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Papers - MIYA Fuyuki

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An organoid library of human esophageal squamous cell carcinomas (ESCCs) uncovers the chemotherapy-resistant ESCC features.

Nakagawa S, Sato T, Ohashi E, Kajita M, Miya F, Yamamoto K, Yotsumata H, Yamaguchi K, Nakajima Y, Miura A, Kinugasa Y, Ohteki T

Communications biology 8 ( 1 ) 507 2025.04

Esophageal squamous cell carcinoma (ESCC) is a deadly cancer with a poor prognosis and a high recurrence rate after chemotherapy, posing a significant clinical challenge. To elucidate the molecular basis of chemotherapy (chemo)-resistance and to develop methods to effectively eliminate chemo-resistant tumor clones, we established an ESCC organoid (ESCCO) library from 24 ESCC patients of various stages, ages, and treatments. These ESCCOs faithfully recapitulate the oncogenic mutations observed in the original ESCC tissues and manifest tumorigenic properties when xenografted. The ESCCOs respond differently to cisplatin and 5-fluorouracil, chemotherapeutic agents commonly used to treat ESCC patients, with 7 ESCCOs exhibiting potent chemo-resistance. Notably, the chemo-resistant ESCCOs show higher genes involved in antioxidant stress response pathways and more accessible chromatin at their loci than the sensitive ESCCOs. These genes can serve as valuable biomarkers to stratify chemo-resistant ESCCs in histopathological specimens. Through drug screening using the ESCCO library, we reveal that fedratinib effectively induces cell death in chemo-resistant ESCCOs. Collectively, our human ESCCO model offers novel insights into the mechanism of chemo-resistance in ESCCs, which is critical for developing effective therapeutic approaches to eradicate the recurrence of ESCCs.

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Effective calcineurin inhibitor treatment in adult-onset steroid-resistant nephrotic syndrome with a novel splice donor site variant of TRPC6: a case report.

Nagasaka T, Uchiyama K, Hama EY, Kojima D, Kaneko K, Yoshimoto N, Yasuda I, Yamada M, Miya F, Suzuki H, Tajima T, Yamaguchi S, Hayashi K, Kanda T, Hashiguchi A, Kosaki K, Itoh H

CEN case reports 14 ( 2 ) 208 - 216 2025.04

Transient receptor potential canonical 6 (TRPC6) variants, which were initially detected in adult-onset familial focal segmental glomerulosclerosis (FSGS), were also identified in pediatric-onset one. Here, we present a patient with adult-onset steroid-resistant nephrotic syndrome (SRNS) who harbored a likely pathogenic TRPC6 variant and partially responded to calcineurin inhibitors (CNIs). A 44-year-old woman with stable rheumatoid arthritis, systemic lupus erythematosus, and Sjögren’s syndrome was presented with nephrotic syndrome. Her renal biopsy results showed minor glomerular abnormalities. Upon admission, she was treated with steroids for around 4 weeks, but it was ineffective. After 1–2 weeks of cyclosporine A (CyA) administration, urine output increased, renal function improved without a decrease in proteinuria, and she was discharged. Her renal function was maintained for 2 months, but after a CyA dose reduction, she was again admitted to the hospital due to relapsing edema, decreased urine output, and worsening renal function. CyA was replaced by tacrolimus (TAC). A second renal biopsy showed nearly the same findings as the first except for tubulointerstitial lesions. After 1–2 weeks of TAC administration, urine output increased, and renal function improved. However, urinary protein levels did not decrease as before. After discharge, a whole exome analysis revealed a heterozygous splice donor site variant NM_004621.6;c.2644 + 1G > A in TRPC6. Genetic testing identified a novel splice donor site variant of TRPC6 in a patient with adult-onset SRNS, which prevented unnecessary steroid continuation. The safety and efficacy of CNI in TRPC6 glomerulopathy must be evaluated in future larger studies with longer follow-up.

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BED-Craft for nanopore adaptive sampling: a tool for generating bed files with gene names as input data for enrichment sequencing.

