A consultation and work-up diagnosis protocol for a multicancer early detection test: a case series study.

The emergence of multicancer early detection (MCED) tests holds promise for improving early cancer detection and public health outcomes. However, positive MCED test results require confirmation through recommended cancer diagnostic imaging modalities. To address these challenges, we have developed a consultation and work-up protocol for definitive diagnostic results post MCED testing, named SPOT-MAS. Developed through circulating tumor DNA (ctDNA) analysis and in line with professional guidelines and advisory board consensus, this protocol standardizes information to aid general practitioners in accessing, interpreting and managing SPOT-MAS results. Clinical effectiveness is demonstrated through a series of identified cancer cases. Our research indicates that the protocol could empower healthcare professionals to confidently interpret circulating tumor DNA test results for 5 common types of cancer, thereby facilitating the clinical integration of MCED tests.

New tests can now screen for multiple types of cancer early, offering hope for better health outcomes. If one of these tests shows a positive result, doctors need to confirm it with imaging tests. We have developed a guide to help doctors understand and confirm these results. This guide could help healthcare professionals interpret results for five common types of cancer, making it easier to use these tests in regular medical practice.

Prenatal diagnosis of autosomal recessive renal tubular dysgenesis caused by variants in the ACE gene: Two fetuses with anhydramnios.

INTRODUCTION: Autosomal recessive renal tubular dysgenesis (ARRTD) is a rare genetic disorder with a very high mortality rate. The typical symptoms of the disease during pregnancy are oligohydramnios, anhydramnios, and nearly all affected fetuses die after birth or have a stillbirth in late gestation, which can adversely increase maternal risks. METHODS: Oligohydramnios/anhydramnios can make both amniocentesis for diagnostic testing and morphological evaluation via ultrasound more difficult. In cases of oligohydramnios/anhydramnios suspicious for urinary tract anomalies, amnioinfusion is a meaningful technique that facilitates sampling of amniotic fluid for genetic diagnosis. RESULTS: We report two cases of fetuses with anhydramnios and invisible urinary bladder. Clinical exome sequencing from amniotic fluid revealed a biparentally inherited homozygous pathogenic nonsense ACE variant c.2503G 〉 T [p.Glu853Ter] in proband 1 and a biparentally inherited homozygous pathogenic nonsense ACE variant c.2992C 〉 T [p.Gln998Ter] in proband 2. The prognosis was poor and the patients elected to terminate the pregnancies. Additional post-mortem histopathological examination from the renal tissue of the second fetus showed renal tubular hypoplasia. CONCLUSION: To our knowledge for the first time, we describe the prenatal diagnosis of ARRTD in Vietnam, and highlight the benefit of detecting ACE variants associated with ARRTD in fetuses with oligohydramnios/anhydramnios through amnioinfusion and amniocentesis, which improves genotype-phenotype correlations and provides valuable information for reproductive counseling.

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 Novel Frameshift Microdeletion of the TEX12 Gene Caused Infertility in Two Brothers with Nonobstructive Azoospermia.

Male infertility is a growing health problem, which affects approximately 7% of the global male population. Nonobstructive azoospermia (NOA) is one of the most severe forms of male infertility caused by genetic defects, including chromosome structural abnormalities, Y chromosome microdeletions, or single-gene alterations. However, the etiology of up to 40% of NOA cases is unidentified. By whole-exome sequencing, we detected a homozygous 5-bp-deletion variant in exon 4 of the TEX12 gene (c.196-200del, p.L66fs, NM_031275.4) in two brothers with NOA of a nonconsanguineous Vietnamese family. This deletion variant of 5 nucleotides (ATTAG) results in a premature stop codon in exon 4 and truncation of the C-terminal. Segregation analysis by Sanger sequencing confirmed that the deletion variant was inherited in an autosomal recessive pattern. The 1st and 3rd infertile sons were homozygous for the deletion, whereas the 2nd fertile son and both parents were heterozygous. The new deletion mutation identified in TEX12 gene caused loss of function of TEX12 gene. The loss of TEX12 function has already caused infertility in male mice. Therefore, we concluded that the loss of TEX12 function may cause infertility in men. To our knowledge, this is the first case reported so far indicating disruption of human TEX12, which leads to infertility in men.

Clinical validation of a ctDNA-Based Assay for Multi-Cancer Detection: An Interim Report from a Vietnamese Longitudinal Prospective Cohort Study of 2795 Participants.

