Health-state utility of patients with HER2-positive breast cancer in Vietnam: A multicenter cross-sectional study.

BACKGROUND: Patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer may have poor prognoses and short overall and disease-free survival. Most previous studies focused on assessing the quality of life and health-state utility of the general population of breast cancer patients. The number of studies for HER2-positive breast cancer patients is negligible. This study investigated the health-state utility and its associated factors among Vietnamese patients with HER2-positive breast cancer. METHODS: We conducted face-to-face interviews with 301 HER2-positive breast cancer patients to collect data. Their health-state utility was measured via the EQ-5D-5L instrument. The Mann-Whitney U and Kruskal-Wallis tests were employed to compare the differences in utility scores between two groups and among three groups or more, respectively. Factors associated with patients' heath-state utility were identified via Tobit regression models. RESULTS: Pain/discomfort (56.1%) and anxiety/depression (39.5%) were the two issues that patients suffered from the most, especially among metastatic breast cancer patients. The severity of distress (depression, anxiety, and stress) in patients was relatively mild. Of 301 patients, their average utility score was 0.86±0.17 (range: 0.03-1.00), and the average EQ-visual analogue scale (VAS) score was 69.12±12.60 (range: 30-100). These figures were 0.79±0.21 and 65.20±13.20 for 102 metastatic breast cancer patients, significantly lower than those of 199 non-metastatic cancer patients (0.89±0.13 and 71.13±11.78) (p<0.001), respectively. Lower health-state utility scores were significantly associated with older age (p = 0.002), lower education level (p = 0.006), lower monthly income (p = 0.036), metastatic cancer (p = 0.001), lower EQ-VAS score (p<0.001), and more severe level of distress (p<0.001). CONCLUSIONS: Our findings showed a significant decrement in utility scores among metastatic breast cancer patients. Patients' health-state utility differed by their demographic characteristics (age, education level, and income) and clinical characteristics (stage of cancer and distress). Their utility scores may support further cost-effectiveness analysis in Vietnam.

Application of short tandem repeats (STRs) in the preimplantation genetic diagnosis (PGD) of α-thalassemia.

OBJECTIVES: α-thalassemia is an autosomal recessive monogenic blood disorder, affecting up to 5% of the world's population. The occurrence rate of the disease in Vietnam varies up to up to 51.5%, with high rate of mutation carriers, of couples consisting of two carriers at risk of bearing a child with fetal Hb Bart, which can develop into hydrops fetalis syndrome, threatening the well-being of the mother and the child. Our study aims to facilitate birth of healthy/asymptomatic children of α-thalassemia carrier couples who received reproductive service at our centre during the period of 2019-2022. MATERIALS AND METHODS: 89 couples at risks of having α-thalassemia offsprings requested IVF procedures and PGD at Post Hospital during 2019-2022 were recruited for investigation. Couple and additional family members' peripheral blood samples of couples and additional family members were subjected to haemoglobin electrophoresis, DNA extraction for α-thalassemia gene mutation detection and STRs linkage analysis. Data were observed and analysed on GeneMarker software. RESULTS: 91 cycles of PGD for α-thalassemia were carried out for 89 couples. α-thalassemia large deletion (--SEA/αα) was the most common mutation identified in 88 couples, in which 4 cases also carried ß-thalassemia point mutations. Combining results of PGS and PGD, 278/424 amplified embryos were transferable (HBA-mutation free or carriers of single heterozygous HBA mutation, without chromosomal abnormality). 64/89 couples have been transferred with the embryos (prioritizing mutation free ones over carriers), resulting in the birth of 36 α-thalassemia disease-free children, 17 ongoing pregnancies, and 11 with miscarriages. CONCLUSION: Successful application of microsatellite-based method in PGD facilitated the birth of 36 healthy children and 17 ongoing pregnancies for 53/64 couples with embryo-transferred. All resulted clinical births displayed confirmation results in line with the PGD results, thus demonstrating the feasibility and credibility of the use of STR markers in PGD.

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.

New species of the eel genera Dysomma and Dysommina from Vietnam, South China Sea (Anguilliformes: Synaphobranchidae).

Two new cutthroat eel species are described from Vietnam. Dysomma intermedium sp. nov. has a relatively long trunk, being about half of head length and anal-fin origin more than twice pectoral-fin length behind the pectoral-fin tip; pectoral fin well developed; dorsal-fin origin over or slightly in front of base of pectoral fin; two intermaxillary teeth; four or five compound teeth on ethmovomer; single row of seven or eight teeth on lower jaw; total lateral-line pores 70-76; and 21 pre-anal and 118-124 total vertebrae. Dysommina brevis sp. nov. differs from congeners by having a trunk shorter than head length, its length 11.1%-11.8% TL; a short pre-anal length 24.6%-25.6% TL, eye diameter 11.8%-12.3% head length; three large and one or two small teeth on ethmovomer; and fewer teeth on the upper and lower jaws. In addition, a specimen representing the first record of Dysommina orientalis in Vietnamese water is documented.