Miya F, Kosaki K

BMC research notes 18 ( 1 ) 79 2025.02

Objective: Adaptive sampling, a nanopore sequencing method that enriches regions of interest (ROI), is cost-effective and useful. However, the process of defining targeted regions and creating the corresponding definition file (.bed file) are time-consuming and laborious. To simplify this process, we have developed a tool to easily create a.bed file for adaptive sampling directly from gene names. Results: The tool is freely available on GitHub at https://github.com/medicalbioinfo/BED-Craft. The input is a text file containing one or more gene names (symbols), and even with a large number of input genes (e.g., thousands), the resulting.bed file is generated in less than a second. The length of the buffer region added upstream and downstream of the ROI is designed to account for genome strand orientation, ensuring efficient adaptive sampling. The buffer length can also be modified by the user. The tool supports the genomes of human hg19, hg38, T2T-CHM13, and other species. For researchers unfamiliar with command-line input, a GUI version of the tool is also available at https://keio-cmg.jp/BED-Craft/. This easy-to-use.bed file generation tool enables adaptive sampling by easily changing the target genes of interest in nanopore sequencing, and provide great benefits to researchers and diagnostic laboratories.

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Gene-based Hardy-Weinberg equilibrium test using genotype count data: application to six types of cancers.

Nishino J, Miya F, Kato M

BMC genomics 26 ( 1 ) 124 2025.02

Background: An alternative approach to investigate associations between genetic variants and disease is to examine deviations from the Hardy–Weinberg equilibrium (HWE) in genotype frequencies within a case population, instead of case–control association analysis. The HWE analysis requires disease cases and demonstrates a notable ability in mapping recessive variants. Allelic heterogeneity is a common phenomenon in diseases. While gene-based case–control association analysis successfully incorporates this heterogeneity, there are no such approaches for HWE analysis. Therefore, we proposed a gene-based HWE test (gene-HWT) by aggregating single-nucleotide polymorphism (SNP)-level HWE test statistics in a gene to address allelic heterogeneity. Results: This method used only genotype count data and publicly available linkage disequilibrium information and has a very low computational cost. Extensive simulations demonstrated that gene-HWT effectively controls the type I error at a low significance level and outperforms SNP-level HWE test in power when there are multiple causal variants within a gene. Using gene-HWT, we analyzed genotype count data from a genome-wide association study of six cancer types in Japanese individuals and suggest DGKE and ANO3 as potential germline factors in colorectal cancer. Furthermore, FSTL4 was suggested through a combined analysis across the six cancer types, with particularly notable associations observed in colorectal and prostate cancers. Conclusions: These findings indicate the potential of gene-HWT to elucidate the genetic basis of complex diseases, including cancer.

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Comparative analysis of tongue cancer organoids among patients identifies the heritable nature of minimal residual disease.

Sase M, Sato T, Sato H, Miya F, Zhang S, Haeno H, Kajita M, Noguchi T, Mori Y, Ohteki T

Developmental cell 60 ( 3 ) 396 - 413.e6 2025.02

ISSN 1534-5807

The relapse of tongue cancer (TC) after chemotherapy is caused by minimal residual disease (MRD), which is a few remaining cancer cells after chemotherapy. To understand the mechanism of MRD in TC, we created a library of TC organoids (TCOs) from 28 untreated TC patients at diverse ages and cancer stages. These TCOs reproduced the primary TC tissues both in vitro and in a xenograft model, and several TCO lines survived after cisplatin treatment (chemo-resistant TCOs). Of note, the chemo-resistant TCOs showed “heritable” embryonic diapause-like features before treatment and activation of the autophagy and cholesterol biosynthetic pathways. Importantly, inhibiting these pathways with specific inhibitors converted the chemo-resistant TCOs into chemo-sensitive TCOs. Conversely, autophagy activation with mTOR inhibitors conferred chemo-resistance on the chemo-sensitive TCOs. This unique model provides insights into the mechanism of MRD formation in TCs, leading to effective therapeutic approaches to reduce the recurrence of TC.

