Maternal Microchimerism is Uncommon in Patients with Hypospadias
Yuki Muranishi, Yuko Katoh-Fukui, Masafumi Kon, Nobuhiko Koga, Satoshi Tamaoka, Atsushi Hattori, Nobuo Shinohara, Takashige Abe, Maki Fukami
Sexual Development, 1, 10, S. Karger AG, 2025年10月27日
研究論文（学術雑誌）, Introduction: Although maternal microchimerism has been implicated in various disorders in children, its association with the risk of 46,XY disorders of sex development remains unknown. Methods: We studied 22 boys with hypospadias using highly sensitive quantitative PCR assays. In seven cases with additional anomalies, microarray-based comparative genomic hybridization and whole-exome sequencing confirmed the lack of apparent pathogenic variants. Results: Maternal microchimeric cells were detected in two patients (1.9 and 32.0 cells per 1,000,000 total cells). The results were comparable to our reference data. Conclusion: This study argues against the significant role of maternal microchimerism in the risk of hypospadias.

Systematic molecular analyses for 115 karyotypically normal men with isolated non-obstructive azoospermia.
Yuki Muranishi, Yoshitomo Kobori, Yuko Katoh-Fukui, Satoshi Tamaoka, Atsushi Hattori, Akiyoshi Osaka, Hiroshi Okada, Kazuhiko Nakabayashi, Kenichiro Hata, Tomoko Kawai, Hiroko Ogata-Kawata, Toshiyuki Iwahata, Kazuki Saito, Masafumi Kon, Nobuo Shinohara, Maki Fukami
Human reproduction (Oxford, England), 39, 5, 1131, 1140, 2024年05月02日, ［国際誌］
英語, 研究論文（学術雑誌）, STUDY QUESTION: Do copy-number variations (CNVs) in the azoospermia factor (AZF) regions and monogenic mutations play a major role in the development of isolated (non-syndromic) non-obstructive azoospermia (NOA) in Japanese men with a normal 46, XY karyotype? SUMMARY ANSWER: Deleterious CNVs in the AZF regions and damaging sequence variants in eight genes likely constitute at least 8% and approximately 8% of the genetic causes, respectively, while variants in other genes play only a minor role. WHAT IS KNOWN ALREADY: Sex chromosomal abnormalities, AZF-linked microdeletions, and monogenic mutations have been implicated in isolated NOA. More than 160 genes have been reported as causative/susceptibility/candidate genes for NOA. STUDY DESIGN, SIZE, DURATION: Systematic molecular analyses were conducted for 115 patients with isolated NOA and a normal 46, XY karyotype, who visited our hospital between 2017 and 2021. PARTICIPANTS/MATERIALS, SETTING, METHODS: We studied 115 unrelated Japanese patients. AZF-linked CNVs were examined using sequence-tagged PCR and multiplex ligation-dependent probe amplification, and nucleotide variants were screened using whole exome sequencing (WES). An optimized sequence kernel association test (SKAT-O), a gene-based association study using WES data, was performed to identify novel disease-associated genes in the genome. The results were compared to those of previous studies and our in-house control data. MAIN RESULTS AND THE ROLE OF CHANCE: Thirteen types of AZF-linked CNVs, including the hitherto unreported gr/gr triplication and partial AZFb deletion, were identified in 63 (54.8%) cases. When the gr/gr deletion, a common polymorphism in Japan, was excluded from data analyses, the total frequency of CNVs was 23/75 (30.7%). This frequency is higher than that of the reference data in Japan and China (11.1% and 14.7%, respectively). Known NOA-causative AZF-linked CNVs were found in nine (7.8%) cases. Rare damaging variants in known causative genes (DMRT1, PLK4, SYCP2, TEX11, and USP26) and hemizygous/multiple-heterozygous damaging variants in known spermatogenesis-associated genes (TAF7L, DNAH2, and DNAH17) were identified in nine cases (7.8% in total). Some patients carried rare damaging variants in multiple genes. SKAT-O detected no genes whose rare damaging variants were significantly accumulated in the patient group. LIMITATIONS, REASONS FOR CAUTION: The number of participants was relatively small, and the clinical information of each patient was fragmentary. Moreover, the pathogenicity of identified variants was assessed only by in silico analyses. WIDER IMPLICATIONS OF THE FINDINGS: This study showed that various AZF-linked CNVs are present in more than half of Japanese NOA patients. These results broadened the structural variations of AZF-linked CNVs, which should be considered for the molecular diagnosis of spermatogenic failure. Furthermore, the results of this study highlight the etiological heterogeneity and possible oligogenicity of isolated NOA. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by Grants from the Japan Society for the Promotion of Science (21K19283 and 21H0246), the Japan Agency for Medical Research and Development (22ek0109464h0003), the National Center for Child Health and Development, the Canon Foundation, the Japan Endocrine Society, and the Takeda Science Foundation. The results of this study were based on samples and patient data obtained from the International Center for Reproductive Medicine, Dokkyo Medical University Saitama Medical Center, Koshigaya, Japan. The authors have no conflicts of interest to disclose. TRIAL REGISTRATION NUMBER: N/A.