Experience of Autologous Immunotherapy for Non-Small Cell Lung Cancer Using Zoledronate-Actived Gammadelta T Cells.

BACKGROUND: Several nations around the world have utilized autologous immune enhancement therapy in the treatment of cancer, with initial positive outcomes. This study describes our experience with autologous gamma delta T cell immunotherapy for the treatment of non-small cell lung cancer patients in Vietnam, a developing nation. METHODS: Five patients with non-small cell lung cancer at stages III - IV were enrolled in the study. Each patient received six infusions of autologous γδT cells, separated by two weeks. Before, during, at the end of treatment, and three and six months after treatment, a comprehensive evaluation of clinical, laboratory, quality of life, and adverse events related to the method was conducted. RESULTS: At the time of culture seeding, the total number of cells ranged from 2.9 to 18.2 x 106, with γδT cells ranging in number from 10.7 to 19.6 x 104. On day 14 of the culture, the number of γδT cells ranged from 3.1 to 8.3 x 108. Regarding the safety of therapy in a total of 30 infusions, two (fever), one (myalgia), and one (joint pain) were graded as 1 by CTCAE criteria. After the course, no toxicity was observed in the hematopoietic system, kidney function, or liver function. Evaluation of the patient's response in accordance with the RECIST 1.1 criteria: 20% of patients (one patient) had partial response disease, and 80% of patients (four patients) had stable disease at the end of treatment. During the follow-up period of the study, three patients were still alive, and the disease remained stable. The patient's quality of life improved after treatment in most functional measures (activity, cognitive, and social), but physical and emotional scores decreased slightly. Two patients' fatigue symptoms increased, but after six months of treatment, the average value dropped from 25.3 to 8.3. Dyspnea symptoms decreased gradually from 33.3 at the start of treatment to 8.3 six months later. CONCLUSIONS: The initial results we obtained regarding the efficacy and safety of autologous γδT cell immunotherapy for patients with non-small cell lung cancer are extremely encouraging and comparable to those of previous studies.

Pediatric Profound Dengue Shock Syndrome and Use of Point-of-Care Ultrasound During Mechanical Ventilation to Guide Treatment: Single-Center Retrospective Study, 2013-2021.

OBJECTIVES: Profound dengue shock syndrome (DSS) complicated by severe respiratory failure necessitating mechanical ventilation (MV) accounts for high case fatality rates among PICU-admitted patients. A major challenge to management is the assessment of intravascular volume, which can be hampered by severe plasma leakage and the use of MV. DESIGN: Retrospective cohort, from 2013 to 2021. PATIENTS: Sixty-seven children with profound DSS supported by MV, some of whom underwent bedside point-of-care ultrasound (POCUS) for assessment and monitoring of hemodynamics and fluid administration. SETTING: PICU of the tertiary Children's Hospital No. 2 in Vietnam. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We analyzed data clinical and laboratory data during PICU stay. In particular, during use of MV (i.e., at times 0-, 6-, and 24-hr after commencement) and fluid resuscitation. The primary study outcome was 28-day in-hospital mortality, and the secondary outcomes were associations with changes in hemodynamics, blood lactate, and vasoactive-inotrope score (VIS). Patients had a median age of 7 years (interquartile range, 4-9). Use of POCUS during fluid management (39/67), as opposed to not using (28/67), was associated with lower mortality (6/39 [15%] vs. 18/28 [64%]; difference 49 % [95% CI, 28-70%], p < 0.001). Use of POCUS was associated with lower odds of death (adjusted odds ratio 0.17 [95% CI, 0.04-0.76], p = 0.02). The utilization of POCUS, versus not, was associated with greater use of resuscitation fluid, and reductions in VIS and pediatric logistic organ dysfunction (PELOD-2) score at 24 hours after MV and PICU discharge. CONCLUSIONS: In our experience of pediatric patients with profound DSS and undergoing MV (2013-2021), POCUS use was associated with lower odds of death, a higher volume of resuscitation fluid, and improvements in the blood lactate levels, VIS, and PELOD-2 score.

Analysis and Visualization of Longitudinal Genomic and Clinical Data from the AACR Project GENIE Biopharma Collaborative in cBioPortal.

