Journal of Human Genetics最新文献

{"title":"Returning genetic risk information for hereditary cancers to participants in a population-based cohort study in Japan","authors":"Kinuko Ohneda, Yoichi Suzuki, Yohei Hamanaka, Shu Tadaka, Muneaki Shimada, Junko Hasegawa-Minato, Masanobu Takahashi, Nobuo Fuse, Fuji Nagami, Hiroshi Kawame, Tomoko Kobayashi, Yumi Yamaguchi-Kabata, Kengo Kinoshita, Tomohiro Nakamura, Soichi Ogishima, Kazuki Kumada, Hisaaki Kudo, Shin-ichi Kuriyama, Yoko Izumi, Ritsuko Shimizu, Mikako Tochigi, Tokiwa Motonari, Hideki Tokunaga, Atsuo Kikuchi, Atsushi Masamune, Yoko Aoki, Chikashi Ishioka, Takanori Ishida, Masayuki Yamamoto","doi":"10.1038/s10038-024-01314-w","DOIUrl":"10.1038/s10038-024-01314-w","url":null,"abstract":"Large-scale population cohort studies that collect genomic information are tasked with returning an assessment of genetic risk for hereditary cancers to participants. While several studies have applied to return identified genetic risks to participants, comprehensive surveys of participants’ understanding, feelings, and behaviors toward cancer risk remain to be conducted. Here, we report our experience and surveys of returning genetic risks to 100 carriers of pathogenic variants for hereditary cancers identified through whole genome sequencing of 50 000 individuals from the Tohoku Medical Megabank project, a population cohort study. The participants were carriers of pathogenic variants associated with either hereditary breast and ovarian cancer (n = 79, median age=41) or Lynch syndrome (n = 21, median age=62). Of these, 28% and 38% had a history of cancer, respectively. We provided information on cancer risk, heritability, and clinical actionability to the participants in person. The comprehension assessment revealed that the information was better understood by younger (under 60 years) females than by older males. Scores on the cancer worry scale were positively related to cancer experiences and general psychological distress. Seventy-one participants were followed up at Tohoku University Hospital; six females underwent risk-reducing surgery triggered by study participation and three were newly diagnosed with cancer during surveillance. Among first-degree relatives of hereditary breast and ovarian cancer carriers, participants most commonly shared the information with daughters. This study showed the benefits of returning genetic risks to the general population and will provide insights into returning genetic risks to asymptomatic pathogenic variant carriers in both clinical and research settings.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"70 3","pages":"147-157"},"PeriodicalIF":2.6,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11802448/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143006558","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Triple mosaic variants of PURA in a patient with multiple congenital anomalies","authors":"Atsushi Fujita, Yuta Suenaga, Eri Takeshita, Yuji Takahashi, Yuichi Suzuki, Sachiko Ohori, Naomi Tsuchida, Yuri Uchiyama, Eriko Koshimizu, Satoko Miyatake, Takeshi Mizuguchi, Naomichi Matsumoto","doi":"10.1038/s10038-024-01315-9","DOIUrl":"10.1038/s10038-024-01315-9","url":null,"abstract":"In monogenic diseases, double mosaic variants of the same gene have rarely been identified. Here, we report the case of triple mosaic variants in PURA, a gene responsible for a neurodevelopmental syndrome (OMIM# 616158). Whole-exome sequencing identified three somatic PURA variants in our case with a similar neurodevelopmental syndrome: NM_005859.5: c.222C>A p.(Tyr74*), c.224T>A p.(Leu75Gln), and c.233A>G p.(Lys78Arg). The two missense variants were on the same sequence read, but the nonsense variant was not. To determine the origin of the alleles, we performed long-read sequencing because of the absence of informative SNPs near the somatic variants. Long-read sequencing revealed that these three somatic variants are derived from the same chromosome. The exact mechanism behind their occurrence is unclear, but the nonsense variant could have occurred de novo as a germline event and incomplete post-zygotic rescue for the germline variant could have led to the two missense variants.