Journal of Human Genetics最新文献

A novel mutation in the WNK1/HSN2 gene causing hereditary sensory and autonomic neuropathy type 2 in Chinese patient.

IF 2.6 3区生物学

Journal of Human Genetics Pub Date : 2024-12-23 DOI: 10.1038/s10038-024-01310-0

Siqing Ma, Chunbo Ji, Jinlan Li, Jie Zhou, Jianying Zhu, Ping Yang

引用次数: 0

Ultra-rare monogenic disorders frequently detected among sex chromosome aneuploidy patients with atypical findings.

IF 2.6 3区生物学

Journal of Human Genetics Pub Date : 2024-12-19 DOI: 10.1038/s10038-024-01312-y

Kiana Magee, William McGonigle, Rena Pressman, Willa Thorson, Deborah Barbouth, Nicholas A Borja

{"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":"https://doi.org/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":" ","pages":""},"PeriodicalIF":2.6,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Genetic inhibition of nicotinamide N-methyltransferase and prevention of alcohol-associated fatty liver in humans.

IF 2.6 3区生物学

Journal of Human Genetics Pub Date : 2024-12-18 DOI: 10.1038/s10038-024-01313-x

Benrui Wu, Xiong Weng, Ying Pan, Zijian Tian, Peng Wu, Jian Shao, Yiying Liu, Rong Huang, Tao Xu, Kaixin Zhou

{"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":"https://doi.org/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":" ","pages":""},"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}

引用次数: 0

Cancer and disease profiles for PTEN pathogenic variants in Japanese population.

IF 2.6 3区生物学

Journal of Human Genetics Pub Date : 2024-12-12 DOI: 10.1038/s10038-024-01311-z

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

{"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":"https://doi.org/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":" ","pages":""},"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}

引用次数: 0

Intron retention caused by a canonical splicing variant in SSR4-related congenital disorder of glycosylation.

IF 2.6 3区生物学

Journal of Human Genetics Pub Date : 2024-12-10 DOI: 10.1038/s10038-024-01309-7

Quanquan Wang, Guangyu Wang, Bing Liang, Chen Zhang, Chuanzhu Yan, Pengfei Lin, Ling Li

引用次数: 0

From benign to pathogenic variants and vice versa: pyrimidine transitions at position -3 of TAG and CAG 3' splice sites.

IF 2.6 3区生物学

Journal of Human Genetics Pub Date : 2024-12-05 DOI: 10.1038/s10038-024-01308-8

Igor Vořechovský

{"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":"https://doi.org/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":" ","pages":""},"PeriodicalIF":2.6,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Preimplantation genetic testing for inborn errors of metabolism: observations from a reproductive genetic laboratory in China. 先天性代谢错误的胚胎植入前基因检测：来自中国生殖基因实验室的观察。

IF 2.6 3区生物学

Journal of Human Genetics Pub Date : 2024-11-25 DOI: 10.1038/s10038-024-01307-9

Xiaoli Li, Qiuxiang Huang, Fuchun Zhong, Yun Liu, Zhibiao Chen, Juan Lin, Zhongli Fan, Fenghua Lan, Zhihong Wang

{"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":" ","pages":""},"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}

引用次数: 0

Identification of biallelic intronic EPM2A mutations in a Lafora disease kindred. 在一个拉弗拉病种系中鉴定出双拷贝内含子 EPM2A 突变。

IF 2.6 3区生物学

Journal of Human Genetics Pub Date : 2024-11-19 DOI: 10.1038/s10038-024-01306-w

Ruo-Nan Duan, Jin-De Liu, Xiu-He Zhao, Cheng-Yuan Song

{"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":" ","pages":""},"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}

引用次数: 0

Expanding the spectrum of HSPB8-related myopathy: a novel mutation causing atypical pediatric-onset axial and limb-girdle involvement with autophagy abnormalities and molecular dynamics studies. 扩大HSPB8相关肌病的范围：一种新型突变导致非典型儿科发病性轴向和肢腰受累，并伴有自噬异常和分子动力学研究。

IF 2.6 3区生物学

Journal of Human Genetics Pub Date : 2024-11-15 DOI: 10.1038/s10038-024-01305-x

Guiguan Yang, Xiaoqing Lv, Mengqi Yang, Yifei Feng, Guangyu Wang, Chuanzhu Yan, Pengfei Lin

