clinical parameters between patients with skewed and random XCI. Analysis of 7 patients with skewed XCI showed a preferential inactivation of paternal X chromosome in 6 patients (86%). CONCLUSIONS: Frequency of skewed XCI was increased in childhood ATD. This observation suggests a possible association of skewed XCI in the development of paediatric ATD.

Medical genetic services in a developing country: lesson from Thailand.

PURPOSE OF REVIEW: The aim of the review was to give an example of how advances in medical genetics impact a developing country and how Thailand struggles to improve medical genetic services. RECENT FINDINGS: Thailand is an example of a developing country with limited resources and low geneticist-to-population ratio. The country formally followed decentralized healthcare system (even though practically centralized) and is a nation with growing public interest in medical genetic technology. Nonetheless, efforts have been and are still being made in expanding clinical genetics services, improving access to laboratory diagnosis, increasing rare disease medication in national formulary, and the training of medical genetics personnel. For an endemic genetic disorder such as thalassemia, a universal prevention and control program is available and has had some success. SUMMARY: Lesson learned in country like Thailand may be a useful model for other developing nations. Several strategies can be attempted to integrate the advances in medical genetics into medical practices in developing countries with relatively low income per capita and geographic discrepancy in healthcare distribution.

Influence of genetic and non-genetic factors on phenytoin-induced severe cutaneous adverse drug reactions.

PURPOSE: The purpose of this study was to investigate the association of genetic factors including variants in HLA-B and CYP2C genes and non-genetic factors with phenotype-specific phenytoin (PHT)-induced severe cutaneous adverse reactions (SCARs) in Thai patients. METHODS: Thirty-six PHT-induced SCAR cases (15 Stevens-Johnson syndrome (SJS) and 21 drug rash with eosinophilia and systemic symptoms (DRESS)/drug hypersensitivity syndrome (DHS)) and 100 PHT-tolerant controls were studied. Variants in HLA-B, CYP2C9, and CYP2C19 genes were genotyped. Fisher's exact test and multiple logistic regression analysis were performed to test the association of genetic and non-genetic factors with specific type of SCARs. RESULTS: Multiple logistic regression models showed that genetic and non-genetic factors associated with PHT-induced SCARs were specified to its phenotype. HLA-B*13:01, HLA-B*56:02/04, CYP2C19*3, and omeprazole co-medication were strong risk factors of DRESS/DHS (adjusted OR = 13.29, p = 0.0001; adjusted OR = 56.23, p = 0.0007; adjusted OR = 6.75, p = 0.0414; and adjusted OR = 9.21, p = 0.0020, respectively). While CYP2C9*3 and having Chinese ancestry were significant risk factors of SJS (adjusted OR = 10.41, p = 0.0042 and adjusted OR = 5.40, p = 0.0097, respectively). Combined genetic and non-genetic risk factors optimized sensitivity and increased specificity for predicting PHT-induced SCARs. CONCLUSION: This study showed that distinct genetic markers were associated with phenotype-specific PHT-induced SCARs. Non-genetic factor, omeprazole co-medication, was strongly associated with PHT-induced DRESS/DHS in addition to variants in HLA-B and CYP2C genes. Combined markers may be better predictors for PHT-induced SCARs.

A novel start codon mutation of the MERTK gene in a patient with retinitis pigmentosa.

