A novel IGHMBP2 variant and clinical diversity in Vietnamese SMARD1 and CMT2S patients.

Background: Pathogenic variants in the IGHMBP2 gene are associated with two distinct autosomal recessive neuromuscular disorders: spinal muscular atrophy with respiratory distress type 1 (SMARD1; OMIM #604320) and Charcot-Marie-Tooth type 2S (CMT2S; OMIM #616155). SMARD1 is a severe and fatal condition characterized by infantile-onset respiratory distress, diaphragmatic palsy, and distal muscular weakness, while CMT2S follows a milder clinical course, with slowly progressive distal muscle weakness and sensory loss, without manifestations of respiratory disorder. Methods: Whole-exome sequencing of the IGHMBP2 gene was performed for eight Vietnamese patients with IGHMBP2-related neuromuscular disorders including five patients with SMARD1 and the others with CMT2S. Results: We identified one novel IGHMBP2 variant c.1574T > C (p.Leu525Pro) in a SMARD1 patient. Besides that, two patients shared the same pathogenic variants (c.1235 + 3A > G/c.1334A > C) but presented completely different clinical courses: one with SMARD1 who deceased at 8 months of age, the other with CMT2S was alive at 3 years old without any respiratory distress. Conclusion: This study is the first to report IGHMBP-2-related neuromuscular disorders in Vietnam. A novel IGHMBP2 variant c.1574T > C (p.Leu525Pro) expressing SMARD1 phenotype was detected. The presence of three patients with the same genotype but distinct clinical outcomes suggested the interaction of variants and other factors including relating modified genes in the mechanism of various phenotypes.

In silico validation revealed the role of SCN5A mutations and their genotype-phenotype correlations in Brugada syndrome.

BACKGROUND: Brugada syndrome (BrS) is a rare genetic disease that causes sudden cardiac death (SCD) and arrhythmia. SCN5A pathogenic variants (about 30% of diagnosed patients) are responsible for BrS. AIMS: Lack of knowledge regarding molecular characteristics and the correlation between genotype and phenotype interfere with the risk stratification and finding the optimal treatment in Vietnam. Therefore, we identified SCN5A variants and evaluated the genotype-phenotype correlation of BrS on 117 Vietnamese probands. MATERIALS AND METHODS: The clinical characteristics and blood samples of BrS patients were collected. To determine SCN5A variants, Sanger sequencing was conducted, and subsequently, these variants were analyzed by bioinformatic tools. RESULTS: In this cohort, the overall rate of detected variants in SCN5A was 25.6%, which could include both pathogenic and benign variants. In genetic testing, 21 SCN5A variants were identified, including eight novels and 15 published variants. Multiple bioinformatic tools were used to predict variant effect with c.551A>G, c.1890+14G>A, c.3338C>T, c.3578G>A, and c.5484C>T as benign, while other variants were predicted as disease-causing. The family history of SCD (risk ratio [RR] = 4.324, 95% CI: 2.290-8.269, p < 0.001), syncope (RR = 3.147, 95% CI: 1.668-5.982, p = 0.0004), and ventricular tachycardia/ventricular fibrillation (RR = 3.406, 95% CI: 1.722-5.400, p = 0.0035) presented a significantly higher risk in the SCN5A (+) group, consisting of individuals carrying any variant in the SCN5A gene, compared to SCN5A (-) individuals. CONCLUSION: The results contribute to clarifying the impact of SCN5A variants on these phenotypes. Further follow-up studies need to be carried out to understand the functional effects of these SCN5A variants on the severity of BrS.

A Model for Gastric Cancer Risk Prediction Based on MUC1 Polymorphisms and Health-risk Behaviors in a Vietnamese Population.

