Journal of Human Genetics最新文献

{"title":"Elevated serum autotaxin levels and multiple system atrophy-like presentation in a patient with PLA2G6-associated neurodegeneration","authors":"So Okubo, Takashi Matsukawa, Norifumi Kawamoto, Masahiko Tsujita, Kenta Orimo, Hiroya Naruse, Jun Mitsui, Masashi Hamada, Wataru Satake, Tatsushi Toda","doi":"10.1038/s10038-025-01342-0","DOIUrl":"10.1038/s10038-025-01342-0","url":null,"abstract":"PLA2G6-associated neurodegeneration (PLAN) encompasses a spectrum of phenotypes caused by biallelic pathogenic variants in PLA2G6. Initially linked to infantile and atypical neuroaxonal dystrophy, PLAN now includes adult-onset conditions such as dystonia-parkinsonism, ataxia, and spastic paraplegia. We report a female patient presenting young-onset parkinsonism with pyramidal tract signs, cerebellar atrophy, and autonomic dysfunction, mimicking multiple system atrophy (MSA). Neuroimaging showed decreased dopamine uptake and cerebellar hypoperfusion. Genetic analysis identified a homozygous pathogenic variant in PLA2G6 (c.967G>A, p.Val323Met), confirming a diagnosis of PLAN. Interestingly, elevated serum autotaxin levels (4.67 ng/mL) without liver abnormalities. Bilateral brachymetatarsia was also observed, which may indicate an association with the PLA2G6 variant. This case underscores the importance of considering PLAN in cases of young-onset parkinsonism with multisystem involvement. Genetic testing is crucial for accurate diagnosis and management of such cases. Elevated serum autotaxin levels may be associated with decreased phospholipase activity in PLAN and warrants further investigation.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"70 7","pages":"381-384"},"PeriodicalIF":2.5,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12137112/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144024130","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":"A random forest-based predictive model for classifying BRCA1 missense variants: a novel approach for evaluating the missense mutations effect","authors":"Hamed KA, Maryam Naghinejad, Akbar Amirfiroozy, Mohd Shahir Shamsir, Sepideh Parvizpour, Jafar Razmara","doi":"10.1038/s10038-025-01341-1","DOIUrl":"10.1038/s10038-025-01341-1","url":null,"abstract":"The right classification of variants is the key to pre-symptomatic detection of disease and conducting preventive actions. Since BRCA1 has a high incidence and penetrance in breast and ovarian cancers, a high-performance predictive tool can be employed to classify the clinical significance of its variants. Several tools have previously been developed for this purpose which poorly classify the significance in specific cases. The proposed tools commonly assign a score without providing any interpretation behind it. To reach an accurate predictive tool with interpretation abilities, in this study, we propose BRCA1-Forest which works based on random forest as a well-known machine learning technique for making interpretable decisions with high specificity and sensitivity in variants classification. The method involves narrowing down available options until reaching the final decision. To this end, a set of BRCA1 benign and pathogenic missense variants was collected first, and then, the dataset was prepared based on the effect of each variant on the protein sequence. The dataset was enriched by adding physicochemical changes and the conservation score of the amino acid position as pathogenicity criteria. The proposed model was trained based on the dataset to classify the clinical significance of variants. The performance of BRCA1-Forest was compared to four state-of-the-art methods, SIFT, PolyPhen2, CADD, and DANN, in terms of different evaluation metrics including precision, recall, false positive rate (FPR), the area under the receiver operator curve (AUC ROC), the area under the precision-recall curve (AUC-PR), and Mathew correlation coefficient (MCC). The results reveal that the proposed model outperforms the abovementioned tools in all metrics except for recall. The software of BRCA1-Forest is available at https://github.com/HamedKAAC/BRCA1Forest .","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"70 7","pages":"341-348"},"PeriodicalIF":2.5,"publicationDate":"2025-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143995771","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":"Report of a missense TJP2 variant associated to PFIC4 with a pronounced phenotypic variability: Focus on the structural effects on the protein level","authors":"Boudour Khabou, Houcemeddine Othman, Manel Guirat, Imen Chabchoub, Sana Kmiha, Bahri Mahjoub, Rania Abdelhadi, Afif Ben Mahmoud, Rim Kallel, Tahya Sellami Boudawara, Thouraya Kammoun, Faiza Fakhfakh, Hassen Hadj Kacem, Hassen Kammoun","doi":"10.1038/s10038-025-01338-w","DOIUrl":"10.1038/s10038-025-01338-w","url":null,"abstract":"PFIC4 is a chronic liver disease which cannot be