The SPOT-MAS assay "Screening for the Presence Of Tumor by Methylation And Size" detects the five most common cancers in Vietnam by evaluating circulating tumor DNA in the blood. Here, we validated its performance in a prospective multi-center clinical trial, K-DETEK. Our analysis of 2795 participants from 14 sites across Vietnam demonstrates its ability to detect cancers in asymptomatic individuals with a positive predictive value of 60%, with 83.3% accuracy in detecting tumor location. We present a case report to support further using SPOT-MAS as a complementary method to achieve early cancer detection and provide the opportunity for early treatment.

Human papillomavirus prevalence and genotype distribution in Vietnamese male patients between 2016 and 2020.

Human papillomavirus (HPV) infection in men is a serious issue because it is associated with genital warts, anogenital cancers, and HPV transmission to their sex partners. This study aimed to investigate the prevalence and genotypes of HPVs in Vietnamese male patients hospitalized with sexually transmitted infection (STI) symptoms between 2016 and 2020 by using polymerase chain reaction and reverse dot blot hybridization analysis. HPV DNA was detected in 191/941 (20.3%) penile cell samples. The HPV patient's mean age was 30.3 in the range of 16- and 69-year-old. The highest HPV prevalence (84.7%) was found in patients between 20- and 39-year-old. A total of 313 HPV genotypes were identified. The multiple-infection rate was 42.9%. The most common high-risk (HR)-HPV genotypes were HPV-16 (8.0%), HPV-51 (7.7%), HPV-52 (4.8%), HPV-56 (4.2%), and HPV-18 (3.8%). Furthermore, HPV-11 and HPV-6 genotypes were the two most common low-risk (LR)-HPV genotypes with the rate of 36.7% and 21.4%, respectively. Notably, HPV-52 was found circulating in Vietnam for the first time. In conclusion, this study results showed that HPV prevalence in Vietnamese male patients was common and diverse. In addition, regarding public health and cancer prevention, the inclusion of the HPV vaccination into the national vaccination program for both men and women is recommended.

Novel and very rare causative variants in the COL7A1 gene of Vietnamese patients with recessive dystrophic epidermolysis bullosa revealed by whole-exome sequencing.

BACKGROUND: Dystrophic epidermolysis bullosa (DEB) is a rare inherited disorder characterized by skin fragility leading to trauma-induced subepidermal blisters and healing with scarring. DEB is caused by mutations in COL7A1, the gene encoding for type VII collagen (COLVII). The DEB inheritance trait is divided into dominant dystrophic epidermolysis bullosa (DDEB) and recessive dystrophic epidermolysis bullosa (RDEB). METHODS: Whole-exome sequencing (WES) was performed for identifying mutations in six affected individuals of five Vietnamese families. RESULTS: Three novel variants in total of eight variants were found in five families. The first novel variant causing glycine substitution (c.8279G>A, p.G2760E), the remaining two novel variants resulted in splice site affecting (c.4518+2delT and c.5821-2A>G). Functional analysis indicated that the splice site at c.4518+2delT resulted in a skipping of exon 43, leading to an in-frame deletion of 12 amino acids. CONCLUSION: Our finding expands the spectrum of COL7A1 mutations and reports altered splicing at c.4518+2delT during the processing of the pre-mRNA. This study provides an additional scientific basis for diagnosis, genetic counseling, and prognosis purposes of EB patients.

Evaluation of sperm DNA fragmentation index, Zinc concentration and seminal parameters from infertile men with varicocele.

The aim of this study was to investigate the effect of varicocele on DNA fragmentation index (DFI), zinc concentration and seminal parameters in infertile patients. In this prospective study, 179 men with at least 1-year history of infertility and varicocele were examined for semen quality at Hanoi Medical University Hospital (HMUH), Hanoi, Vietnam. In addition, an inverse correlation between zinc concentration and the degree of sperm DNA fragmentation in patients with clinical varicocele was found. The difference in mean values of sperm DNA fragmentation index in patients with various grades of varicoceles can be neglected, whereas most patients with varicocele of grades II and III had DFI >30%. Varicocele is associated with high levels of DNA damage in spermatozoa and reduced zinc levels that correlate with different grades of disease. Therefore, DNA fragmentation index and zinc concentration can be used as essential additional diagnostic test for patients with clinical varicocele. A study should be conducted to evaluate the benefits of zinc supplementation to improve seminal parameters in patients with varicocele.