BACKGROUND/AIM: Although the expression of mucin 1(MUC1) and prostate stem cell antigen (PSCA) genes is correlated with gastric cancer development and progression, the utility of these two genes as biomarkers of gastric cancer prognosis still needs to be confirmed in clinical practice. This study aimed to develop a model predictive of gastric cancer that integrates several significant single nucleotide polymorphisms (SNPs) of MUC1 and PSCA genes, and some health-risk behavior factors in a Vietnamese population. PATIENTS AND METHODS: A total of 302 patients with primary gastric carcinoma and 304 healthy persons were included in a case-control study. The generalized linear model was used with the profile of age, sex, history of smoking and using alcohol, personal and family medical history of stomach diseases, and the SNPs of MUC1 and PSCA. The prognostic value of the model was assessed by the area under a receiver operating characteristic curve (AUC) and Akaike Information Criterion (AIC) values. RESULTS: In male participants, the final model, consisting of age, sex, history of smoking and using alcohol, personal and family medical history of stomach diseases and SNP MUC1 rs4072037, provided acceptable discrimination, with an AUC of 0.6374 and the lowest AIC value (539.53). In female participants, the predictive model including age, sex, history of smoking and using alcohol, personal and family medical history of stomach diseases, SNPs MUC1 rs4072037 and rs2070803 had an AUC of 0.6937 and AIC of 266.80. The calibration plots of the male model approximately fitted the ideal calibration line. CONCLUSION: The predictive model based on age, sex, medical history, and genetic and health-risk behavior factors has a high potential in determining gastric cancer. Further studies that elucidate other genetic variants should be carried out to define high-risk gastric cancer groups and propose appropriate personalized prevention.

Merosin-deficient congenital muscular dystrophy type 1a: detection of LAMA2 variants in Vietnamese patients.

Background: Merosin-deficient congenital muscular dystrophy type 1A (MDC1A), also known as laminin-α2 chain-deficient congenital muscular dystrophy (LAMA2-MD), is an autosomal recessive disease caused by biallelic variants in the LAMA2 gene. In MDC1A, laminin- α2 chain expression is absent or significantly reduced, leading to some early-onset clinical symptoms including severe hypotonia, muscle weakness, skeletal deformity, non-ambulation, and respiratory insufficiency. Methods: Six patients from five unrelated Vietnamese families presenting with congenital muscular dystrophy were investigated. Targeted sequencing was performed in the five probands. Sanger sequencing was carried out in their families. Multiplex ligation-dependent probe amplification was performed in one family to examine an exon deletion. Results: Seven variants of the LAMA2 (NM_000426) gene were identified and classified as pathogenic/likely pathogenic variants using American College of Medical Genetics and Genomics criteria. Two of these variants were not reported in the literature, including c.7156-5_7157delinsT and c.8974_8975insTGAT. Sanger sequencing indicated their parents as carriers. The mothers of family 4 and family 5 were pregnant and a prenatal testing was performed. The results showed that the fetus of the family 4 only carries c.4717 + 5G>A in the heterozygous form, while the fetus of the family 5 carries compound heterozygous variants, including a deletion of exon 3 and c.4644C>A. Conclusion: Our findings not only identified the underlying genetic etiology for the patients, but also provided genetic counseling for the parents whenever they have an offspring.

Nutritional Status, Refeeding Syndrome and Some Associated Factors of Patients at COVID-19 Hospital in Vietnam.

Multisystem inflammatory syndrome is associated with COVID-19 and can result in reduced food intake, increased muscle catabolism, and electrolyte imbalance. Therefore COVID-19 patients are at high risk of being malnourished and of refeeding syndrome. The present study aimed to determine the prevalence and correlates of malnutrition and refeeding syndrome (RS) among COVID-19 patients in Hanoi, Vietnam. This prospective cohort study analyzed data from 1207 patients who were treated at the COVID-19 hospital of Hanoi Medical University (HMUH COVID-19) between September 2021 and March 2022. Nutritional status was evaluated by the Global Leadership Initiative on Malnutrition (GLIM) and laboratory markers. GLIM-defined malnutrition was found in 614 (50.9%) patients. Among those with malnutrition, 380 (31.5%) and 234 (19.4%) had moderate and severe malnutrition, respectively. The prevalence of risk of RS was 346 (28.7%). Those with severe and critical COVID symptoms are more likely to be at risk of RS compared to those with mild or moderate COVID, and having severe and critical COVID-19 infection increased the incidence of RS by 2.47 times, compared to mild and moderate disease. There was an association between levels of COVID-19, older ages, comorbidities, the inability of eating independently, hypoalbuminemia and hyponatremia with malnutrition. The proportion of COVID-19 patients who suffered from malnutrition was high. These results underscore the importance of early nutritional screening and assessment in COVID-19 patients, especially those with severe and critical infection.

