Genetic variant databases are vital for interpreting genetic variations in clinical settings and research. However, misclassified variants can create challenges. A recent study analyzed archives of ClinVar and HGMD databases over six years, focusing on inborn errors of metabolism (IEMs) in newborns. The research found that false-positive rates in both databases have improved over time. Notably, HGMD variants indicated more affected individuals than ClinVar variants, especially for African ancestry individuals. Reclassification of variants has contributed to better accuracy. The study underscores the importance of updated variant classification guidelines and diverse genetic samples in improving database accuracy. Read more about this under Article 1 below.
- Article 1: ClinVar and HGMD genomic variant classification accuracy has improved over time, as measured by implied disease burden
- Article 2: Fecal microbiota transplantation plus anti-PD-1 immunotherapy in advanced melanoma: a phase I trial
- Article 3: Utility of exome sequencing for diagnosis in unexplained pediatric-onset epilepsy
- Article 4: Identifying high-grade serous ovarian carcinoma–specific extracellular vesicles by polyketone-coated nanowires
Article 1: ClinVar and HGMD genomic variant classification accuracy has improved over time, as measured by implied disease burden
A study published in Genome Medicine revealed that genetic variant databases have become more accurate with time. Researchers analyzed changes in variant misclassifications within ClinVar and the Human Gene Mutation Database (HGMD) over six years, focusing on variants related to inborn errors of metabolism. They found fewer misclassifications over time, particularly in ClinVar, which also had a lower false-positive rate due to more frequent reclassifications. This progress is crucial for clinicians, researchers, and computational experts who use these databases for genetic variant interpretation and testing, leading to a better understanding and treatment of genetic disorders. Read the full article here.
In summary: Improved accuracy in genetic variant databases over time
Article 2: Fecal microbiota transplantation plus anti-PD-1 immunotherapy in advanced melanoma: a phase I trial
A recent study shows that fecal microbiome transplants (FMTs) from healthy donors, combined with anti-PD-1 immunotherapy, are safe and effective for advanced melanoma patients. In a Phase I trial, 20 patients with unresectable or metastatic melanoma received FMT before nivolumab or pembrolizumab treatment. The approach was well-tolerated, with no severe adverse events from FMT alone. However, some patients experienced immune-related side effects. The study also reported a 65% objective response rate and a 20% complete response rate. This research explores the link between the microbiome, immune system, and cancer treatment, offering hope for better melanoma outcomes. Read the full article here.
In summary: Fecal transplants improve melanoma treatment
Article 3: Utility of exome sequencing for diagnosis in unexplained pediatric-onset epilepsy
Recent findings indicate that exome sequencing can provide important diagnoses for children with unexplained epilepsy. The team sequenced the exomes of 522 pediatric patients and their parents and found genetic diagnoses for 19% of them. Diagnoses were more common in patients with intellectual disability, early-onset seizures, or motor impairment. For 71 patients who received a genetic diagnosis, 29 saw changes in disease treatment, management, or prognosis, such as new medications or diets. The study brought relief to families who had been searching for answers and offered hope to others still seeking a diagnosis. Read the full article here.
In summary: Exome sequencing offers hope for children with unexplained epilepsy
Article 4: Identifying high-grade serous ovarian carcinoma–specific extracellular vesicles by polyketone-coated nanowires
Researchers have identified three protein markers in extracellular vesicles that can help detect high-grade serous ovarian carcinoma (HGSC). They isolated cancer cell-derived extracellular vesicles and found distinct proteomic profiles in small and medium/large vesicles using LC-MS/MS* analysis. They validated the presence of FRα, Claudin-3, and TACSTD2 proteins in small vesicles, confirming their role as biomarkers for HGSC. To improve detection, they developed a specialized tool to separate small vesicles from biofluids. These findings offer potential for early and personalized ovarian cancer diagnosis, allowing doctors to optimize treatment strategies based on individual biomarker profiles. Read the full article here.
*Liquid Chromatography-Mass Spectrometry/Mass Spectrometry
In summary: Promising protein markers for ovarian cancer diagnosis
New in Genetics issue July 2023. Every month, Medicover Genetics curates the most important peer-reviewed scientific publications related to genetics.
 Sharo, A. G., Zou, Y., Adhikari, A. N., & Brenner, S. E. (2023). ClinVar and HGMD genomic variant classification accuracy has improved over time, as measured by implied disease burden. Genome medicine, 15(1), 51. https://doi.org/10.1186/s13073-023-01199-y
 Routy, B., Lenehan, J. G., Miller, W. H., Jr, Jamal, R., Messaoudene, M., Daisley, B. A., Hes, C., Al, K. F., Martinez-Gili, L., Punčochář, M., Ernst, S., Logan, D., Belanger, K., Esfahani, K., Richard, C., Ninkov, M., Piccinno, G., Armanini, F., Pinto, F., Krishnamoorthy, M., … Maleki Vareki, S. (2023). Fecal microbiota transplantation plus anti-PD-1 immunotherapy in advanced melanoma: a phase I trial. Nature medicine, 10.1038/s41591-023-02453-x. Advance online publication. https://doi.org/10.1038/s41591-023-02453-x
 Koh, H. Y., Smith, L., Wiltrout, K. N., Podury, A., Chourasia, N., D’Gama, A. M., Park, M., Knight, D., Sexton, E. L., Koh, J. J., Oby, B., Pinsky, R., Shao, D. D., French, C. E., Shao, W., Rockowitz, S., Sliz, P., Zhang, B., Mahida, S., Moufawad El Achkar, C., … BCH Neurology Referral and Phenotyping Group (2023). Utility of Exome Sequencing for Diagnosis in Unexplained Pediatric-Onset Epilepsy. JAMA network open, 6(7), e2324380. https://doi.org/10.1001/jamanetworkopen.2023.24380
 Yokoi, A., Ukai, M., Yasui, T., Inokuma, Y., Hyeon-Deuk, K., Matsuzaki, J., Yoshida, K., Kitagawa, M., Chattrairat, K., Iida, M., Shimada, T., Manabe, Y., Chang, I. Y., Asano-Inami, E., Koya, Y., Nawa, A., Nakamura, K., Kiyono, T., Kato, T., Hirakawa, A., … Kajiyama, H. (2023). Identifying high-grade serous ovarian carcinoma-specific extracellular vesicles by polyketone-coated nanowires. Science advances, 9(27), eade6958. https://doi.org/10.1126/sciadv.ade6958