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"70 4","pages":"227-230"},"PeriodicalIF":2.6,"publicationDate":"2025-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142983622","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A novel mutation in the WNK1/HSN2 gene causing hereditary sensory and autonomic neuropathy type 2 in Chinese patient","authors":"Siqing Ma, Chunbo Ji, Jinlan Li, Jie Zhou, Jianying Zhu, Ping Yang","doi":"10.1038/s10038-024-01310-0","DOIUrl":"10.1038/s10038-024-01310-0","url":null,"abstract":"Hereditary sensory and autonomic neuropathy type 2 (HSAN2) is a group of extremely rare autosomal recessive neurological disorders characterized by predominant sensory dysfunction and attendant severe complications, such as limb destruction. Our study reports a Chinese patient who met the diagnostic criteria for HSAN2 and harbored a homozygous mutation in the WNK1 gene (NM_213655.4: c.2689 G > T; p. Glu897*), Which led to nonsense-mediated mRNA decay of the transcript. Sanger sequencing revealed that the mutation segregates with disease status in the pedigree. These results expanded the spectrum of mutations in the WNK1 gene by identifying a novel mutation in a Chinese patient, providing a valuable reference for clinical diagnosis and treatment.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"70 4","pages":"223-226"},"PeriodicalIF":2.6,"publicationDate":"2024-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142877377","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ultra-rare monogenic disorders frequently detected among sex chromosome aneuploidy patients with atypical findings","authors":"Kiana Magee, William McGonigle, Rena Pressman, Willa Thorson, Deborah Barbouth, Nicholas A. Borja","doi":"10.1038/s10038-024-01312-y","DOIUrl":"10.1038/s10038-024-01312-y","url":null,"abstract":"Sex chromosome aneuploidies (SCA) such as Turner, Klinefelter, Jacobs, and Trisomy X syndromes are prevalent genetic disorders with well-established phenotypes. Challenges persist, however, in determining the need for further genetic evaluation in cases of affected individuals exhibiting atypical symptoms. The present study retrospectively examined 54 pediatric patients with an SCA diagnosis at a single institution between January 2015 and December 2023. Twelve patients (22.2%) exhibited a discordant phenotype, of which five were confirmed to have a distinct monogenic disorder, a diagnostic rate of 41.7%. The monogenic conditions identified included DNAH5-related primary ciliary dyskinesia, Burn-McKeown syndrome, Tatton-Brown-Rahman syndrome, SETD1B-related neurodevelopmental disorder, and SET-related disorder. The median age at SCA diagnosis was 3.5 months versus 7.0 years for the second genetic condition, indicating significant diagnostic delays. Our findings highlight the importance of comprehensive genetic evaluation in pediatric patients with SCA who exhibit atypical phenotypes.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"70 3","pages":"177-179"},"PeriodicalIF":2.6,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11802447/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142854381","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genetic inhibition of nicotinamide N-methyltransferase and prevention of alcohol-associated fatty liver in humans","authors":"Benrui Wu, Xiong Weng, Ying Pan, Zijian Tian, Peng Wu, Jian Shao, Yiying Liu, Rong Huang, Tao Xu, Kaixin Zhou","doi":"10.1038/s10038-024-01313-x","DOIUrl":"10.1038/s10038-024-01313-x","url":null,"abstract":"Recent studies of animal models reported Nicotinamide N-methyltransferase (NNMT) as a potential therapeutic target for preventing alcohol-associated fatty liver (AFL), yet its efficacy and safety in humans remain unknown. We aim to estimate the effectiveness and safety of inhibiting NNMT in humans. We leveraged Electronic Medical Records (EMRs) data coupled with genetic information to perform a retrospective drug target validation study. We examined longitudinal clinical data from 612 individuals with excessive alcohol consumption. Two variants lowering NNMT protein levels were combined to calculate a weighted NNMT genetic score that could mimic mild inhibition of NNMT. Participants with an NNMT score above the median were classified as genetically inhibited, while others were considered non-inhibited. We then evaluated whether genetic inhibition of NNMT would affect the incidence of AFL or the risk of liver injury, to illuminate the effectiveness and safety of genetic inhibition of NNMT respectively. NNMT genetic inhibition correlated with a reduced AFL risk (hazard ratio [HR] 0.67, 95% confidence interval [CI] 0.49–0.90, P = 0.009) without a significant increase in serum aminotransferase levels (P > 0.10). Notably, elevated ALT and AST levels were observed (P < 0.05) in the genetically inhibited group prior to alcohol exposure. These findings suggest NNMT inhibition is a promising avenue for AFL prevention among individuals with excessive alcohol intake. They also underscore the need for precise target population identification to mitigate potential adverse effects.