Targeted next-generation sequencing determined a novel SGCG variant that is associated with limb-girdle muscular dystrophy type 2C: A case report.

Limb-girdle muscular dystrophy-type 2C (LGMD2C) is caused by mutations in the SGCG gene. Here, we report a case of a 26-year-old male who had inactive walking due to proximal muscle weakness. Targeted next-generation sequencing found a novel variant c.412C > T (Q138*) in the SGCG gene.

Feasibility of combining short tandem repeats (STRs) haplotyping with preimplantation genetic diagnosis (PGD) in screening for beta thalassemia.

ß-thalassemia is an autosomal recessive disease with the reduction or absence in the production of ß-globin chain in the hemoglobin, which is caused by mutations in the Hemoglobin subunit beta (HBB) gene. In Vietnam, the number of ß-thalassemia carriers range from 1.5 to 25.0%, depending on ethnic and geographical areas, which is much higher than WHO's data worldwide (1.5%). Hence, preimplantation genetic diagnosis (PGD) plays a crucial role in reducing the rate of ß-thalassemia affected patients/carriers. In this research, we report the feasibility and reliability of conducting PGD in combination with the use of short tandem repeat (STR) markers in facilitating the birth of healthy children. Six STRs, which were reported to closely linked with the HBB gene, were used on 15 couples of ß-thalassemia carriers. With 231 embryos, 168 blastocysts were formed (formation rate of 72.73%), and 88 were biopsied and examined with STRs haplotyping and pedigree analysis. Thus, the results were verified by Sanger sequencing, as a definitive diagnosis. Consequently, 11 over 15 couples have achieved pregnancy of healthy or at least asymptomatic offspring. Only three couples failed to detect any signs of pregnancy such as increased Human Chorionic Gonadotropin (HCG) level, foetal sac, or heart; and one couple has not reached embryo transfer as they were proposed to continue with HLA-matching to screen for a potential umbilical cord blood donor sibling. Thus, these results have indicated that the combination of PGD with STRs analysis confirmed by Sanger sequencing has demonstrated to be a well-grounded and practical clinical strategy to improve the detection of ß-thalassemia in the pregnancies of couples at-risk before embryo transfer, thus reducing ß-thalassemia rate in the population.

Molecular Characterization and Genotype-Phenotype Correlation of G6PD Mutations in Five Ethnicities of Northern Vietnam.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common enzyme disorder and is caused by G6PD gene mutations. To date, more than 400 variants in the G6PD gene have been discovered, and about 160 identified variants are associated with a significant decrease in the G6PD enzyme activity. However, the molecular characterization and epidemiological study of G6PD deficiency are still limited in Vietnam. Therefore, we conducted this study to determine the G6PD variants among the Vietnamese populations and evaluate their correlation to G6PD enzyme activity. A total of 339 patients (302 males and 37 females) were enrolled in this study. The G6PD variants were identified by Sanger sequencing. Our results indicate that males are more severely deficient in G6PD than females. This enzyme activity in males (1.27 ± 1.06 IU/g·Hb) is significantly lower than in females (2.98 ± 1.57 IU/g·Hb) (p < 0.0001). The enzyme activity of the heterozygous-homozygous females and heterozygous females-hemizygous males was found to be significantly different (p < 0.05), which is interpreted due to random X-inactivation. For G6PD molecular characteristics, Viangchan (c.871G>A), Canton (c.1376G>T) and Kaiping (c.1388G>A) variants were the most dominant, accounting for 24.48%, 17.70%, and 22.42%, respectively, whereas the highest frequency of complex variants was observed in Viangchan/Silent with 20.35%. In terms of G6PD activity, the Union variant presented the lowest mean value (1.03 IU/g·Hb) compared to the other variants (p < 0.05). Computational analysis using Polyphen-2 tool investigated that all variants were relative to G6PD deficiency and separated the levels as benign and damaged. The result will establish effective methods to screen G6PD variants in Vietnam.

Whole exome sequencing analysis in a couple with three children who died prematurely due to carnitine-acylcarnitine translocase deficiency.