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Brain calcification in congenital heart defects and ectodermal dysplasia (CHDED).

Watanabe D, Hasebe Y, Yagasaki H, Nakato D, Yamada M, Suzuki H, Kono Y, Sunaga Y, Yoshizawa M, Narusawa H, Miya F, Takenouchi T, Inukai T, Kosaki K

European journal of medical genetics 73 104992 2025.02

ISSN 1769-7212

Congenital Heart Defect and Ectodermal Dysplasia (CHDED) is an autosomal dominant disorder caused by the PRKD1 gene. CHDED is characterized by heart defects and ectodermal dysplasia. To date, eight patients with CHDED have been described. Calcifications were present in three patients with CHDED. (two patients; renal calcifications, one patient; brain calcifications). The organ distribution of calcifications in CHDED has been unclear. We report here another patient with CHDED and brain calcifications. The patient was a 9-month-old Japanese girl. She presented with heart defects and ectodermal dysplasia. At 6 months of age, she had generalized seizures, and a CT scan revealed calcifications in the bilateral deep cerebral white matter. The seizures resolved with the administration of levetiracetam. The patient had a de novo, heterozygous pathogenic variant, c.1808G > A, p.(Arg603His), in the PRKD1 gene. Together with the previously reported patients mentioned above, we demonstrated the role of the PRKD1 variant in brain calcification. We propose that PRKD1 and two genes, ITGB2 and JAM2, which are known to be associated with brain calcification, act through a common signaling pathway abnormality. In support of our hypothesis, there are some experimental results that link PRKD1 and JAM2. PRKD1 functions with the integrin ITGB2 as a partner. JAM2, which is associated with brain calcification and is critical for maintaining of the tight junction of the endothelial cells, interacts with integrins including ITGB2. Therefore, PRKD1 could lead to the pathological phenotype of brain calcification.

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Vigabatrin投与が難治West症候群に有効であった先天性眼球異常を伴うCOL4A1関連疾患の1例

丸金拓蔵, 兵頭勇紀, 柴田敬, 秋山倫之, 高見容子, 宮冬樹, 加藤光広, 小林勝弘

脳と発達 ((一社)日本小児神経学会) 57 ( 1 ) 29 - 33 2025.01

ISSN 0029-0831

COL4A1変異は,IV型コラーゲンの異常により血管などの基底膜を障害し,多臓器に多彩な症状を呈する.てんかんを合併した場合は難治なことが多い.症例は5歳4ヵ月の男児.先天性の眼病変を認め,Peters異常と診断された.発達遅滞を伴い,頭部画像所見に異常を認めた.10ヵ月時にてんかん性スパズムを発症し,West症候群と診断された.ACTH療法を含む初期治療で発作は一時消失したが再発した.1歳9ヵ月時にvigabatrin(VGB)を眼病変の悪化を考慮し慎重に導入し,VGBは適量(100mg/kg/day)で発作は抑制された.眼科的検査を複数回実施し,網膜電図に異常は認めなかった.3歳6ヵ月にVGBを中止後も発作は抑制されている.COL4A1にde novoの既知の病的変異NM_001845.6:c.3620G>A,p.(G1207E)を認めた.COL4A1関連疾患の難治West症候群に対しては先天性眼球異常を伴う例でもVGBを試みる意義があると考えられた.(著者抄録)

Genetic landscape in undiagnosed patients with syndromic hearing loss revealed by whole exome sequencing and phenotype similarity search.