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"70 3","pages":"141-146"},"PeriodicalIF":2.6,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142854376","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cancer and disease profiles for PTEN pathogenic variants in Japanese population","authors":"Yuki Kanazashi, Yoshiaki Usui, Yusuke Iwasaki, Shota Sasagawa, Mikiko Endo, Mitsuyo Yamaguchi, Todd A. Johnson, Kazuhiro Maejima, Kouya Shiraishi, Takashi Kohno, Teruhiko Yoshida, Kokichi Sugano, Yoshinori Murakami, Yoichiro Kamatani, Naomichi Matsumoto, Koichi Matsuda, Yukihide Momozawa, Hidewaki Nakagawa","doi":"10.1038/s10038-024-01311-z","DOIUrl":"10.1038/s10038-024-01311-z","url":null,"abstract":"A germline alteration in the PTEN gene causes a spectrum of disorders conceptualized as PTEN hamartoma tumor syndrome (PHTS), which show high risk of tumor development and a highly variable and complex phenotype. The diagnosis of PHTS is established in a proband by identification of a heterozygous germline PTEN pathogenic variant on molecular genetic testing. In this study, to understand more PTEN-associated clinical phenotype and PHTS in a Japanese population, we extracted 128 germline PTEN rare variants from 113,535 adult Japanese registered in Biobank Japan (BBJ), and categorized 29 pathogenic/likely pathogenic variants in 30 individuals (0.0264%) with ClinVar classifications and ACMG/AMP guideline for PTEN. We examined case-control association in 75,238 patients with various types of cancer and 38,297 non-cancer controls, and identified that PTEN pathogenic variants (PVs) were significantly associated with endometrial cancer (OR = 35.7, P = 9.73E-04) and marginally associated with female breast cancer (OR = 19.5, P = 3.92E-03), especially at young onset and with multiple cancers. We observed that among the 127 disease phenotypes the PTEN PV carriers had uterine fibroid, goiter, ovarian cyst, and epilepsy, which is consistent with PTEN-related phenotypes. We also found that weight/height were significantly higher in adult female carriers with PTEN PV (P = 3.1E-04 and P = 0.0014, respectively), which is consistent with overgrowth syndrome of PHTS. Our results indicate the phenotypical features associated with PTEN PVs in a Japanese population, especially female, and can contribute to the screening for PTEN variants and its associated several phenotypes.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"70 3","pages":"135-140"},"PeriodicalIF":2.6,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142813339","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Intron retention caused by a canonical splicing variant in SSR4-related congenital disorder of glycosylation","authors":"Quanquan Wang, Guangyu Wang, Bing Liang, Chen Zhang, Chuanzhu Yan, Pengfei Lin, Ling Li","doi":"10.1038/s10038-024-01309-7","DOIUrl":"10.1038/s10038-024-01309-7","url":null,"abstract":"Congenital disorder of glycosylation type Iy (CDG-Iy) is an X-linked monogenic inherited disease caused by variants in the SSR4 gene. To date, a total of 11 variants have been identified in 14 CDG-Iy patients. Our study identified a novel canonical splicing variant, c.67+2T>C, in the SSR4 gene (according to the transcript NM_006280.3) in a Chinese CDG-Iy family. Functional analysis revealed that the c.67+2T>C variant induced the retention of the first 46 bp of intron 1 via the recognition of the downstream GC dinucleotide as a non-canonical cryptic donor splice site. This aberrant mRNA splicing resulted in the occurrence of a premature termination codon, triggered nonsense-mediated mRNA decay, and decreased the SSR4 gene expression. Our study is the first to identify aberrant mRNA processing in SSR4-related CDG-Iy and further emphasizes the activation of the non-canonical GC donor splice site in aberrant mRNA processing caused by splicing variants.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"70 3","pages":"171-176"},"PeriodicalIF":2.6,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142801121","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"From benign to pathogenic variants and vice versa: pyrimidine transitions at position -3 of TAG and CAG 3'' splice sites","authors":"Igor Vořechovský","doi":"10.1038/s10038-024-01308-8","DOIUrl":"10.1038/s10038-024-01308-8","url":null,"abstract":"In the human genome, CAG 3'' splice sites (3''ss) are more than twice as frequent as TAG 3''ss. The greater abundance of the former has been attributed to a higher probability of exon skipping upon cytosine-to-thymine transitions at intron position -3 (-3C > T) than thymine-to-cytosine variants (-3T > C). However, molecular mechanisms underlying this bias and its clinical impact are poorly understood. In this study, base-pairing probabilities (BPPs) and RNA secondary structures were compared between CAG 3''ss that produced more skipping of downstream exons than their mutated UAG versions (termed “laggard” CAG 3''ss) and UAG 3''ss that resulted in more skipping than their mutated CAG counterparts (canonical 3''ss). The