International cancer registries make real-world genomic and clinical data available, but their joint analysis remains a challenge. AACR Project GENIE, an international cancer registry collecting data from 19 cancer centers, makes data from >130,000 patients publicly available through the cBioPortal for Cancer Genomics (https://genie.cbioportal.org). For 25,000 patients, additional real-world longitudinal clinical data, including treatment and outcome data, are being collected by the AACR Project GENIE Biopharma Collaborative using the PRISSMM data curation model. Several thousand of these cases are now also available in cBioPortal. We have significantly enhanced the functionalities of cBioPortal to support the visualization and analysis of this rich clinico-genomic linked dataset, as well as datasets generated by other centers and consortia. Examples of these enhancements include (i) visualization of the longitudinal clinical and genomic data at the patient level, including timelines for diagnoses, treatments, and outcomes; (ii) the ability to select samples based on treatment status, facilitating a comparison of molecular and clinical attributes between samples before and after a specific treatment; and (iii) survival analysis estimates based on individual treatment regimens received. Together, these features provide cBioPortal users with a toolkit to interactively investigate complex clinico-genomic data to generate hypotheses and make discoveries about the impact of specific genomic variants on prognosis and therapeutic sensitivities in cancer. SIGNIFICANCE: Enhanced cBioPortal features allow clinicians and researchers to effectively investigate longitudinal clinico-genomic data from patients with cancer, which will improve exploration of data from the AACR Project GENIE Biopharma Collaborative and similar datasets.

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.

Mutation spectrum of retinoblastoma patients in Vietnam.

BACKGROUND: Retinoblastoma (RB), an intraocular malignancy commonly diagnosed in children, is mostly caused by inactivating mutations of both alleles of the RB1 gene. Early genetic screening for RB1 gene mutations would greatly improve treatment outcomes and patient management. METHODS: In this study, both somatic and germline mutations were detected in blood and tumour samples of 42 RB patients using direct sequencing and multiplex ligation-dependent probe amplification. RESULTS: In total, 34 different mutations were found in 36 patients, including 1 SNP, 4 large deletions, 5 splicing sites, 1 missense, 7 frameshifts and 17 nonsense mutations. There were five novel mutations and one unreported which have not been found in large databases such as Leiden Open Variation Database (LOVD) and ClinVar. CONCLUSION: A higher rate of RB patients carrying heterozygous germline mutation and highly prevalent with pathogenic truncated mutation, hence, early detection of RB is essential for vision salvation and genetic counselling.

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.

The GENIE BPC NSCLC Cohort: A Real-World Repository Integrating Standardized Clinical and Genomic Data for 1,846 Patients with Non-Small Cell Lung Cancer.

PURPOSE: We describe the clinical and genomic landscape of the non-small cell lung cancer (NSCLC) cohort of the American Association for Cancer Research (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE) Biopharma Collaborative (BPC). EXPERIMENTAL DESIGN: A total of 1,846 patients with NSCLC whose tumors were sequenced from 2014 to 2018 at four institutions participating in AACR GENIE were randomly chosen for curation using the PRISSMM data model. Progression-free survival (PFS) and overall survival (OS) were estimated for patients treated with standard therapies. RESULTS: In this cohort, 44% of tumors harbored a targetable oncogenic alteration, with EGFR (20%), KRAS G12C (13%), and oncogenic fusions (ALK, RET, and ROS1; 5%) as the most frequent. Median OS (mOS) on first-line platinum-based therapy without immunotherapy was 17.4 months [95% confidence interval (CI), 14.9-19.5 months]. For second-line therapies, mOS was 9.2 months (95% CI, 7.5-11.3 months) for immune checkpoint inhibitors (ICI) and 6.4 months (95% CI, 5.1-8.1 months) for docetaxel ± ramucirumab. In a subset of patients treated with ICI in the second-line or later setting, median RECIST PFS (2.5 months; 95% CI, 2.2-2.8) and median real-world PFS based on imaging reports (2.2 months; 95% CI, 1.7-2.6) were similar. In exploratory analysis of the impact of tumor mutational burden (TMB) on survival on ICI treatment in the second-line or higher setting, TMB z-score harmonized across gene panels was associated with improved OS (univariable HR, 0.85; P = 0.03; n = 247 patients). CONCLUSIONS: The GENIE BPC cohort provides comprehensive clinicogenomic data for patients with NSCLC, which can improve understanding of real-world patient outcomes.

Case Report: Novel rare mutation c.6353C > G in the ABCA12 gene causing harlequin ichthyosis identified by whole exome sequencing.