PURPOSE: Retinitis pigmentosa (RP) is a clinically and genetically heterogeneous group of inherited retinal degenerations characterized by progressive loss of photoreceptor cells and RPE functions. More than 70 causative genes are known to be responsible for RP. This study aimed to identify the causative gene in a patient from a consanguineous family with childhood-onset severe retinal dystrophy. METHODS: To identify the defective gene, whole exome sequencing was performed. Candidate causative variants were selected and validated using Sanger sequencing. Segregation analysis of the causative gene was performed in additional family members. To verify that the mutation has an effect on protein synthesis, an expression vector containing the first ten amino acids of the mutant protein fused with the DsRed2 fluorescent protein was constructed and transfected into HEK293T cells. Expression of the fusion protein in the transfected cells was measured using fluorescence microscopy. RESULTS: By filtering against public variant databases, a novel homozygous missense mutation (c.3G>A) localized in the start codon of the MERTK gene was detected as a potentially pathogenic mutation for autosomal recessive RP. The c.3G>A mutation cosegregated with the disease phenotype in the family. No expression of the first ten amino acids of the MerTK mutant fused with the DsRed2 fluorescent protein was detected in HEK293T cells, indicating that the mutation affects the translation initiation site of the gene that may lead to loss of function of the MerTK signaling pathway. CONCLUSIONS: We report a novel missense mutation (c.3G>A, p.0?) in the MERTK gene that causes severe vision impairment in a patient. Taken together with previous reports, our results expand the spectrum of MERTK mutations and extend our understanding of the role of the MerTK protein in the pathogenesis of retinitis pigmentosa.

Liddle's Syndrome: A Case Report.

A thirty-eight years old female presented with frequent proximal weakness, severe hypertension, and persistent kaliuresis despite hypokalemia. After normalized serum potassium level, hyporeninemic hypoaldosteronism was detected Pedigree study supported an autosomal dominant inherited disease. A causative mutation for Liddle's syndrome (LS) in this patient was identified to be a novel frameshift mutation. DNA sequencing resulted in exon 13 of SCNN1B gene: SCNN1B NM_000336.2:c.1 724_1730dupGGCCCAC [p.Pro5 75Argfs*17]. Since LS is a rare existing clinical syndrome in Thailand, correct diagnosis should be confirmed by genetic studies. Therefore, proper management could be given.

Effects of PCSK1 genetic variants on obesity among Thai children and their family members: in relation to health risk, and biochemical and anthropometric parameters.

Single nucleotide polymorphisms (SNPs) in PCSK1, namely, rs6234, rs6235, and rs271939 have been linked to obesity in European population; and rs3811951 has also been connected to type 2 diabetes and obesity parameters in Chinese population. In this family-based case-control study, we analyzed links between PCSK1 genetic variants and obesity in Thai children and their families. Eleven obese children with a percent weight for height > or = 140 who had family history of obesity and 69 family members were recruited. SNPs rs6234, rs6235, rs3811951, and rs271939 of PCSK1 were analyzed using PCR and gene sequencing methods. DNA of 200 normal weight subjects was used as control. Participants with variant genotypes in the rs6234-6235 pair are at significantly more risk of being obese [OR = 2.44 (1.35-4.43), p = 0.003], and also at increased risk of being severely obese (obese class III) [OR = 3.03 (1.20-7.66), p = 0.015]. Variant rs3811951 showed no association with being obese, but is significantly linked to an increased risk of being severely obese [OR = 3.59 (1.42-9.08) p = 0.005]. Moreover, high density lipoprotein (HDL)-C levels between normal and variant rs3811951 group differed considerably, with patients with variant genotype having a lower HDL-C level (p = 0.037). Thus, Thais carrying SNPs rs6234-5 are at increased risk of being obese, and the risk of severe obesity increases when carrying both rs6234-5 and rs3811951, but not with rs271939. Furthermore, patients with genetic variations at rs3811951 are at risk of having low HDL-C levels.

Gene Distribution in Pediatric-Onset Inherited Peripheral Neuropathy: A Single Tertiary Center in Thailand.

