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.
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.
Carnitine-acylcarnitine translocase deficiency is a severe neonatal metabolic disorder caused by SLC25A20 variants. We report a case of sudden neonatal death in which post-mortem CT revealed diffuse fatty liver, and subsequent genetic analysis identified compound heterozygous variants in SLC25A20, including a known variant, c.824G>A p.(Arg275Gln), and a novel nonsense variant, c.334C>T p.(Gln112Ter). These findings demonstrate the utility of post-mortem genetic analysis in determining the cause of sudden neonatal death.
Abstract GNE myopathy is a rare autosomal recessive myopathy caused by biallelic pathogenic variants in GNE , which encodes an essential enzyme for sialic acid biosynthesis. Most variants are located in exonic regions, whereas significance of intronic variants remains unclear, leaving many suspected cases genetically unresolved. We aimed to assess the pathogenicity of intronic GNE variants using targeted whole-genome and RNA sequencing. We performed combined long amplicon sequencing in two siblings with GNE myopathy. DNA and RNA were extracted from muscle biopsy specimens and peripheral blood mononuclear cells. Variants were validated using Sanger sequencing. Splicing effects were predicted using SpliceAI and SpliceRover and validated by RNA sequencing. Muscle sialylation was assessed using peanut agglutinin lectin staining. An uncharacterized intronic variant, NC_000009.12(NM_001128227): c.1163+5G>T, was identified in trans with a known missense variant (NM_001128227): c.1807C>G, p.V603L. RNA sequencing demonstrated aberrant splicing caused by intronic mutation, leading to a non-productive transcript in muscle and blood cells. Reduced sialic acid biosynthesis further supported the pathogenicity of the intronic mutation. These findings demonstrate that combined long amplicon sequencing can elucidate the genetic basis of GNE myopathy undetectable by exome sequencing. This approach provides a clinically applicable, less invasive diagnostic strategy and expands the spectrum of pathogenic GNE variants.
Cleidocranial dysplasia is an autosomal dominant disorder caused by RUNX2 variants. We report a Japanese boy with enlarged fontanelles in infancy, initially suspected of hypophosphatasia. Exome sequencing identified a novel de novo RUNX2 splice-site variant (c.685+2T>G), affecting the canonical donor site, and predicted to disrupt splicing. This novel variant expands the mutational spectrum of RUNX2-associated cleidocranial dysplasia and highlights the value of early genetic diagnosis.
Abstract Carney complex is a rare multiple neoplasia syndrome caused primarily by inactivating variants in the PRKAR1A gene, which encodes the regulatory subunit type I alpha of protein kinase A. Although classically associated with myxomas, lentigines, and endocrine tumors, the full tumor spectrum related to PRKAR1A loss of function is not completely defined. Here, we report a patient with a molecularly confirmed diagnosis of Carney complex carrying a de novo PRKAR1A (NM_002734.5):c.348+1G>A splice-site variant. In addition to typical manifestations, the patient developed two uncommon malignancies: invasive breast carcinoma (luminal B-like) at a young age and fibrolamellar hepatocellular carcinoma lacking the DNAJB1–PRKACA fusion typically found in sporadic cases. The coexistence of these two rare tumors in a single carrier of a pathogenic PRKAR1A variant expands the phenotypic variability associated with this condition and supports the possibility that PRKAR1A loss contributes to oncogenesis beyond the classical endocrine and mesenchymal tissues. This Data Report provides clinically relevant documentation of an unusual tumor presentation associated with a pathogenic PRKAR1A variant and underscores the importance of ongoing clinical surveillance in affected individuals.
Hemizygous pathogenic variants in MBTPS2 located at Xp22.12 cause IFAP syndrome, which is characterized by the triad of ichthyosis, alopecia and photophobia. Here we identified a hemizygous intronic variant in MBTPS2 (NM_015884: c.970+5G>A) in a patient with alopecia, follicular keratinization, developmental delay and epilepsy which were compatible with IFAP syndrome. The variant has been reported to cause skipping of 20 bases in exon 7, leading to the premature termination codon. To further investigate the consequence of the variant, we performed long-read RNA sequencing using RNA extracted from fibroblasts cultured from the patient's skin. Long-read RNA sequencing revealed skipping of exons 6 and 7, in addition to the previously reported 20-base skipping in exon 7. Furthermore, the expression of normal transcripts, as observed in healthy skin, was markedly reduced. Long-read RNA sequencing is a powerful tool for simultaneously identifying diverse transcript isoforms, making it highly valuable for elucidating the effects of splice-altering variants.