Mutai H, Miya F, Nara K, Yamamoto N, Inoue S, Murakami H, Namba K, Shitara H, Minami S, Nakano A, Arimoto Y, Morimoto N, Kawasaki T, Wasano K, Fujioka M, Uchida Y, Kaga K, Yamazawa K, Kikkawa Y, Kosaki K, Tsunoda T, Matsunaga T

Human genetics 144 ( 1 ) 93 - 112 2025.01

ISSN 0340-6717

There are hundreds of rare syndromic diseases involving hearing loss, many of which are not targeted for clinical genetic testing. We systematically explored the genetic causes of undiagnosed syndromic hearing loss using a combination of whole exome sequencing (WES) and a phenotype similarity search system called PubCaseFinder. Fifty-five families with syndromic hearing loss of unknown cause were analyzed using WES after prescreening of several deafness genes depending on patient clinical features. Causative genes were identified in 22 families, including both established genes associated with syndromic hearing loss (PTPN11, CHD7, KARS1, OPA1, DLX5, MITF, SOX10, MYO7A, and USH2A) and those associated with nonsyndromic hearing loss (STRC, EYA4, and KCNQ4). Association of a DLX5 variant with incomplete partition type I (IP-I) anomaly of the inner ear was identified in a patient with cleft lip and palate and acetabular dysplasia. The study identified COL1A1, CFAP52, and NSD1 as causative genes through phenotype similarity search or by analogy. ZBTB10 was proposed as a novel candidate gene for syndromic hearing loss with IP-I. A mouse model with homozygous Zbtb10 frameshift variant resulted in embryonic lethality, suggesting the importance of this gene for early embryonic development. Our data highlight a wide spectrum of rare causative genes in patients with syndromic hearing loss, and demonstrate that WES analysis combined with phenotype similarity search is a valuable approach for clinical genetic testing of undiagnosed disease.

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Accumulation of ether phospholipids in induced pluripotent stem cells and oligodendrocyte-lineage cells established from patients with Sjögren-Larsson syndrome.

Yamaguchi Y, Okuno H, Tokuoka S, Kita Y, Sanosaka T, Kohyama J, Kurosawa K, Sakai N, Miya F, Takahashi T, Kosaki K, Okano H

Congenital anomalies 65 ( 1 ) e12587 2025.01

ISSN 0914-3505

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Effective treatment with vigabatrin for intractable West syndrome in a case of COL4A1-related disorder with congenital ocular anomalies

Marukane T., Hyodo Y., Shibata T., Akiyama T., Takami Y., Miya F., Kato M., Kobayashi K.

No To Hattatsu 57 ( 1 ) 29 - 33 2025

ISSN 00290831

Aberrations in the COL4A1 gene lead to the faulty secretion of type IV collagen, resulting in damage to vascular basement membrane and various symptoms affecting multiple organs. Epilepsy associated with COL4A1-related disorder is often challenging to treat. We report a 5-year-old boy with developmental delay, congenital ocular abnormalities diagnosed with Peters anomaly, and abnormal neuroimaging findings. The patient had epileptic spasms starting at the age of 10 months and was diagnosed with West syndrome. Initial treatment, including adrenocorticotropic hormone(ACTH), was only transiently effective. At 1 year 9 months of age, vigabatrin(VGB)administration was introduced cautiously considering its potential adverse effects that might worsen ocular lesions. His seizures were suppressed with a modest dose(100 mg/kg/day)of VGB with no signs of electroretinogram abnormalities on repeated ophthalmological examinations. VGB was discontinued successfully at 3 years 6 months of age with no recurrence of seizures. A de novo pathogenic variant NM_001845.6:c.3620G> A(p.G1207E)was found in COL4A1. These findings suggest that VGB may be used effectively and safely in treating refractory West syndrome, even in patients with congenital ocular abnormalities associated with COL4A1-related disorder.

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Clonal Hematopoiesis in Chronic Thromboembolic Pulmonary Hypertension.