PTPN11 and FLNA variants in a boy with ambiguous genitalia, short stature, and non-specific dysmorphic features.
Yuki Muranishi, Tomoyo Itonaga, Kenji Ihara, Yuko Katoh-Fukui, Satoshi Tamaoka, Atsushi Hattori, Masafumi Kon, Nobuo Shinohara, Maki Fukami
Clinical pediatric endocrinology : case reports and clinical investigations : official journal of the Japanese Society for Pediatric Endocrinology, 33, 3, 169, 173, 2024年, ［国内誌］
英語, 研究論文（学術雑誌）, Noonan syndrome is a congenital disorder characterized by distinctive facial appearance, congenital heart defects, short stature, and skeletal dysplasia. Although boys with Noonan syndrome frequently exhibit cryptorchidism, a mild form of 46,XY disorders of sex development (DSD), they barely manifest more severe genital abnormalities. Here, we report a boy with ambiguous genitalia, short stature, and non-specific dysmorphic features. He had no cardiac abnormalities or skeletal dysplasia. His score in the Noonan syndrome diagnostic criteria (36 of 157 points, 23%) was lower than the cutoff for diagnosis (50%). Whole-exome sequencing identified a de novo heterozygous variant (c.922A>G: p.Asn308Asp) in PTPN11 and a maternally inherited hemizygous variant (c.1439C>T: p.Pro480Leu) in FLNA. The PTPN11 variant was a known causative mutation for Noonan syndrome. FLNA is a causative gene for neurodevelopmental and skeletal abnormalities and has also been implicated in 46,XY DSD. The p.Pro480Leu variant of FLNA was assessed as deleterious by in silico analyses. These results provide evidence that whole-exome sequencing is a powerful tool for diagnosing patients with atypical disease manifestations. Furthermore, our data suggest a possible role of digenic mutations as phenotypic modifiers of Noonan syndrome.

Compound heterozygous KCTD19 variants in a man with isolated nonobstructive azoospermia.
Yuki Muranishi, Yuko Katoh-Fukui, Atsushi Hattori, Yoshitomo Kobori, Akiyoshi Osaka, Hiroshi Okada, Toshiyuki Iwahata, Masafumi Kon, Nobuo Shinohara, Maki Fukami
Reproductive medicine and biology, 23, 1, e12608, 2024年, ［国内誌］
英語, 研究論文（学術雑誌）, CASE: A 40-year-old Japanese man with nonobstructive azoospermia (NOA) was found to carry rare variants in KCTD19, a newly identified causative gene for spermatogenic failure. This patient was identified through mutation screening of KCTD19 in 97 men with etiology-unknown isolated NOA. OUTCOME: The patient had two heterozygous variants in KCTD19 that affect consensus sequences of splice-donor sites [c.300+2T>A and c.2667C>T (p.E889E)]. Both variants were predicted to cause exon skipping. Long-read sequencing confirmed the compound heterozygosity of the variants. The patient exhibited small testes and a mildly elevated level of follicle-stimulating hormone but no other phenotypic abnormalities. Testicular histology showed borderline findings between spermatocyte maturation arrest and severe hypospermatogenesis. CONCLUSION: These results provide evidence that biallelic loss-of-function variants of KCTD19 represent rare causes of isolated NOA.