diagnosed based on clinical and biochemical findings with an unpredictable evolution. Here, we reported three consanguineous families with 9 children suffering from intrahepatic cholestasis with low GGT-activity. Three probands were chosen to undergo genetic testing. In silico analyses were conducted to assess the functional impact of the identified variant, along with variants occurring at highly conserved positions within the protein. Additionally, close clinical monitoring was carried. Targeted-NGS sequencing ruled out the diagnosis of PFIC1 and PFIC2. Subsequently, WES allowed the establishment of PFIC4 diagnosis for the three families through the identification of a homozygous TJP2 variant p. Gly532Arg classified as likely pathogenic with a structural damage predicted based on biomolecular modeling and simulation analysis. In-depth in silico analysis of 90 nsSNPs occurring in highly conserved residues in PDZ domains showed 14 ones seems to be relevant in the clinical practice. Clinically, a pronounced phenotypic variability is noted. In conclusion, our study described a homozygous missense PFIC4-related variant with a highlight on the pathogenic power of such types of variants. The clinical evaluation provided information about the importance of close monitoring to prevent liver failure and clarified the unexpected course of PFIC4.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"70 7","pages":"331-339"},"PeriodicalIF":2.5,"publicationDate":"2025-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144013131","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":"GPD1 deficiency—a rare, overlooked cause of liver disease","authors":"Necati Emrecan Türk, Serkan Belkaya, Selçuk Teke, Ceyda Tuna Kırsaçlıoğlu, Fatma Tuba Eminoğlu, Tunahan Çalıkoğlu, Aydan Kansu, Zarife Kuloglu","doi":"10.1038/s10038-025-01339-9","DOIUrl":"10.1038/s10038-025-01339-9","url":null,"abstract":"Transient infantile hypertriglyceridemia is one of the diseases that should be considered in case of unexplained elevated liver enzymes, hypertriglyceridemia and hepatosteatosis. We report 2 siblings with novel homozygous variants in the GPD1 gene with transient infantile hypertriglyceridemia. Two siblings born from consanguineous marriage were referred due to hepatomegaly, elevated transaminases and fatty liver. After excluding other possible causes of fatty liver and elevated transaminase levels; whole-exome sequencing (WES) was performed on genomic DNA isolated from the peripheral blood samples of both patients. Whole exome sequencing revealed the identification of a novel homozygous variant, c.628 G > C:p.G210R, in GPD1. Our report underscores the importance of genome sequencing in diagnosing unexplained childhood fatty liver disease and/or elevated enzyme levels. In patients with transient infantile hypertriglyceridemia, investigation into novel homozygous variants in the GPD1 gene should be conducted using whole exome sequencing.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"70 7","pages":"375-379"},"PeriodicalIF":2.5,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12137118/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143969627","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":"Regulation of MCCC1 expression by a Parkinson’s disease-associated intronic variant: implications for pathogenesis","authors":"Shunsaku Sogabe, Hiroko Nakano, Yusuke Ogasahara, Pei-Chieng Cha, Yuko Ando, Mariko Taniguchi-Ikeda, Ryusaku Matsumoto, Motoi Kanagawa, Kazuhiro Kobayashi, Shigeo Murayama, Takashi Aoi, Tatsushi Toda, Wataru Satake","doi":"10.1038/s10038-025-01335-z","DOIUrl":"10.1038/s10038-025-01335-z","url":null,"abstract":"Parkinson’s disease (PD) is a common neurodegenerative disorder characterized by dopaminergic neuron loss and α-synuclein aggregation. While some familial cases result from single-gene mutations, most are sporadic, involving complex genetic and environmental interactions. Among PD risk loci identified through genome-wide association studies, MCCC1 encodes a mitochondrial enzyme essential for leucine catabolism; however, the causal variant remains unclear. Here, we investigated whether the intronic variant rs12637471 regulates MCCC1 mRNA expression and influences PD risk. Postmortem brain analysis revealed significantly elevated MCCC1 mRNA levels in G-allele carriers, consistent with peripheral tissue eQTL data from GTEx. Using CRISPR/Cas9-edited induced pluripotent stem cells, we generated isogenic lines differing only at rs12637471 and observed increased MCCC1 expression in G-allele dopaminergic neurons. Given MCCC1’s mitochondrial role, its dysregulation may impact mitochondrial homeostasis, autophagy, or inflammation, potentially contributing to PD pathogenesis.