Momoi M, Katsumata Y, Kunimoto H, Inami T, Miya F, Anzai A, Goto S, Miura A, Shinya Y, Hiraide T, Shirakawa K, Endo J, Fukuda K, Ieda M, Kosaki K, Nakajima H, Kataoka M

Journal of the American Heart Association 13 ( 23 ) e035498 2024.12

BACKGROUND: The cause of chronic thromboembolic pulmonary hypertension (CTEPH) remains largely unknown. Recently, clonal hematopoiesis (CH) has been reported to be associated with cardiovascular and thromboembolic diseases. Here, we investigated the prevalence and clinical impact of CH in patients with CTEPH. METHODS AND RESULTS: Whole-exome sequencing and deep-panel sequencing were performed in 214 patients with CTEPH. Clinical data before and after treatment were compared between patients with and without CH. RNA sequencing and serum analysis were performed to explore the pathogenesis that CH contributes to CTEPH. Among the enrolled patients, 20.1%, notably 44.4% who were 80 to 89 years old, had variants in CH-associated genes. In regard to clinical impact, B-type natriuretic peptide levels and home oxygen therapy rate were significantly higher, and 6-minute walk distance was significantly shorter after treatment in patients with CH than in those without CH. Moreover, novel clot reformation in the pulmonary artery despite the use of anticoagulants and additional angioplasty events after treatment completion were more frequent in patients with CH. RNA sequencing analysis revealed that blood coagulation and neutrophil extracellular trap formation pathways were enriched in patients with CH. Additionally, serum citrullinated histone H3 levels were higher in patients with CH than those without CH. These results were consistent in the subgroup of patients who did not have the history of hematological disorders. CONCLUSIONS: The findings in this study raise the possibility that CH will induce a more prothrombotic state through neutrophil activation and neutrophil extracellular trap formation, contributing to pathogenesis and poor treatment response in patients with CTEPH.

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De novo variants in UPF1 associated with intellectual disabilities: Human genetic and functional evidences using Drosophila model.

Nakato D, Yasue Y, Matsubara K, Suzuki H, Kosaki R, Takenouchi T, Yamada M, Miya F, Takano-Shimizu T, Kosaki K

European journal of medical genetics 72 104983 2024.12

ISSN 1769-7212

Nonsense-mediated mRNA decay represents a biologic clearing system against aberrant mRNAs harboring nonsense and frameshift mutations and depends on three factors, UPF1, UPF2, and UPF3 (UPF3A, UPF3B). While germline pathogenic variants of UPF3B and UPF2 are known to be associated with neurodevelopmental disorders, germline variants in UPF1 have not been reported, until date, as being associated with any human disorders. Herein, we report two unrelated patients with de novo UPF1 variants. Patient 1 was a 5-year-old girl with intellectual disabilities, frontal bossing, hypertelorism, high frontal hairline, and thin upper lip. Patient 2 was a 2-year-old female child with intellectual disabilities and similar features. Trio exome analysis revealed a de novo heterozygous variant in UPF1 in both the patients (Patient 1: NM_002911.4): c.949_951del, p.(Asp317del); Patient 2: c.1984G>A, p.(Asp662Asn)). We conducted experiments using Drosophila models to evaluate the functional relevance of these UPF1 variants. Enforced expression of the wild-type Upf1 allele under the control of the pan-neuronal nSyb-GAL4 driver caused mortality, mostly at the pupal stage, but still yielded adult flies. By contrast, expression of the Asp294del (Asp317del in humans) variant caused embryonic or early larval lethality and that of the Asp643Asn (Asp662Asn in humans) caused third instar larval lethality; neither produced pupa nor adult fly. Thus, the developmental defects caused by the variants, especially Asp294del, were more severe than those caused by the wild-type allele. These observations suggest that both variants are deleterious mutations. In conclusion, germline variants in UPF1 are associated with intellectual disabilities in humans.

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Biallelic null variants in PNPLA8 cause microcephaly by reducing the number of basal radial glia.

