Journal of Human Genetics最新文献

{"title":"Beyond CHD7 gene: unveiling genetic diversity in clinically suspected CHARGE syndrome","authors":"Dohyung Kim, Ji-Hee Yoon, Hyunwoo Bae, Soojin Hwang, Go Hun Seo, June-Young Koh, Young Seok Ju, Hyo-Sang Do, Soyoung Kim, In Hee Choi, Gu-Hwan Kim, Ja Hye Kim, Jin-Ho Choi, Beom Hee Lee","doi":"10.1038/s10038-025-01325-1","DOIUrl":"10.1038/s10038-025-01325-1","url":null,"abstract":"The Verloes or Hale diagnostic criteria have been applied for diagnosing CHARGE syndrome in suspected patients. This study was conducted to evaluate the diagnostic rate of CHD7 according to these diagnostic criteria in suspected patients and also to investigate other genetic defects in CHD7-negative patients. The clinical findings and the results of genetic testing of CHD7, chromosome microarray, exome sequencing, or genome sequencing of 59 subjects were reviewed. CHD7 pathogenic variants were identified in 78% of 46 subjects who met either the Verloes or Hale diagnostic criteria and in 87% of 38 subjects who met both criteria, whereas no CHD7 variant was detected in 13 subjects who met neither criterion. Among 23 patients without the CHD7 variant, six genetic diseases were identified in 7 patients, including Wolf–Hirschhorn syndrome, 1q21 deletion syndrome, 19q13 microdeletion, and pathogenic variants in PLCB4, TRRAP, and OTX2. Based on these comprehensive analyses, the overall diagnostic rate was 73% for seven different genetic diseases. This study emphasizes the importance of comprehensive clinical and genetic evaluation in patients with clinically suspected CHARGE syndrome, recognizing the overlapping phenotypes in other rare genetic disorders.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"70 5","pages":"243-248"},"PeriodicalIF":2.5,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143501879","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":"Novel FBN1 intron variant causes isolated ectopia lentis via in-frame exon skipping","authors":"Norihiro Shimizu, Yoichi Mashimo, Hirotaka Yokouchi, Yosuke Nishio, Setsu Sawai, Tomohiko Ichikawa, Tomoo Ogi, Takayuki Baba, Yoshihiro Onouchi","doi":"10.1038/s10038-025-01318-0","DOIUrl":"10.1038/s10038-025-01318-0","url":null,"abstract":"Mutations in fibrillin-1 (FBN1) cause various clinical conditions, such as Marfan syndrome (MFS). However, the genotype–phenotype relationships underlying MFS and other conditions relevant to FBN1 mutations have not been fully elucidated. We performed whole-exome sequencing on three participants, including an affected mother–daughter pair, in a three-generation Japanese family with isolated ectopia lentis (IEL). The sequencing identified a novel single-nucleotide variant (c.1327+3A>C) in intron 11 of FBN1 that was shared between the two patients. We confirmed the co-segregation of the variant with IEL in two additional affected relatives in the family. The Combined Annotation-Dependent Depletion score of the variant was 26.1, which was indicated by SpliceAI to influence splicing, with a score of 0.93. Reverse transcription-polymerase chain reaction (RT-PCR) of mRNAs isolated from peripheral blood mononuclear cells revealed aberrant bands in all four affected individuals. Subsequent sequencing revealed that these bands originated from FBN1 transcripts lacking exon 11. The causality of the variant in the skipping of exon 11, which results in an in-frame deletion of 60 amino acids corresponding to the “hinge” region of FBN1 protein, was confirmed in a minigene experiment. Interestingly, the same result was observed for a minigene for c.1327+1G>A, a variant previously identified in two unrelated EL families without MFS manifestations. These results suggest that the c.1327+3A>C mutation in FBN1 likely leads to IEL. The findings expand our knowledge of FBN1 and provide insights into FBN1-related diseases.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"70 4","pages":"199-205"},"PeriodicalIF":2.6,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s10038-025-01318-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143408627","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":"Phenotype puzzle: the role of novel LMBRD1 gene variant in Cbl deficiency causing Dyskeratosis Congenita-like clinical manifestations","authors":"Anjali Shah, Santosh Khuba, Selvaa Kumar C, Chandrakala Shanmukhaiah, Merin George, Somprakash Dhangar, Jagdeeshwar Ghatanatti, Babu Rao Vundinti","doi":"10.1038/s10038-025-01320-6","DOIUrl":"10.1038/s10038-025-01320-6","url":null,"abstract":"Cobalamin (Cbl) metabolism deficiencies are a heterogeneous group (CblA, CblB, CblC, CblD, CblE, CblF, CblG) of autosomal recessive disorders. CblF deficiency occurs due to mutations in LMBRD1 gene, causing variable phenotype, including neurological, haematological, developmental and dermatological defects. Here, we describe a 15-year-old male, presented with clinical features of Dyskeratosis Congenita (DC) such as dystrophic nails, skin discoloration with additional clinical features of uniform reticulate-brown hued hyperpigmentation, developmental delay, mild intellectual disability, mucositis and anemia. Genomic analysis using high throughput next generation sequencing (NGS) identified a novel splice site deletion (c.562+4_562+7del) in the LMBRD1 gene resulting in Cbl deficiency. cDNA sequencing elucidated exon 6 skipping as a consequence of a novel deletion, resulting in significant structural alterations of LMBD1 protein, which was further validated by in-silico computational analysis. Computational modeling and docking studies revealed a reduced interaction affinity between the LMBD1 protein and its partner protein ABCD4. These alterations contribute to a disrupted cascade mechanism in cobalamin (Cbl) metabolism resulting in development of variable clinical phenotypes. In our case, the proband was treated with intravenous hydroxocobalamin therapy and follow up showed a significant improvement in clinical symptoms of skin hyperpigmentation, angular cheilitis and aphthous ulcers. Hence the genomic analysis is essentially important for the appropriate genetic counseling and management of the disease.