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"70 7","pages":"371-374"},"PeriodicalIF":2.5,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12137145/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143988309","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":"A copy number variant overlapping the 3ʹUTR of PLP1 causes spastic paraplegia","authors":"Malak Alghamdi, Essa Alharbi, Salman Aljarallah, Ghaida Alghamdi, Reham M. Balahmar, Nisserin Jado, Hebattalah Hamed, Dima Jamjoom, Fahad A. Bashiri, Naif A. M. Almontashiri","doi":"10.1038/s10038-025-01340-2","DOIUrl":"10.1038/s10038-025-01340-2","url":null,"abstract":"Leukodystrophy presents a significant diagnostic challenge due to its varied clinical presentation and similarity to other myelin disorders, characterized by abnormalities in myelin and white matter. Hypomyelination disorders, including Pelizaeus-Merzbacher disease (PMD) and hereditary spastic paraplegias (SPG), are associated with variants in the proteolipid protein 1 (PLP1) gene, leading to symptoms ranging from severe dysmyelination in infancy to delayed dysmyelination and axonal degeneration in adulthood. Family history was taken, and pedigree was constructed. Recruitment included seven males and females with spastic paraplegia and nine healthy relatives, who were clinically investigated, and tested with molecular genetic assays including whole exome sequencing (WES), whole genome sequencing (WGS), and PCR amplification with fragment analysis on gel electrophoresis to identify and confirm the genetic cause. Family history was consistent with hereditary condition marked by progressive spastic paraplegia in 10 family members. Males had early onset and progressive paraplegia, and neurodegenerative conditions, resulting in a decline in the neurocognitive functions. However, in some females, the symptoms manifested later in their 30s–40s, leading to neurodegenerative conditions and spastic paraplegias. A total of 16 family members were available for genetic testing and segregation studies. Initial clinical WES in four members was negative. Next, WGS identified a novel copy number variant (CNV) loss (75.5 kb) involving the 3’UTR of the PLP1 gene in three members (the mother, affected son, but not in the unaffected son). Segregation studies in all 16 family members confirmed the presence of the CNV in five additional affected individuals and an asymptomatic female, but not in the eight asymptomatic individuals. Our study reports a novel 3ʹUTR CNV in PLP1 in a large family with several individuals affected with SPG. This finding expands the mutational landscape of the PLP1-related diseases to include CNV and, possibly, small sequence changes in the regulatory regions of PLP1, that would otherwise be overlooked during the interpretation of the next generation sequencing data.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"70 7","pages":"365-370"},"PeriodicalIF":2.5,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143811478","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":"Mosaic deletions detected by genome sequencing in two families","authors":"Naomi Tsuchida, Yuri Uchiyama, Kohei Hamanaka, Nobuhiko Okamoto, Ayataka Fujimoto, Hideo Enoki, Eriko Koshimizu, Atsushi Fujita, Kazuharu Misawa, Satoko Miyatake, Takeshi Mizuguchi, Naomichi Matsumoto","doi":"10.1038/s10038-025-01336-y","DOIUrl":"10.1038/s10038-025-01336-y","url":null,"abstract":"Trio-based genome sequencing (GS) is useful for genetic analysis of cases in which exome sequencing failed to resolve the disease-causing variants. In this paper, we report two unrelated families with pathogenic deletions (one outside exome-covering genomic regions and the other involving a single exon) successfully identified by GS. Notably, mosaic deletions were found in both families, which were carefully evaluated in detail by analyzing GS data using Integrative Genomics Viewer, breakpoint PCR, quantitative PCR, and digital PCR. This study emphasizes the benefit of trio-based GS, enabling straightforward interpretation, further aided by other confirmatory experimental methods.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"70 6","pages":"307-312"},"PeriodicalIF":2.5,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143811480","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":"Heterogeneity of the Southeast Belarusian mitochondrial gene pool","authors":"Boris Malyarchuk, Galina Denisova, Andrey Litvinov","doi":"10.1038/s10038-025-01337-x","DOIUrl":"10.1038/s10038-025-01337-x","url":null,"abstract":"The study of mitochondrial DNA (mtDNA) variability at the level of whole mitogenomes has significant implications for the fields of human evolution and population genetics. In this paper, we present the results of a study of the complete mtDNA variability in Belarusians from the southeastern part of the Republic of Belarus. It was found that Southeast Belarusians are characterized by a high diversity of mitochondrial genomes. The analysis of genetic distances between European populations showed significant differences between the studied Belarusian