Ichthyosis follicularis, alopecia and photophobia (IFAP) syndrome type I is a rare, X-linked disorder resulting from pathogenic variants in MBTPS2. Here we report a Pakistani IFAP pedigree of three affected individuals harboring the recurrent MBTPS2 splice-site variant c.970+5G>A that was reported previously in Chinese and Argentinian families. Haplotype analyses across these three families excluded a founder effect, establishing c.970+5G>A as a recurrent mutational hotspot. In addition, phenotypic severity varied across the families, suggesting additional modifiers.
Abstract Large language models (LLMs) have recently been adopted to assist in the interpretation of human genomic variants. However, general-purpose LLMs can produce incorrect outputs (commonly termed ‘hallucinations’), particularly on specialized queries, raising concerns about their reliability for variant interpretation. Here, to mitigate this risk, we developed ChatTogoVar, a retrieval-augmented generation system that queries TogoVar, a variant database that integrates information, such as allele frequency and clinical significance, and incorporates the retrieved results into prompts. We constructed a benchmark of 150 questions sampled from a predefined pool of 1500 template–variant combinations (50 templates × 30 variants). For large-scale assessment, we used the full 1500-question pool for automated LLM-based scoring. ChatTogoVar achieved the highest score for 135/150 questions, outperforming both a general-purpose LLM and an existing specialized system. Furthermore, automatic evaluation of all 1500 questions by an LLM confirmed the same trend. These results suggest that integrating a reliable variant database with an LLM can improve the accuracy of variant interpretation and that ChatTogoVar may serve as a practical tool to support genomic medicine and personalized healthcare.
Here we describe unrelated Japanese patients with distinct novel heterozygous retinoic acid receptor beta (RARB) gene variants underlying syndromic microphthalmia-12: case 1 with a frameshift variant, c.1205_1206del, had bilateral microphthalmia, corneal opacity, anterior segment dysgenesis, widespread multiorgan anomalies, hypotonia and cognitive impairment; case 2 with a missense variant, c.844G>T had Peters anomaly, extreme microphthalmia, spasticity, profound psychomotor delay and refractory epilepsy. These findings highlight the need for RARB testing.
MSX1 variants are associated with autosomal dominant craniofacial developmental anomalies, including congenital tooth agenesis. Here, whole-exome sequencing in a Japanese patient with congenital tooth agenesis identified a novel de novo heterozygous frameshift variant in MSX1 (NM_002448.3:c.299delC). The variant is predicted to generate a truncated protein, p.(Pro100Argfs*60), that lacks the C-terminal region of MSX1 and is expected to result in loss of function. The patient presented with congenital tooth agenesis, including canine agenesis. Taken together with the genetic findings, this case supports the involvement of MSX1 in congenital tooth agenesis and broadens the reported phenotypic presentation of MSX1-related tooth agenesis. This report adds to the spectrum of disease-associated MSX1 variants and supports the utility of genomic testing for molecular diagnosis in rare dental developmental anomalies.
Here we report a case of a Japanese girl with Wiedemann-Steiner syndrome carrying a novel heterozygous frameshift variant of KMT2A (NM_001197104.2:c.10123del, p.Thr3375ProfsTer7). Her clinical features included severe pre- and postnatal growth failure, global developmental delay, hypertrichosis and complete agenesis of the corpus callosum. The identified variant truncates the protein, abolishes the C-terminal SET domain required for histone methyltransferase activity, and is predicted to trigger nonsense-mediated mRNA decay, resulting in KMT2A haploinsufficiency-the primary pathogenic mechanism of Wiedemann-Steiner syndrome. This report documents a previously unreported loss-of-function variant in KMT2A with detailed molecular interpretation and phenotypic characterization, contributing to refinement of the mutational spectrum associated with Wiedemann-Steiner syndrome.