Rare sequence variants associated with the risk of non-syndromic biliary atresia.
Satoshi Tamaoka, Akinari Fukuda, Kazuhiko Nakabayashi, Keiko Matsubara, Hiroko Ogata-Kawata, Yuki Muranishi, Kenichiro Hata, Yuko Kato-Fukui, Seisuke Sakamoto, Mureo Kasahara, Maki Fukami
Hepatology research : the official journal of the Japan Society of Hepatology, 53, 11, 1134, 1141, 2023年11月, ［国際誌］
英語, 研究論文（学術雑誌）, AIM: The etiology of non-syndromic biliary atresia (BA) remains largely unknown. In this study, we performed genome-wide screening of genes associated with the risk of non-syndromic BA. METHODS: We analyzed exome data of 15 Japanese patients with non-syndromic BA and 509 control individuals using an optimal sequence kernel association test (SKAT-O), a gene-based association study optimized for small-number subjects. Furthermore, we examined the frequencies of known BA-related single-nucleotide polymorphisms in the BA and control groups. RESULTS: SKAT-O showed that rare damaging variants of MFHAS1, a ubiquitously expressed gene encoding a Toll-like receptor-associated protein, were more common in the BA group than in the control group (Bonferroni corrected p-value = 0.0097). Specifically, p.Val106Gly and p.Arg556Cys significantly accumulated in the patient group. These variants resided within functionally important domains. SKAT-O excluded the presence of other genes significantly associated with the disease risk. Of 60 known BA-associated single-nucleotide polymorphisms, only eight were identified in the BA group. In particular, p.Ile3421Met of MYO15A and p.Ala421Thr of THOC2 were more common in the BA group than in the control group. However, the significance of these two variants is questionable, because MYO15A has been linked to deafness, but not to BA, and the p.Ala421Thr of THOC2 represents a relatively common single-nucleotide polymorphism in Asia. CONCLUSIONS: The results of this study indicate that rare damaging variants in MFHAS1 may constitute a risk factor for non-syndromic BA, whereas the contribution of other monogenic variants to the disease predisposition is limited.

[Urinary Retention Caused by Necrotic Tissues in the Bladder of a Female Recipient of a Living-Donor Kidney Transplant : A Case Report].
Yuki Muranishi, Nobuyuki Fukuzawa, Yoshiki Wada, Takashige Abe, Nobuo Shinohara, Hiroshi Harada
Hinyokika kiyo. Acta urologica Japonica, 64, 10, 409, 413, 2018年10月, ［国内誌］
日本語, 研究論文（学術雑誌）, We report a patient who developed urinary retention due to the presence of necrotic tissues in the bladder 5 months after kidney transplantation. The patient was a 47-year-old female who had been diagnosed with immunoglobulin A nephropathy. She requested to receive a living-donor kidney transplant from her husband, and was referred to our hospital. Given that the patient had anuria preoperatively, her bladder capacity was presumed to have decreased following the transplantation. There were no events regarding vascular anastomosis during the surgery. However, since ureteroneocystostomy was difficult to perform due to the thinning of the bladder wall, the recipient's own ureter was anastomosed to the ureter of the transplanted kidney. Since the patient had difficulty voiding soon after the indwelling urinary catheter was removed, clean intermittent self-catheterization was initiated. Abdominal computed tomography revealed perforation of the bladder and extravesical urinary leakage on postoperative day 15. An indwelling urinary catheter was reinserted as conservative treatment. We removed the indwelling urinary catheter on postoperative day 25. The patient was discharged on postoperative day 30. Five months after transplantation, the patient suddenly developed urinary retention. Cystoscopy revealed some tissue hanging from the anterior wall of the bladder. The tissue was removed, and her voiding function improved. On pathology, the tissue was found to be non-specific necrotic tissue. This finding suggested that the necrotic tissue had caused urinary retention 5 months after transplantation. The symptoms of urinary retention markedly improved after the treatment.

北海道大学病院・関連施設における小児泌尿器救急疾患の現状(急性陰嚢症について)
今雅史, 村西雄貴, 樋口まどか, 千葉博基, 安部崇重, 日本小児外科学会雑誌, 61, 4, 2025年