OBJECTIVE: We investigated a strategy of exome sequencing DNA from the unaffected parents and applied a set of filtering criteria to identify genes where both partners are heterozygous for a potentially pathogenic variant. CASE REPORT: We report a non-consanguineous couple who had three daughters, all spontaneous preterm birth at 36 weeks gestation and died in the first period after birth, suspected inborn errors of metabolism. Two days after birth, the first daughter presented with difficulty breathing, cyanosis and died; the second died at 33 days old; the third daughter was isolated under special care and was taken to the mother's room, developed the same symptoms and died after 5 days. Dried blood spot testing screen of 55 congenital metabolic disorders was negative. CONCLUSION: Heterogenous variant in SLC25A20 gene was found in both parents, contributing to the delineations of the neonatal phenotypes related to SLC25A20 mutation in CACTD.

BRCA1/2 Mutations in Vietnamese Patients with Hereditary Breast and Ovarian Cancer Syndrome.

(1) Background: Individuals with BRCA1/2 gene mutations are at increased risk of breast and ovarian cancer. The prevalence of BRCA1/2 mutations varies by race and ethnicity, and the prevalence and the risks associated with most BRCA1/2 mutations has not been unknown in the Vietnamese population. We herein screen the entire BRCA1 and BRCA2 genes for breast and ovarian cancer patients with a family history of breast cancer and ovarian cancer, thereby, suggesting a risk score associated with carrier status and history for aiding personalized treatment; (2) Methods: Between December 2017 and December 2019, Vietnamese patients who had a pathological diagnosis of breast and epithelial ovarian cancer were followed up, prospectively, after treatment from two large institutions in Vietnam. Blood samples from 33 Vietnamese patients with hereditary breast and ovarian cancers (HBOC) syndrome were collected and analyzed using Next Generation Sequencing; (3) Results: Eleven types of mutations in both BRCA1 (in nine patients) and BRCA2 (in three patients) were detected, two of which (BRCA1:p.Tyr1666Ter and BRCA2:p.Ser1341Ter) have not been previously documented in the literature. Seven out of 19 patient's relatives had BRCA1/2 gene mutations. All selected patients were counselled about the likelihood of cancer rising and prophylactic screening and procedures. The study established a risk score associated with the cohorts based on carrier status and family history; (4) Conclusions: Our findings suggested the implications for the planning of a screening programme for BRCA1 and BRCA2 genes testing in breast and ovarian cancer patients and genetic screening in their relatives. BRCA1/2 mutation carriers without cancer should have early and regular cancer screening, and prophylactic measures. This study could be beneficial for a diverse group in a large population-specific cohort, related to HBOC Syndrome.

Polymorphism of MUC1 Gene in Vietnamese Gastric Cancer Patients: A Multicenter Case-Control Study.

BACKGROUND: A few studies revealed that the polymorphisms of Mucin 1 gene have a role and significance as a susceptible factor contributing to gastric cancer. To better understand the roles of two MUC1 genotype polymorphisms of rs4072037 and rs2070803 in the development of gastric cancer in Vietnamese population, a multicenter, large-sample, case-control study was conducted to investigate the potential association of these single-nucleotide polymorphisms (SNPs) of MUC1 gene with gastric cancer risk and to evaluate the combination factors in relation with these SNPs. METHODS: This case-control study included 302 gastric cancer patients and 304 controls at four national medical hospitals between 2016 and 2018. All participants were interviewed for sociodemographic characteristics, smoking and drinking status, and personal and family history of gastric diseases. Genotyping was done using polymerase chain reaction-restriction fragment length polymorphism analysis. The association of SNPs with gastric cancer was explored using logistic regression models. RESULTS: AA genotype for rs4072037 was significantly associated with increased gastric cancer. Those with AA genotype had higher gastric cancer risk than had patients with AG (OR: 2.09, 95% CI: 1.48-2.96) and a combination of AG+GG (OR: 1.85, 95% CI: 1.33-2.56). In rs2070803, GG genotype increased gastric cancer risk when compared with AG (OR: 1.97, 95% CI: 1.39-2.80) and AG+AA (OR: 1.71, 95% CI: 1.23-2.39). AG genotypes in both SNPs decreased gastric cancer risk when compared with homogenous genotype, more specifically AA (OR: 0.51, 95% CI: 0.35-0.72) and GG (OR: 0.58, 95% CI: 0.35-0.97). These genotypes in combination with above-60-year-old age, male gender, alcoholism, and personal history of gastric disease were also significantly elevated risk factors for gastric cancer. CONCLUSIONS: rs4072037 and rs2070803 of Mucin 1 genes are two genotypic risk factors for gastric cancer. Those in combination with gender, family history, smoking, and drinking habits significantly increase the risk of gastric cancer.