sample from the bulk of East European populations, including Slavic ethnic groups. The results of the phylogeographic analysis indicated the presence of the West Asian component (12.6%) in the Belarusian mitochondrial gene pool, which can account for the observed genetic differences between Belarusians and other Eastern Slavs (Russians and Ukrainians). The East Asian component of the mitochondrial gene pool of the studied group of Belarusians is represented by haplogroup C5c1a (2.3%). The results of the phylogeographic analysis indicated that this mtDNA subclade is predominantly present in the gene pools of Slavic peoples, including Poles, Belarusians, Ukrainians, and Russians. The evolutionary age of haplogroup C5c1a is ~4000 years and, consequently, the appearance of C5c1-haplotypes in the eastern regions of Europe may be linked to the migrations of the Caspian steppe populations to the west during the Bronze Age.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"70 6","pages":"313-320"},"PeriodicalIF":2.5,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143803516","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":"Profiling of runs of homozygosity from whole-genome sequence data in Japanese biobank","authors":"Aye Ko Ko Minn, Motomichi Matsuzaki, Akira Narita, Takamitsu Funayama, Yurii Kotsar, Satoshi Makino, Jun Takayama, Tohoku Medical Megabank Project Study Group, Shinichi Kuriyama, Gen Tamiya","doi":"10.1038/s10038-025-01331-3","DOIUrl":"10.1038/s10038-025-01331-3","url":null,"abstract":"Runs of homozygosity (ROHs) are widely observed across the genomes of various species and have been reported to be associated with many traits and common diseases, as well as rare recessive diseases, in human populations. Although single nucleotide polymorphism (SNP) array data have been used in previous studies on ROHs, recent advances in whole-genome sequencing (WGS) technologies and the development of nationwide cohorts/biobanks are making high-density genomic data increasingly available, and it is consequently becoming more feasible to detect ROHs at higher resolution. In the study, we searched for ROHs in two high-coverage WGS datasets from 3552 Japanese individuals and 192 three-generation families (consisting of 1120 family members) in prospective genomic cohorts. The results showed that a considerable number of ROHs, especially short ones that may have remained undetected in conventionally used SNP-array data, can be detected in the WGS data. By filtering out sequencing errors and leveraging pedigree information, longer ROHs are more likely to be detected in WGS data than in SNP-array data. Additionally, we identified gene families within ROH islands that are associated with enriched pathways related to sensory perception of taste and odors, suggesting potential signatures of selection in these key genomic regions.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"70 6","pages":"287-296"},"PeriodicalIF":2.5,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12058513/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143772418","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":"Hyaluronidase 2 deficiency due to novel compound heterozygous variants in HYAL2: a case report of siblings with HYAL2 deficiency showing different clinical severity and literature review","authors":"Ryuta Orimoto, Eriko Adachi, Maki Gau, Yoko Saito, Haruki Yamano, Hisae Nakatani, Shizuka Kirino, Kengo Moriyama, Yohei Yamaguchi, Tomoko Mizuno, Taku Ishii, Masayuki Yoshida, Kenichi Kashimada, Kei Takasawa","doi":"10.1038/s10038-025-01333-1","DOIUrl":"10.1038/s10038-025-01333-1","url":null,"abstract":"This study reports the first Asian case of syndromic cleft lip and palate resembling CHARGE-like syndrome, caused by novel compound heterozygous variants of the HYAL2 gene. Hyaluronidase-2 (HYAL2) plays a critical role in hyaluronic acid degradation and tissue remodelling. A 2-year-old Japanese boy presented with growth deficiency, congenital heart disease, craniofacial dysmorphism, micropenis, and developmental delays–features that overlapped with those of CHARGE syndrome. Genetic analysis identified two rare HYAL2 missense variants (c.1133G>A, p.Arg378His; c.1271A>G, p.His424Arg), classified as “likely pathogenic” based on ACMG/AMP criteria. This case highlights the importance of considering HYAL2 deficiency in the syndromic presentation of cleft lip and palate with congenital heart disease, particularly in the absence of CHD7 abnormalities. This study also emphasizes potential primary testicular dysfunction in male patients with HYAL2 deficiency and underscores the need for further research to clarify genotype-phenotype correlations and pathology.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"70 6","pages":"321-324"},"PeriodicalIF":2.5,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143753057","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}