Nakamura Y, Shimada IS, Maroofian R, Falabella M, Zaki MS, Fujimoto M, Sato E, Takase H, Aoki S, Miyauchi A, Koshimizu E, Miyatake S, Arioka Y, Honda M, Higashi T, Miya F, Okubo Y, Ogawa I, Scardamaglia A, Miryounesi M, Alijanpour S, Ahmadabadi F, Herkenrath P, Dafsari HS, Velmans C, Al Balwi M, Vitobello A, Denommé-Pichon AS, Jeanne M, Civit A, Abdel-Hamid MS, Naderi H, Darvish H, Bakhtiari S, Kruer MC, Carroll CJ, Ghayoor Karimiani E, Khailany RA, Abdulqadir TA, Ozaslan M, Bauer P, Zifarelli G, Seifi T, Zamani M, Al Alam C, Alvi JR, Sultan T, Efthymiou S, Pope SAS, Haginoya K, Matsunaga T, Osaka H, Matsumoto N, Ozaki N, Ohkawa Y, Oki S, Tsunoda T, Pitceathly RDS, Taketomi Y, Houlden H, Murakami M, Kato Y, Saitoh S

Brain : a journal of neurology 147 ( 11 ) 3949 - 3967 2024.11

ISSN 0006-8950

Patatin-like phospholipase domain-containing lipase 8 (PNPLA8), one of the calcium-independent phospholipase A2 enzymes, is involved in various physiological processes through the maintenance of membrane phospholipids. Biallelic variants in PNPLA8 have been associated with a range of paediatric neurodegenerative disorders. However, the phenotypic spectrum, genotype–phenotype correlations and the underlying mechanisms are poorly understood. Here, we newly identified 14 individuals from 12 unrelated families with biallelic ultra-rare variants in PNPLA8 presenting with a wide phenotypic spectrum of clinical features. Analysis of the clinical features of current and previously reported individuals (25 affected individuals across 20 families) showed that PNPLA8-related neurological diseases manifest as a continuum ranging from variable developmental and/or degenerative epileptic–dyskinetic encephalopathy to childhood-onset neurodegeneration. We found that complete loss of PNPLA8 was associated with the more profound end of the spectrum, with congenital microcephaly. Using cerebral organoids generated from human induced pluripotent stem cells, we found that loss of PNPLA8 led to developmental defects by reducing the number of basal radial glial cells and upper-layer neurons. Spatial transcriptomics revealed that loss of PNPLA8 altered the fate specification of apical radial glial cells, as reflected by the enrichment of gene sets related to the cell cycle, basal radial glial cells and neural differentiation. Neural progenitor cells lacking PNPLA8 showed a reduced amount of lysophosphatidic acid, lysophosphatidylethanolamine and phosphatidic acid. The reduced number of basal radial glial cells in patient-derived cerebral organoids was rescued, in part, by the addition of lysophosphatidic acid. Our data suggest that PNPLA8 is crucial to meet phospholipid synthetic needs and to produce abundant basal radial glial cells in human brain development.

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Novel germline STAT3 gain-of-function mutation causes autoimmune diseases and severe growth failure.

Saito K, Fujimoto M, Funajima E, Serada S, Ohkawara T, Ishihara M, Yamada M, Suzuki H, Miya F, Kosaki K, Fujieda M, Naka T

The journal of allergy and clinical immunology. Global 3 ( 4 ) 100312 2024.11

Background: In recent years, germline gain-of-function (GOF) mutations in signal transducer and activator of transcription 3 (STAT3) have been identified as a cause of early-onset multiorgan autoimmune diseases with the widespread use of next-generation sequencing, and targeted therapies such as tocilizumab have been reported to be effective. Objective: We sought to assess whether a novel STAT3 mutation detected by whole-exome sequencing is pathogenic and examine the efficacy of targeted therapy. Methods: A pediatric patient with idiopathic pulmonary hemosiderosis, autoimmune thyroiditis, inflammatory bowel disease unclassified, leukocytosis, thrombocytosis, and severe growth failure was examined. Results: This 7-year-old boy had idiopathic pulmonary hemosiderosis at the age of 6 months. Despite high-dose steroid therapy, pulmonary fibrosis progressed. Furthermore, he presented with severe growth failure, autoimmune thyroiditis, leukocytosis, thrombocytosis, and inflammation bowel disease unclassified. Given the presence of multiple autoimmune diseases, whole-exome sequencing was performed, which detected germline de novo heterozygous STAT3 mutation (NM_139276.2; c.2144C>A, p.(P715Q)). Dual-luciferase reporter assay revealed this novel STAT3 mutation as GOF. After starting tocilizumab therapy at the age of 6, hospital stays decreased, and the progression of pulmonary fibrosis was decelerated without increasing the steroid dose. New autoimmune diseases did not develop, and no apparent adverse effects on growth have been observed. Conclusions: Tocilizumab may be effective for patients with STAT3 GOF mutation, including those requiring long-term management of idiopathic pulmonary hemosiderosis. Diagnosis of patients with early-onset multiorgan autoimmune diseases in which STAT3 GOF is suspected should be confirmed by genetic testing and functional analysis to consider the introduction of targeted therapies.