Family based and case-control designs reveal an association of TFAP2A in nonsyndromic cleft lip only among Vietnamese population.

AIMS: Dozens of causative genes and their mechanisms of nonsyndromic cleft lip with or without cleft palate (NSCL/P) were revealed through genome-wide association and linkage studies. Results were, however, not always replicated in different populations or methodologies. This study used case-control and family based approaches to investigate the etiology of NSCL/P and its two subtypes: nonsyndromic cleft lip only (NSCLO) and nonsyndromic cleft lip and palate (NSCLP) among the Vietnamese population. METHODS: Two hundred and seventeen NSCL/P case-parent trios (one affected child and two parents), including 105 NSCLO and 112 NSCLP were involved for a family based design; and 273 ethnic and region-matched healthy controls with no cleft history in their families were recruited for a case-control design. Three SNPs consisting of TFAP2A (rs1675414 and rs303048) and 8q24 (rs987525) were genotyped using the TaqMan SNP genotyping assay. RESULTS: TFAP2A rs1675414 was associated with NSCLO, replicated by both case-control and family based tests. Other SNPs yielded no evidence of susceptibility to NSCL/P or two subtypes. CONCLUSION: The current investigation suggests an intriguing role of TFAP2A in the etiology of NSCLO among the Vietnamese population.

Association of the STAT4, CDKN1A, and IRF5 variants with risk of lupus nephritis and renal biopsy classification in patients in Vietnam.

BACKGROUND: Lupus nephritis is a common complication of systemic lupus erythematosus (SLE, OMIM #15200) in the Asian population and a main contributor to mortality and morbidity. In this study, we evaluate the variants on three genes STAT4, CDKN1A, and IRF5 and their association with lupus nephritis. METHOD: One hundred fifty-two SLE patients with confirmed lupus nephritis (through biopsy) and 76 healthy controls were recruited. Genotyping of SNPs on three gene STAT4, CDKN1A, and IRF5, phenotypic, and laboratory assessment were performed; renal biopsy and classification were carried out for the patient group. RESULTS: Carriers of rs7582694 C alleles on STAT4 have higher risk of lupus nephritis (OR 2.0; 95% CI [1.14, 3.19]; p = 0.015), at higher risk of hematuria and higher serum level of dsDNA antibodies compared to controls (p < 0.05) and were more likely to have nephrotic histopathology grading of class III or higher. No association was observed for CDKN1A; and no variation was observed for the IRF5 gene in both the study and control group. CONCLUSION: This study investigates the relationship between STAT4, CDKN1A, and IRF5 gene and SLE in a Vietnamese patient population. Patients with the C allele (STAT4) in rs7582694 were associated with a more severe disease phenotype.

A case of self-improving collodion ichthyosis in Vietnam.

Autosomal recessive congenital ichthyosis is a heterogeneous group of congenital disorders characterized by aberrant skin cornification and diffuse skin scaling. Some patients with this condition are born encased in a collodion membrane which is later shed, revealing the underlying skin disorder. Self-healing collodion baby (SHCB) is a less common phenotype of this disorder, accounting for about 10% of the patients, in which the membrane peels after several weeks, leaving no underlying skin aberration. Here, we report and discuss the diagnosis and management of an infant with SHCB in Vietnam due to compound heterozygous pathogenic mutations in TGM1.

Breast Cancer Survival Defined by Biological Receptor and Menopausal Status in Vietnamese Women.