Background: Harlequin ichthyosis (HI) is a severe rare genetic disease that mainly affects the skin. Neonates with this disease are born with thick skin and large diamond-shaped plates covering most of their bodies. Affected neonates lose the ability to control dehydration and regulate temperature and are more susceptible to infections. They also face respiratory failure and feeding problems. These clinical symptoms are factors associated with high mortality rates of neonates with HI. Until now, there are still no effective treatments for HI patients and most patients die in the newborn period. Mutation in the ABCA12 gene, which encodes an adenosine triphosphate-binding cassette (ABC) transporter, has been demonstrated as the major cause of HI. Case presentation: In this study, we report the case who is one infant that was born prematurely at 32 gestational weeks with the whole body covered with thick plate-like scales of skin. The infant was severely infected with mild edema, multiple cracked skins full of the body, yellow discharge, and necrosis of fingers and toes. The infant was suspected to be affected by HI. Whole exome sequencing (WES) was performed as a tool for detecting the novel mutation in one prematurely born Vietnam infant with HI phenotype. And after that, the mutation was confirmed by the Sanger sequencing method in the patient and the members of his family. In this case, one novel mutation c.6353C > G (p.S2118X, Hom) in the ABCA12 gene, was detected in the patient. The mutation has not been reported in any HI patients previously. This mutation was also found in a heterozygous state in the members of the patient's family, including his parents, an older brother, and an older sister who are no symptoms. Conclusions: In this study, we identified a novel mutation in a Vietnamese patient with HI by whole exome sequencing. The results for the patient and the members of his family will be helpful in understanding the etiology of the disease, diagnosing carriers, assisting in genetic counseling, and emphasizing the need for DNA-based prenatal screening for families with a history of the disease.

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.

A case of response to combination treatment with autologous immunotherapy and bevacizumab in advanced non-small cell lung cancer.

Natural killer (NK) cells have developed as a potent tool in cancer immunotherapy. Especially, patients who have failed in the first-line or maintenance treatment received a good response with immunotherapy in association with other approaches. We report the case of a 61-year-old male patient with programmed cell death ligand - 1(PD-L1) expression in advanced non-small cell lung cancer (NSCLC) (stage IV). Even though the patient was treated with standard therapy using keytruda, he still appeared with new lesions. Therefore, the patient was treated in combination with autologous NK cells therapy, gemcitabine, bevacizumab. NK cells were expanded from peripheral blood mononuclear cells (PBMCs) of the patient, and after that, they were transferred back to the patient. After 6 infusions of autologous NK cells in combination with gemcitabine, bevacizumab, the patient decreased significantly the size of primary, metastatic lesions and had a marked improvement in the quality of life. Besides, during combination therapy, no side effects have been reported and there was no toxicity observed in the hematopoietic system, liver as well as kidneys. Our case suggests that this treatment regimen is a potential treatment approach for advanced NSCLC with PD-L1 expression.

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.

Preimplantation genetic testing (PGT) for hemophilia A: Experience from one center.

OBJECTIVE: Hemophilia A (HA) is an X-linked recessive bleeding disease caused by a deficiency or dysfunction of blood coagulation factor VIII (FVIII). Available treatment to replenish the missing factor may not reach a good outcome for all patients because of potential complications that include the development of inhibitor antibodies directed against factor VIII. Therefore, the prevention of transmitting pathogenic mutations to the next generation is the best solution for this disease. Preimplantation genetic testing for a monogenic disorder (PGT-M) has become a standard method to prevent the transmission of monogenic heritable disease. The gold standard of the molecular technique used for PGT-M nowadays is the co-amplification of the polymorphic microsatellite linkage markers that use microsatellite DNA technique that overcomes the limitation of other methods. The important issue of this technique is the definition of markers that are specific for each allele on different loci. Each gene locus needs a characteristic design to allow accurate diagnosis that can be applied on PGT-M due to the limited quantity of DNA available. Here we present our study of four specific self-designed linked polymorphic markers applied on screening the embryos before implantation for hemophilia A families in Vietnam. MATERIAL AND METHODS: In this study, we investigated the feasibility of application and diagnostic value of 4 STR loci (FXS1108, DXS9897, F8int22, DXS9901) in the intragenic or neighbouring regions of the F8 gene. 35 hemophilia A families were recruited for STR analysis to define at least two characteristic heterologous markers for each family and 12 cases of pre-implantation genetic testing (PGT-M) for carrier mothers were performed. RESULT: All 4 of these loci (FXS1108, DXS9897, F8int22, DXS9901) were found practical and useful for preimplantation genetic testing (PGT-M). All 12 cases of PGT-M using the method had informative STR results and correct diagnosis was achieved. 9 out of the 12 mothers (75%) were implanted with 1-2 thawed embryos after the biopsy resulting in the birth of 5 healthy babies (55%). CONCLUSION: We conclude that specific 4 STR markers for rapid pre-implantation genetic testing of hemophilia A can be successfully applied with high confidence and accuracy in clinical settings. The results of the study provide solid evidence confirming that the microsatellite DNA technique is a highly reliable method, suitable for hemophilia A families wishing to determine carrier status or having healthy babies.