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Japanese Public Health Insurance System's new genomic strategic action to shorten the "diagnostic odyssey" for patients with rare and intractable diseases.

Ezaki J, Takahashi Y, Saijo H, Miya F, Kosaki K

Journal of human genetics 69 ( 11 ) 549 - 552 2024.11

ISSN 1434-5161

In June 2024, the Japanese government introduced a new genomic strategic action to shorten the “diagnostic odyssey” for patients with rare and intractable diseases: Six groups of rare diseases, (i) Muscle weakness group, (ii) Growth retardation, intellectual disability, and characteristic facial features group, (iii) Intellectual disability/epilepsy group, (iv) Cardiomyopathy group (mainly adult onset) (v) Proteinuria group, (vi) Fever, inflammation, skin rash, osteoarthritis group, have been newly recognized as “difficult-to-differentiate disorders” and comprehensive genomic testing can be reimbursed when patients belong to one of the six groups and certain requirements are met. The introduction of comprehensive genomic testing will improve the diagnosis rate of diseases and have significant potential to enhance Japan’s rare and intractable disease policy. The new strategy in Japan and its rationale will be a reference for insurance reimbursement of comprehensive genomic testing in other countries that have universal health coverage supported by the public health insurance system.

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Café-au-lait Spots and Cleft Palate: Not a Chance Association.

Yamada M, Tanito K, Suzuki H, Nakato D, Miya F, Takenouchi T, Kosaki K

The Cleft palate-craniofacial journal : official publication of the American Cleft Palate-Craniofacial Association 61 ( 11 ) 1932 - 1936 2024.11

ISSN 1055-6656

The recognition of syndromic forms of cleft palate is important for condition-specific management. Here, we report a patient with cleft palate, congenital heart disease, intellectual disability, and café-au-lait spots who had a deletion of chromosome 15q14. The identification of the precise breakpoints using a Nanopore-based long-read sequencer showed that the deletion spanned MEIS2 and SPRED1 loci. Cleft palate and café-au-lait spots can be ascribed to MEIS2 and SPRED1, respectively. Patients with cleft palate and café-au-lait spots should be encouraged to undergo a detailed genomic evaluation, including screening for a 15q14 deletion, to enable appropriate anticipatory medico-surgical management and genetic counseling.

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Functional and dynamic profiling of transcript isoforms reveals essential roles of alternative splicing in interferon response.

Ueda MT, Inamo J, Miya F, Shimada M, Yamaguchi K, Kochi Y

Cell genomics 4 ( 10 ) 100654 2024.10

Type I interferon (IFN-I) plays an important role in the innate immune response through inducing IFN-I-stimulated genes (ISGs). However, how alternative splicing (AS) events, especially over time, affect their function remains poorly understood. We generated an annotation (113,843 transcripts) for IFN-I-stimulated human B cells called isoISG using high-accuracy long-read sequencing data from PacBio Sequel II/IIe. Transcript isoform profiling using isoISG revealed that isoform switching occurred in the early response to IFN-I so that ISGs would gain functional domains (e.g., C4B) or higher protein production (e.g., IRF3). Conversely, isoforms lacking functional domains increased during the late phase of IFN-I response, mainly due to intron retention events. This suggests that isoform switching both triggers and terminates IFN-I responses at the translation and protein levels. Furthermore, genetic variants influencing the isoform ratio of ISGs were associated with immunological and infectious diseases. AS has essential roles in regulating innate immune response and associated diseases.