{"title":"Expanding the spectrum of HSPB8-related myopathy: a novel mutation causing atypical pediatric-onset axial and limb-girdle involvement with autophagy abnormalities and molecular dynamics studies.","authors":"Guiguan Yang, Xiaoqing Lv, Mengqi Yang, Yifei Feng, Guangyu Wang, Chuanzhu Yan, Pengfei Lin","doi":"10.1038/s10038-024-01305-x","DOIUrl":"https://doi.org/10.1038/s10038-024-01305-x","url":null,"abstract":"Variants in HSPB8 are predominantly associated with peripheral neuropathies, but their occurrence in myopathies remains exceedingly rare. The genetic and clinical spectrum of HSPB8-related myopathy is not yet complete. Herein, we not only described the first Chinese case of HSPB8-related myopathy characterized by a novel heterozygous frameshift variant (c.576_579delinsCAG, p.Glu192Aspfs*55) in the C-terminal region of HSPB8, but also established the first association between this specific HSPB8 variant and pediatric-onset axial and limb-girdle myopathy. Muscle pathology revealed myofibrillar myopathy features and the novel pathological findings of inflammatory responses and vacuoles with sarcolemmal features pathology. Functional studies demonstrated significant colocalization of HSPB8 with autophagy markers and upregulation of autophagy-related proteins, which suggested that autophagic dysregulation may contribute to the pathological process of this disease. Furthermore, comprehensive bioinformatics analysis and molecular dynamics simulations revealed an increased propensity for aggregation, as well as altered structural and biochemical properties in the mutant HSPB8. Our study highlights the importance of considering HSPB8 mutations in early-onset axial and limb-girdle myopathy, expanding the genetic and phenotypic spectrum of the disease. Notably, our results underscore the critical role of autophagy dysregulation and aberrant protein aggregation in the pathogenesis, providing novel insights into potential therapeutic targets.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":2.6,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142639197","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}

引用次数: 0

Novel variants in DNAH9 are present in two infertile patients with severe asthenospermia. 两名患有严重少精症的不育患者体内存在 DNAH9 的新型变体。

IF 2.6 3区生物学

Journal of Human Genetics Pub Date : 2024-11-11 DOI: 10.1038/s10038-024-01304-y

Fei Yan, Weiwei Zhi, Yazhen Wei, Li Dai, Wenming Xu, Rui Zheng

{"title":"Novel variants in DNAH9 are present in two infertile patients with severe asthenospermia.","authors":"Fei Yan, Weiwei Zhi, Yazhen Wei, Li Dai, Wenming Xu, Rui Zheng","doi":"10.1038/s10038-024-01304-y","DOIUrl":"https://doi.org/10.1038/s10038-024-01304-y","url":null,"abstract":"Asthenospermia is a type of sperm that has malformed sperm with movement disorders that lead to male infertility. DNAH9 is a member of the dynein family and a central part of the outer dynein arm of cilia and flagella. DNAH9 gene defects are associated with primary ciliary dyskinesia and ultrastructural abnormalities in ciliary axial ultrastructure. However, the role of DNAH9 in sperm motility remains unclear, prompting us to investigate its function in spermatozoa. Familial Sanger sequencing showed that sterile males carried homozygous DNAH9 variants (c. 12218A>C, p. N4073T) and compound heterozygous variants (c.8617G>A, p.V2873M; c.11742A>T, p.E3914D), respectively. Transmission electron microscopy revealed these variants resulted in a significant lack of outer dynein arms in the cross-sectional view of the axoneme in both patients. Immunofluorescence results showed that these variants can lead to decline in DNAH9 protein expression, which led to the dysfunction of flagellar ultrastructure-related proteins, including DNAI1, DNAH1 and DNAH10. In conclusion, we identified novel biallelic variants in DNAH9 that likely bring about sharply decreased motility of spermatozoa in the two patients with asthenospermia. Our findings will widen the variant spectrum of known DNAH9 variants involving asthenospermia and further offer more proofs for genetic counseling and diagnosis.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":2.6,"publicationDate":"2024-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142621968","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}

引用次数: 0