Little is known about breast cancer in Vietnamese women. Previous studies have reported the frequencies of prognostic factors of breast cancer in this population. The aim of this study was to examine the prognostic factors associated with the survival rates of patients with breast cancer treated at the National Cancer Hospital, Hanoi, Vietnam. We recruited 248 women with operable breast cancer treated with surgery and adjuvant therapy. Tumor tissue samples were stained by many immunohistochemical approaches and analyzed for estrogen receptor, progesterone receptor, and HER2 gene amplification status. A Cox model was used to determine the relationship between survival and the prognostic factors. The disease-free survival rate, overall survival rate, and cancer-specific survival rate were 75.8%, 80.6%, and 86.4%, respectively, at 5 years and 62.3%, 68.1%, and 78.9%, respectively, at 10 years. The lung was the most common metastatic site. Women with factors associated with a poor prognosis (eg, advanced clinical stage, high tumor grade, progesterone receptor [PR] negativity, HER2 amplification) had significantly lower survival rates. Patients with PR-negative breast cancer had significantly worse survival rates compared to those who were PR positive, according to multivariate analysis (hazard ratio = 1.77, 95% confidence interval: 1.01-3.11, P = .045); however, there was only a statistically significant difference in postmenopausal patients. The PR was a prognostic factor in postmenopausal women with breast cancer, but not in premenopausal women.

Quality of Life in Vietnamese Gastric Cancer Patients.

BACKGROUND: Gastric cancer (GC) is one of the leading causes of cancer-related death in Vietnam. Research on health-related quality of life of Vietnamese gastric cancer patients is still in its infancy. AIM: To assess the health-related quality of life (HRQOL) of GC patients using the 15D instrument. MATERIALS AND METHOD: 182 Vietnamese gastric cancer patients were selected to be interviewed and their HRQOL was assessed using the generic 15D questionnaire. Tables regarding history, disease characteristics, and HRQOL of participants were formulated according to genders using STATA 12.0. RESULTS: The average age of the participants was 60.8 ± 11.6. The average time from diagnosis to the date of interview was 14.8 ± 8.4 months. The health-related quality of life (HRQOL) index score of gastric cancer patients using the 15D instrument was 0.92 ± 0.08, in which the "sexual activity" dimension had the lowest score of 0.66. Also, our study found several factors affecting HRQOL, including age, occupation, education, disease stage, treatment, and time from the date of diagnosis. CONCLUSION: The 15D instrument was a suitable tool to assess Vietnamese gastric cancer patients' quality of life. Findings from the study suggest the importance of frequently measuring personal functioning and performance of GC patients as parts of QOL assessment during clinical examination. It also implies the needs for more focused policies on raising the overall quality of life of patients such as encouragement of periodical HQROL assessment and acknowledging HRQOL as a treatment/intervention goal besides the 5-year survival rate.

Prenatal diagnosis of a case with SEA-HPFH deletion thalassemia with whole HBB gene deletion.

OBJECTIVE: The thalassemias is a group of hereditary disorders with impaired production of functional hemoglobin. In this report we described a rare case of compound heterozygous mutation of South-East Asia type hereditary persistence of fetal hemoglobin (SEA-HPFH) and ß -thalassemia that allowed prenatal diagnosis to be performed in a subsequent pregnancy in the family. CASE REPORT: The father showed a SEA-HPFH thalassemia trait phenotype, while his genotype revealed that he was heterozygous for the SEA-HPFH deletion; The mother genotype was heterozygote for IVS-II-654 mutation; the second child had co-inherited both parental mutations and was, thus, a compound heterozygote for ß-thalassemia (IVS-II-654)/SEA-HPFH deletion. His phenotype was intermediate ß-thalassemia. Prenatal genotyping of a fetal sample during the third pregnancy confirmed the fetus was only heterozygote for SEA-HPFH deletion and the parents elected to continue the pregnancy. CONCLUSION: We described the clinical and molecular characterization of the first detected case of compound ß-Thalassemia/SEA-HPFH deletion in Northern Vietnam. The report also highlighted the accuracy and necessity of mutation screening for families with thalassemia to inform accurate genetic counseling and targeted prenatal diagnosis when desired.

Analysis of the cause of recurrent pregnancy loss in Vietnam: A cross-sectional study.

Recurrent pregnancy loss (RPL) is a physical and mental burden for women. In Vietnam, exploring the cause of miscarriages is still a challenge to clinical physicians. We aimed to investigate the etiology of RPL in the National Hospital of Obstetrics and Gynecology in Vietnam from 2012 to 2014. The cross-sectional study included 301 pregnant women with a history of RPL. The patients were examined and offered medical testing to determine the cause(s). Based on the testing, we determined causation for (11.29%) patients who had positive scores on an antiphospholipid antibody test and who were subsequently successfully treated for their problem.