Purpose: Accurate profiling of population-specific recessive diseases is essential for the design of cost-effective carrier screening programs. However, minority populations and ethnic groups, including Vietnamese, are still under-represented in existing genetic studies. Here we reported the first comprehensive study of recessive diseases in the Vietnamese population. Methods: Clinical exome sequencing (CES) data of 4,503 disease-associated genes obtained from a cohort of 985 Vietnamese individuals was analyzed to identify pathogenic variants, associated diseases and their carrier frequencies in the population. Results: Eighty-five recessive diseases were identified in the Vietnamese population, among which seventeen diseases had carrier frequencies of at least 1% (1 in 100 individuals). Three diseases were especially prevalent in the Vietnamese population with carrier frequencies of 2-12 times higher than in other East Asia or the world populations, including Beta-thalassemia (1 in 25), citrin deficiency (1 in 33) and phenylketonuria (1 in 40). Seven novel pathogenic and three likely pathogenic variants associated with nine recessive diseases were also discovered. Conclusions: The comprehensive profile of recessive diseases identified in this study shall enable the design of cost-effective carrier screening programs specific to the Vietnamese population. The newly discovered pathogenic variants may also exist in other populations at extremely low frequencies, thus representing a valuable resource for future research. Our study has demonstrated the advantage of population-specific genetic studies to advance the knowledge and practice of medical genetics. Keywords: carrier frequency; carrier screening; recessive diseases.

BackgroundHereditary cancer syndromes (HCS) are responsible for 5-10% of cancer cases. Genetic testing to identify pathogenic variants associated with cancer predisposition has not been routinely available in Vietnam. Consequently, the prevalence and genetic landscape of HCS remain unknown.Methods1165 Vietnamese individuals enrolled in genetic testing at our laboratory in 2020. We performed analysis of germline mutations in 17 high- and moderate- penetrance genes associated with HCS by next generation sequencing.ResultsA total of 41 pathogenic variants in 11 genes were detected in 3.2% individuals. The carrier frequency was 4.2% in people with family or personal history of cancer and 2.6% in those without history. The percentage of mutation carriers for hereditary colorectal cancer syndromes was 1.3% and for hereditary breast and ovarian cancer syndrome was 1.6%. BRCA1 and BRCA2 mutations were the most prevalent with the positive rate of 1.3% in the general cohort and 5.1% in breast or ovarian cancer patients. Most of BRCA1 mutations located at the BRCA C-terminus domains and the top recurrent mutation was NM_007294.3:c.5251C>T (p.Arg1751Ter). One novel variant NM_000038.6(APC):c.6665C>A (p.Pro2222His) was found in a breast cancer patient with a strong family history of cancer. A case study of hereditary cancer syndrome was illustrated to highlight the importance of genetic testing.ConclusionThis is the first largest analysis of carrier frequency and mutation spectrum of HCS in Vietnam. The findings demonstrate the clinical significance of multigene panel testing to identify carriers and their at-risk relatives for better cancer surveillance and management strategies.

Accurate profiling of population‐specific recessive diseases is essential for the design of cost‐effective carrier screening programs. However, minority populations and ethnic groups, including Vietnamese, are still underrepresented in existing genetic studies. Here, we reported the first comprehensive study of recessive diseases in the Vietnamese population. Clinical exome sequencing data of 4503 disease‐associated genes obtained from a cohort of 985 Vietnamese individuals was analyzed to identify pathogenic variants, associated diseases and their carrier frequencies in the population. A total of 118 recessive diseases associated with 164 pathogenic or likely pathogenic variants were identified, among which 28 diseases had carrier frequencies of at least 1% (1 in 100 individuals). Three diseases were prevalent in the Vietnamese population with carrier frequencies of 2–12 times higher than in the world populations, including beta‐thalassemia (1 in 23), citrin deficiency (1 in 31), and phenylketonuria (1 in 40). Seven novel pathogenic and two likely pathogenic variants associated with nine recessive diseases were discovered. The comprehensive profile of recessive diseases identified in this study enables the design of cost‐effective carrier screening programs specific to the Vietnamese population.

Copy number variation (CNV) analysis is a powerful tool for discovering structural genomic variation. Still, no program uses this tool to analyze chromosomal aneuploidies in the Vietnamese population. Pregnant women attending routine prenatal checkups in Vietnam from October 2018 to May 2021 were included in this study and contributed fetal tissue to test the utility of CNV analysis for prenatal screening. Among 5,008 women screened, 958 (19.13%) harbored at least one CNV, comprising segmental aneuploidy (8.49%), trisomy (6.91%), multiple anomalies (2.10%), and sex chromosome abnormality (1.64%). The rate of segmental aneuploidy detection increased with gestational age, but trisomy and sex chromosomal abnormalities detection decreased as the pregnancy continued. This study also found an association between abnormal CNVs and several phenotypic markers. For ultrasound soft markers, an increased nuchal fold thickness correlated with a higher risk of abnormal CNVs. In addition, many soft indicators or structural abnormalities were significantly associated with an increased likelihood of abnormal CNVs. This work highlights the importance of CNV analysis for the early detection of prenatal congenital abnormalities, especially in the first trimester. This study’s findings will meaningfully aid policymakers in developing cost-effective genetic prenatal screening programs.