laggard CAG 3’ss showed significantly higher BPPs across intron-exon boundaries than canonical 3''ss. The difference was centered on positions -5 to -1 relative to the intron-exon junction, the region previously shown to exhibit the strongest high-resolution ultraviolet crosslinking to the small subunit of auxiliary factor of U2 snRNP (U2AF1). RNA secondary structure predictions suggested that laggard CAG 3''ss were more often sequestered in paired conformations and in longer stem structures while canonical 3''ss were more frequently unpaired. Taken together, the excess of base-pairing at 3''ss has a potential to alter the hierarchy in intrinsic splicing efficiency of human YAG 3''ss from canonical CAG > UAG to non-canonical UAG > CAG, to modify the clinical impact of transitions at this position and to change their classification from pathogenic to benign or vice versa.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"70 3","pages":"125-133"},"PeriodicalIF":2.6,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11802449/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142785965","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Preimplantation genetic testing for inborn errors of metabolism: observations from a reproductive genetic laboratory in China","authors":"Xiaoli Li, Qiuxiang Huang, Fuchun Zhong, Yun Liu, Zhibiao Chen, Juan Lin, Zhongli Fan, Fenghua Lan, Zhihong Wang","doi":"10.1038/s10038-024-01307-9","DOIUrl":"10.1038/s10038-024-01307-9","url":null,"abstract":"In this study, we aimed to apply preimplantation genetic testing for monogenic disorders (PGT-M) based on mutated allele revealed by sequencing with aneuploidy and linkage analyses (MARSALA) to block the transmission of inborn errors of metabolism (IEMs). After the disease-causing variants were identified through genetic testing, four carrier couples having children affected with IEMs, including methylmalonic aciduria, glutaric acidemia type 1, beta-ketothiolase deficiency, and ornithine transcarbamylase deficiency, sought PGT-M. A series of PGT procedures involving intracytoplasmic sperm injection, blastocyst culture, biopsy of trophectoderm cells, and next-generation sequencing (NGS)-based MARSALA, was performed to provide comprehensive chromosome screening and variant gene analysis. Finally, embryos were selected for transfer, and prenatal diagnosis was conducted to confirm the PGT-M results. All four carrier couples obtained transferrable embryos after PGT. The results of the prenatal diagnosis were consistent with the PGT results, and all couples gave birth to healthy babies free of IEMs. The results of this study confirm that NGS-based MARSALA is an effective approach for families with IEMs to prevent the subsequent transmission of pathological genetic variants to the next generation.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"70 2","pages":"113-119"},"PeriodicalIF":2.6,"publicationDate":"2024-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142710441","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of biallelic intronic EPM2A mutations in a Lafora disease kindred","authors":"Ruo-Nan Duan, Jin-De Liu, Xiu-He Zhao, Cheng-Yuan Song","doi":"10.1038/s10038-024-01306-w","DOIUrl":"10.1038/s10038-024-01306-w","url":null,"abstract":"Lafora disease (LD) is a severe autosomal recessive disease, which usually presents as seizure and myoclonus, followed by behavioral changes, dysarthria, intellectual decline, and finally progressed to dementia and a vegetative state. The main cause of LD is the loss-of-function mutations in EPM2A and NHLRC1 that encode laforin and malin, respectively. Targeted genetic testing is the gold standard to confirm the diagnosis of LD. To describe the pathogenic role of biallelic EPM2A intronic mutations carried by patients in a family diagnosed as LD. Here, we present clinical findings in a patient presenting with epileptic seizures and Lafora bodies in muscle biopsy. Long-read DNA and RNA sequencing were performed to identify the causative mutation. Western blot and qPCR confirmed the pathogenic role of biallelic EPM2A intronic mutations. Genetic testing identified two intronic mutations in EPM2A which caused aberrant mRNA splicing. c.301+1 G > A in EPM2A caused aberrant splicing at donor site and resulted in intron retention in transcript NM_005670.4, while c.476+14860 C > A caused aberrant splicing in transcript NM_001368129.2 and NM_001368132.1. Our findings expand the spectrum of variants in LD disease, additionally providing evidence linking non-coding regulatory regions mutations to LD disease.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"70 3","pages":"167-170"},"PeriodicalIF":2.6,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142668303","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}