BACKGROUND: Inherited peripheral neuropathy presents a diagnostic and therapeutic challenge due to its association with mutations in over 100 genes. This condition leads to long-term disability and poses a substantial healthcare burden on society. OBJECTIVE: This study aimed to investigate the distribution of genes and establish the genotype-phenotype correlations, focusing on pediatric-onset cases. METHODS: Exome sequencing and other analytical techniques were employed to identify pathogenic variants, including duplication analysis of the PMP22 gene. Each patient underwent physical examination and electrophysiological studies. Genotypes were correlated with phenotypic features, such as age at disease onset and ulnar motor nerve conduction velocity. RESULTS: We identified 35 patients with pediatric-onset inherited peripheral neuropathy. Pathogenic or likely pathogenic variants were confirmed in 24 out of 35 (68.6%) patients, with 4 of these variants being novel. A confirmed molecular diagnosis was achieved in 90.9% (10/11) of patients with demyelinating Charcot-Marie-Tooth disease (CMT) and 56.3% (9/16) of patients with axonal CMT. Among patients with infantile-onset CMT (≤2 years), the most common causative genes were MFN2 and NEFL, while GDAP1 and MFN2 were frequent causes among patients with childhood- or adolescent-onset CMT (3-9 years). CONCLUSIONS: The MFN2 gene was the most commonly implicated gene, and the axonal type was predominant in this cohort of Thai patients with pediatric-onset inherited peripheral neuropathy.

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.

Problems in determining thalassemia carrier status in a program for prevention and control of severe thalassemia syndromes: a lesson from Thailand.

BACKGROUND: Prevention and control of severe ß thalassemia by carrier detection and identification of couples at risk in developed countries is one of the most successful stories in modern medicine. Similar programs in developing countries especially Southeast Asia, are more problematic because both α and ß thalassemias are highly prevalent. In Thailand, there are limited data on whether we could determine, based on hematological phenotypes, the mutation severity and/or coinheritance of α thalassemia in ß thalassemia traits. METHODS: Comprehensive molecular, hematology and hemoglobin analyses of the α and ß globin genes were performed in 141 healthy individuals identified as ß thalassemia carriers. RESULTS: Seventeen different ß globin mutations were successfully identified out of all cases analyzed. Although the majority of the mutations identified were the ß° or severe ß⁺ thalassemia alleles, a high proportion of mild mutations (25%) was observed. Of these ß thalassemia traits, 22.3% were found to co-inherit the α thalassemias. Milder hematological phenotypes were noted in ß⁺ compared with ß° thalassemia traits when the α globin genes were intact. Although co-inheritance of α° thalassemia might be suspected in cases with skewed profiles, due to the overlapping values, it remains difficult to apply these parameters for reliable carrier determination. CONCLUSIONS: A combination of hemoglobin analysis and DNA testing seems to be the best way to confirm carrier status in a region with high frequency for both α and ß thalassemias. Underdiagnoses of carrier status could hamper the effectiveness of a thalassemia prevention and control program.

Identification of Genomic Alterations in Thai Patients With Colorectal Cancer Using Next-Generation Sequencing-Based Multigene Cancer Panel.

Introduction Colorectal cancer (CRC) is one of the leading causes of death and illness in the general population. Although the incidence of CRC is steadily decreasing worldwide, it is being diagnosed more in individuals under 50 years of age. Multiple disease-causing variants have been reported to be involved in the development of CRC. This study aimed to investigate the molecular and clinical characteristics of Thai patients with CRC. Methods NGS-based multigene cancer panel testing was performed on 21 unrelated patients. Target enrichment was performed using a custom-designed Ion AmpliSeq on-demand panel. Thirty-six genes associated with CRC and other cancer were analyzed for variant detection. Results Sixteen variants (five nonsense, eight missense, two deletions, and one duplication) in nine genes were identified in 12 patients. Eight (66.7%) patients harboring disease-causing deleterious variants in genes APC, ATM, BRCA2, MSH2, and MUTYH. One of the eight patients also carried additional heterozygous variants in genes ATM, BMPR1A, and MUTYH. In addition, four patients carried variants of uncertain significance in genes APC, MLH1, MSH2, STK11, and TP53. Among all detected genes, APC was the most frequent causative gene observed in CRC patients, which is consistent with previous reports. Conclusion This study demonstrated the comprehensive molecular and clinical characterization of CRC patients. These findings showed the benefits of using multigene cancer panel sequencing for pathogenic gene detection and showed the prevalence of genetic aberrations in Thai patients with CRC.