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Digital clubbing without hypoxia for lysinuric protein intolerance.

Watanabe D, Tsujioka Y, Nakato D, Yamada M, Suzuki H, Ohnishi T, Tamai N, Kijima T, Takenouchi T, Miya F, Narumi S, Kosaki K

European journal of medical genetics 71 104967 2024.10

ISSN 1769-7212

Digital clubbing is characterized by bulbous enlargement of the terminal segments of the fingers. Hypotheses including hypoxia have been proposed for the pathogenesis of digital clubbing, but the exact pathogenesis of digital clubbing is still uncertain. Lysinuric protein intolerance (LPI) is caused by pathogenic variants in SLC7A7 and is often associated with interstitial lung disease. Previously two patients of LPI with digital clubbing but without hypoxia have been reported. It is unclear whether digital clubbing in LPI is secondary to hypoxia or directly related to SLC7A7 deficiency. Here we report a 6-year-old Japanese boy presented with digital clubbing without hypoxia. He had episodic vomiting, each episode consisting of a single vomiting event occurring once a month, and his growth had been delayed. He had interstitial lung disease and hepatomegaly. He had compound heterozygous pathogenic variants in the SLC7A7, leading to the diagnosis of LPI. Together with the two previously reported patients mentioned above, we conclude that digital clubbing can occur in the absence of hypoxia. Digital clubbing in the absence of hypoxia has been observed in two genetic disorders related to prostaglandin (PG) E2, HPGD and SLCO2A1. PGE2 synthesis is primarily regulated by the cyclooxygenase 2, which plays a critical role in the control of inflammation. A high urine PGE level in the patient was compatible with the notion that PGE2 production may be increased in LPI. The occurrence of digital clubbing in the absence of hypoxia in LPI patients with SLC7A7 may be attributed to the mechanism of increased PGE2 production.

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Biallelic structural variants in three patients with ERCC8-related Cockayne syndrome and a potential pitfall of copy number variation analysis.

Watanabe D, Okamoto N, Kobayashi Y, Suzuki H, Kato M, Saitoh S, Kanemura Y, Takenouchi T, Yamada M, Nakato D, Sato M, Tsunoda T, Kosaki K, Miya F

Scientific reports 14 ( 1 ) 19741 2024.08

Cockayne syndrome (CS) is a rare autosomal recessive disorder caused by mutations in ERCC8 or ERCC6. Most pathogenic variants in ERCC8 are single nucleotide substitutions. Structural variants (SVs) have been reported in patients with ERCC8-related CS. However, comprehensive molecular detection, including SVs of ERCC8, in CS patients remains problematic. Herein, we present three Japanese patients with ERCC8-related CS in whom causative SVs were identified using whole-exome-based copy number variation (CNV) detection tools. One patient showed compound heterozygosity for a 259-kb deletion and a deletion of exon 4 which has previously been reported as an Asia-specific variant. The other two patients were homozygous for the same exon 4 deletion. The exon 4 deletion was detected only by the ExomeDepth software. Intrigued by the discrepancy in the detection capability of various tools for the SVs, we evaluated the analytic performance of four whole-exome-based CNV detection tools using an exome data set from 337 healthy individuals. A total of 1,278,141 exons were predicted as being affected by the 4 CNV tools. Interestingly 95.1% of these affected exons were detected by one tool alone. Thus, we expect that the use of multiple tools may improve the detection rate of SVs from aligned exome data.

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GATA2 deficiency of a novel missense variant with multiorgan inflammation.

Baba H, Kimura N, Kanegane H, Miya F, Kosaki K, Morio T, Koike R

Rheumatology (Oxford, England) 63 ( 8 ) e226 - e228 2024.08

ISSN 1462-0324

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