Genetic Ancestry Correlates with Somatic Differences in a Real-World Clinical Cancer Sequencing Cohort.

Accurate ancestry inference is critical for identifying genetic contributors of cancer disparities among populations. Although methods to infer genetic ancestry have historically relied upon genome-wide markers, the adaptation to targeted clinical sequencing panels presents an opportunity to incorporate ancestry inference into routine diagnostic workflows. We show that global ancestral contributions and admixture of continental populations can be quantitatively inferred using markers captured by the MSK-IMPACT clinical panel. In a pan-cancer cohort of 45,157 patients, we observed differences by ancestry in the frequency of somatic alterations, recapitulating known associations and revealing novel associations. Despite the comparable overall prevalence of driver alterations by ancestry group, the proportion of patients with clinically actionable alterations was lower for African (30%) compared with European (33%) ancestry. Although this result is largely explained by population-specific cancer subtype differences, it reveals an inequity in the degree to which different populations are served by existing precision oncology interventions. SIGNIFICANCE: We performed a comprehensive analysis of ancestral associations with somatic mutations in a real-world pan-cancer cohort, including >5,000 non-European individuals. Using an FDA-authorized tumor sequencing panel and an FDA-recognized oncology knowledge base, we detected differences in the prevalence of clinically actionable alterations, potentially contributing to health care disparities affecting underrepresented populations. This article is highlighted in the In This Issue feature, p. 2483.

Modeling human multi-lineage heart field development with pluripotent stem cells.

The cardiomyocyte (CM) subtypes in the mammalian heart derive from distinct lineages known as the first heart field (FHF), the anterior second heart field (aSHF), and the posterior second heart field (pSHF) lineages that are specified during gastrulation. We modeled human heart field development from human pluripotent stem cells (hPSCs) by using single-cell RNA-sequencing to delineate lineage specification and progression. Analyses of hPSC-derived and mouse mesoderm transcriptomes enabled the identification of distinct human FHF, aSHF, and pSHF mesoderm subpopulations. Through staged manipulation of signaling pathways identified from transcriptomics, we generated myocyte populations that display molecular characteristics of key CM subtypes. The developmental trajectory of the human cardiac lineages recapitulated that of the mouse, demonstrating conserved cardiovascular programs. These findings establish a comprehensive landscape of human embryonic cardiogenesis that provides access to a broad spectrum of cardiomyocytes for modeling congenital heart diseases and chamber-specific cardiomyopathies as well as for developing new therapies to treat them.

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.

Investigation of target sequencing of SARS-CoV-2 and immunogenic GWAS profiling in host cells of COVID-19 in Vietnam.

BACKGROUND: A global pandemic has been declared for coronavirus disease 2019 (COVID-19), which has serious impacts on human health and healthcare systems in the affected areas, including Vietnam. None of the previous studies have a framework to provide summary statistics of the virus variants and assess the severity associated with virus proteins and host cells in COVID-19 patients in Vietnam. METHOD: In this paper, we comprehensively investigated SARS-CoV-2 variants and immune responses in COVID-19 patients. We provided summary statistics of target sequences of SARS-CoV-2 in Vietnam and other countries for data scientists to use in downstream analysis for therapeutic targets. For host cells, we proposed a predictive model of the severity of COVID-19 based on public datasets of hospitalization status in Vietnam, incorporating a polygenic risk score. This score uses immunogenic SNP biomarkers as indicators of COVID-19 severity. RESULT: We identified that the Delta variant of SARS-CoV-2 is most prevalent in southern areas of Vietnam and it is different from other areas in the world using various data sources. Our predictive models of COVID-19 severity had high accuracy (Random Forest AUC = 0.81, Elastic Net AUC = 0.7, and SVM AUC = 0.69) and showed that the use of polygenic risk scores increased the models' predictive capabilities. CONCLUSION: We provided a comprehensive analysis for COVID-19 severity in Vietnam. This investigation is not only helpful for COVID-19 treatment in therapeutic target studies, but also could influence further research on the disease progression and personalized clinical outcomes.