Escobar syndrome is a rare congenital disorder characterized by contractures, pterygia and craniofacial anomalies. Here we report a school-age girl harboring compound-heterozygous CHRNG variants, NM_005199.5:c.[2T>C];[428C>G] p.[(Met1?)];[(Pro143Arg)]. She presented with neonatal asphyxia, congenital limb contractures and low-frequency hearing loss but without pterygia, maintaining normal cognition. This case underscores the phenotypic variability of CHRNG-related disease and alerts clinicians to recognize milder presentations that lack pterygia and to consider targeted genetic testin.
Zinc finger MYND-type containing 11 (ZMYND11)-related neurodevelopmental disorder is an autosomal dominant condition caused by pathogenic variants in ZMYND11. Most previously reported patients harbor loss-of-function (LoF) variants, whereas missense variants are rare and their clinical and mechanistic characteristics remain insufficiently defined. Here we report a patient with a heterozygous ZMYND11 c.1798C>T, p.(Arg600Trp) variant identified through the Initiative on Rare and Undiagnosed Diseases program. Detailed clinical evaluation, developmental assessment and whole-exome sequencing were performed. In addition, a systematic review of previously published ZMYND11 cases was conducted to compare genotype-phenotype correlations between missense and LoF variants. The present patient showed global developmental delay, hypotonia, distinctive craniofacial features, microcephaly, short stature, cryptorchidism and right-sided inguinal hernia. Comparison with two previously reported individuals carrying the same c.1798C>T variant demonstrated consistent shared features, including microcephaly, broad nasal alae, short stature, cryptorchidism and nipple anomalies, findings that are not typically emphasized in LoF-associated cases. Aggregate analysis of reported 13 missense variants suggested higher frequencies of strabismus, hypotonia and severe intellectual disability compared with LoF variants, supporting the hypothesis that missense variants including c.1798C>T may define a partially distinct clinical subgroup. These findings expand the phenotypic spectrum associated with ZMYND11 missense variants and suggest variant-specific clinical patterns, particularly for c.1798C>T, which may reflect a mechanism different from simple haploinsufficiency.
Microcephaly with or without chorioretinopathy, lymphedema or mental retardation is a rare KIF11-related disorder. Here we report the case of a patient with microcephaly, lymphedema, nystagmus and familial exudative vitreoretinopathy carrying a novel de novo KIF11 nonsense variant (NM_004523.4:p.Glu123Ter), which is considered pathogenic. This case expands the phenotypic range of KIF11 pathogenic variants and highlights the importance of early ophthalmological evaluation, genetic counseling and family assessment.
Personalized thiopurine therapy is among the most established examples of pharmacogenomics translated into clinical practice. Variants in TPMT (rs1800462, rs1800460, rs1142345) and NUDT15 (rs116855232) are recognized clinical predictors of thiopurine efficacy and toxicity. Additional variants in genes such as PACSIN2 (rs2413739), ITPA (rs1127354) and MTHFR (rs1801133 and rs1801131), also contribute to variability in drug response. Here we characterize the frequency of the pharmacogenetic variants involved in thiopurine metabolism in a healthy population of Kosovo. We genotyped 299 healthy blood donors for polymorphisms. Among TPMT variant alleles, TPMT*3A was observed at a frequency of 2.0%, and the TPMT*3C at 0.1%. Notably, the MTHFR 677T variant (rs1801133) was significantly more frequent in the Kosovo population (49.8%) compared with the global and European frequencies. The minor allele frequency of MTHFR rs1801131 was 27.4%. Minor allele frequencies for PACSIN2 rs2413739 and ITPA rs1127354 variants were 48.8% and 4.0%, respectively. Sequencing of NUDT15 revealed six variants, with rs116855232 present at frequency of 0.8%. These findings provide important insights into the pharmacogenomic profile of the Kosovo population and support the implementation of pre-emptive genotyping to improve the safety and efficacy of thiopurine therapy in the region.
Array-based comparative genomic hybridization for a boy, his mother and his half-sister with etiology-unknown nonsyndromic short stature identified a hitherto unreported heterozygous ~1.5-Mb deletion at 16q24.2–q24.3. Whole-exome sequencing detected no pathogenic variants. Our results, in conjunction with previous reports of cases with similar deletions, indicate that the 16q24.2–q24.3 region provides a platform for submicroscopic deletions and possibly contains a gene(s) or regulatory elements involved in skeletal growth.
