Down syndrome (DS) is the most prevalent chromosomal disorder worldwide and is primarily caused by chromosome 21 nondisjunction (Ch21 NDJ). Categorizing trisomy 21 cases by parental origin allows a more precise assessment of maternal age (MA) as a DS risk factor. This study aimed to investigate the association between MA and parental allele transmission patterns at the D21S11 locus in individuals with DS. A familial-based study was conducted by collecting blood samples from 55 DS Libyan families, categorizing into two groups based on MA (<35 years and ≥35 years). Short tandem repeat analysis of D21S11 marker on Ch21 was used to trace allelic transmission from parents to offspring. The parental NDJ errors were traceable in 24 (58.5%) of 41 informative families, with maternal and paternal NDJ errors accounting for 20/24 (83.3%) and 4/24 (16.7%), respectively. Given the limited traceability rate, this investigation should be considered a preliminary study. Among the 24 informative cases, maternal-origin trisomy accounted for 8 of 10 cases (80.0%) in mothers aged <35 years and 12 of 14 cases (85.7%) in mothers aged ≥35 years. The present results suggest that MA may be associated with the distribution of trisomy 21 based on D21S11 parental allele transmission patterns; however, no statistically significant association was detected in the present cohort (P = 0.563). Although additional Ch21 markers are needed, this study provides preliminary insights into MA-related patterns of allele transmission in Libyan individuals with DS. Down syndrome (DS) is a common chromosomal disorder caused by an extra chromosome 21, often linked to advanced maternal age (MA). This study explores the association between advanced MA and trisomy 21 in Libyan DS cases by analyzing parental allele transmission patterns using the D21S11 marker. Researchers collected blood samples from 55 families and used DNA profiling to determine the parental origin of the extra chromosome. The study found that 83.3% of trisomy 21 cases were of maternal origin, with a higher occurrence in mothers aged 35 and older. However, no significant statistical association was found between MA and the origin of trisomy 21. The study highlights the need for larger sample sizes and additional markers to improve the accuracy of parental-origin analysis. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant vascular disorder mainly caused by pathogenic variants in ACVRL1 or ENG. We identified a novel heterozygous ACVRL1 p.Cys95Ser variant in a Japanese family with HHT. The variant co-segregated with clinical features and was associated with impaired BMP9-induced signaling, as evidenced by reduced cell-surface expression and increased endoplasmic reticulum retention. These findings expand the HHT mutational spectrum and support early genetic diagnosis.
Abstract The use of comprehensive genomic profiling (CGP) in cancer, also known as cancer gene panel tests, continues to expand; however, the interpretation of the results of these tests requires a tremendous amount of manual work. To improve the efficiency of this evaluation process, we developed the CGP support software named Varporter. This software automatically imports multiple data files and can display various information contained within the CGP results. In tumor-only tests, TP53 variants often require pathogenicity evaluation as presumed germline pathogenic variants. Varporter enables the automated determination of several criteria in the Variant Interpretation Guidelines established by the ClinGen TP53 Variant Curation Expert Panel. Direct links to the websites on therapeutic evidence are also automatically generated from each variant, and multiple test reports can be summarized onto a single sheet, thus making it easy to review newly added variants to clinical trials. Varporter has made it possible to automate and streamline complicated manual tasks related to CGP evaluation and to redirect human resources to more essential tasks. Varporter is designed for use with two CGP tests covered by Japanese national health insurance, FoundationOne CDx and Guardant360 CDx.
We report a child with severe developmental and epileptic encephalopathy carrying a rare SCN8A splice‑site variant. Although its pathogenicity was initially unclear, a minigene assay demonstrated aberrant splicing, indicating a loss‑of‑function mechanism. Integrated clinical, genetic and functional evidence classified the variant as pathogenic, underscoring the importance of splicing assays for interpreting rare SCN8A variants.
Marfan syndrome is caused by pathogenic variants in FBN1. We identified a novel heterozygous frameshift variant in FBN1 (NM_000138.5: c.6784_6787del, NP_000129.3:p.(Gln2262TrpfsTer28)) in an adult male with severe cardiovascular manifestations. The variant was absent from population databases and fulfilled PVS1 and PM2 criteria. This finding expands the mutational and phenotypic spectrum of FBN1 and highlights the clinical utility of genetic testing in family-based clinical management of Marfan syndrome.