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"70 4","pages":"207-213"},"PeriodicalIF":2.6,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143408693","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 missense pathogenic variants of TMEM53 in an Iranian family with craniotubular dysplasia, Ikegawa type","authors":"Kaitao Ren, Niloofar Pirmarzdashti, Farzad Pakdel, Jinhui Zhu, Wanqi Liu, Lin Wang, Moosa Sadrhosseini, Farzaneh Abassi, Yao Xiong, Jiaqi Han, Lianying Jiao, Gen Nishimura, Takahiro Yamada, Rong Qiang, Long Guo","doi":"10.1038/s10038-025-01319-z","DOIUrl":"10.1038/s10038-025-01319-z","url":null,"abstract":"Craniotubular dysplasia, Ikegawa type (CTDI) is a rare autosomal recessive skeletal dysplasia characterized by hyperostosis of the calvaria and skull base, metadiaphyseal undermodeling of the long tubular bones, and mild shortening and diaphyseal broadening of the short tubular bones. Its causal gene is TMEM53. Six CTDI families have been reported; however, its clinical course and prognosis still remain to be determined. Here, we report two Iranian siblings carrying a novel homozygous missense variant of TMEM53. The affected individuals were referred for progressive severe visual loss of unknown cause. The patient had severe optic atrophy and optic canal narrowing. Radiographic evaluation suggested the diagnosis of CTDI, which was confirmed by the identification of TMEM53 variant (c.704G > T, p.R235L) co-segregating in the consanguineous family. The proband underwent trans-nasal endoscopic optic canal decompression and showed remarkable improvement in visual acuity and daily visual tasks. We recommend early comprehensive clinical and genetic evaluation followed by proper treatment to improve the prognosis of CTDI.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"70 4","pages":"195-198"},"PeriodicalIF":2.6,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143123079","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":"Pathogenic variants in SHROOM3 associated with hemifacial microsomia","authors":"Qin Li, Bing-Hua Zhang, Qi Chen, Yaoyao Fu, Xiang Zuo, Peng Lu, Weiwei Zhang, Bingqing Wang","doi":"10.1038/s10038-025-01317-1","DOIUrl":"10.1038/s10038-025-01317-1","url":null,"abstract":"Hemifacial microsomia (HFM) is a rare congenital disorder that affects facial symmetry, ear development, and other congenital anomalies. However, known causal genes account for only approximately 6% of patients, indicating the need to discover more pathogenic genes. Association tests demonstrated an association between common variants in SHROOM3 and HFM (P = 1.02E-4 for the lead SNP), while gene burden analysis revealed a significant enrichment of rare variants in HFM patients compared to healthy controls (P = 2.78E-5). We then evaluated the expression patterns of SHROOM3 and the consequences of its deleterious variants. Our study identified 7 deleterious variants in SHROOM3 among the 320 Chinese HFM patients and 2 deleterious variants in two HFM trios, respectively, suggesting a model of dominant inheritance with incomplete penetrance. These variants were predicted to significantly impact SHROOM3 function. Furthermore, the gene expression pattern of SHROOM3 in the pharyngeal arches and the presence of facial abnormalities in gene-edited mice suggest that SHROOM3 plays important roles in facial development. Our findings suggest that SHROOM3 is a likely pathogenic gene for HFM.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"70 4","pages":"189-194"},"PeriodicalIF":2.6,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143059342","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":"Clinical and genetic spectrum of patients with IRF2BPL syndrome","authors":"Kazuhiro Iwama, Mitsuhiro Kato, Yuri Uchiyama, Masamune Sakamoto, Ryosuke Miyamoto, Yuishin Izumi, Kei Ohashi, Ayako Hattori, Noboru Yoshida, Yoshiteru Azuma, Akito Watanabe, Chizuru Ikeda, Yuko Shimizu-Motohashi, Shohei Kusabiraki, Eiji Nakagawa, Masayuki Sasaki, Kenji Sugai, Sachiko Ohori, Naomi Tsuchida, Kohei Hamanaka, Eriko Koshimizu, Atsushi Fujita, Mitsuko Nakashima, Satoko Miyatake, Toru Sengoku, Kazuhiro Ogata, Shinji Saitoh, Hirotomo Saitsu, Shuichi Ito, Takeshi Mizuguchi, Naomichi Matsumoto","doi":"10.1038/s10038-025-01316-2","DOIUrl":"10.1038/s10038-025-01316-2","url":null,"abstract":"Interferon regulatory factor 2 binding protein-like (IRF2BPL) is a single-exon gene that is ubiquitously expressed in various tissues, including the brain. IRF2BPL encodes a transcription factor with two zinc-finger domains that potentially downregulate WNT signaling in the nervous system. Pathogenic IRF2BPL variants have been reported to cause developmental delay, seizures, myoclonus epilepsies, autistic spectrum disorder, and other neurodevelopmental disorders. Exome sequencing of 10 patients with developmental delay and/or epilepsy from nine families revealed nine pathogenic IRF2BPL variants, of which eight were novel: five missense, one in-frame indel, and three truncating variants. Using reported pathogenic and benign variants, we highlight here several regions of IRF2BPL that deviate in the frequency of pathogenic and benign variants. This study of detailed clinical and genetic information shows that IRF2BPL missense and in-frame indel variants are often associated with seizures and developmental delay.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"70 4","pages":"181-188"},"PeriodicalIF":2.6,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143023585","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":"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}