Human Genetics最新文献_第10页

Unfolding the genetic map of monogenic liver diseases in Egypt. 揭示埃及单基因肝病的遗传图谱。

IF 3.4 2区生物学

Human Genetics Pub Date : 2025-12-01 Epub Date: 2025-10-30 DOI: 10.1007/s00439-025-02776-4

Hanaa El-Karaksy, Engy A Mogahed, Sherif Baroudy, Haytham Ghita, Afaf Enayet, Marwa El-Sharkawy, Noha A Radwan, Heba Hosny, Mohamed A Elmonem

{"title":"Unfolding the genetic map of monogenic liver diseases in Egypt.","authors":"Hanaa El-Karaksy, Engy A Mogahed, Sherif Baroudy, Haytham Ghita, Afaf Enayet, Marwa El-Sharkawy, Noha A Radwan, Heba Hosny, Mohamed A Elmonem","doi":"10.1007/s00439-025-02776-4","DOIUrl":"10.1007/s00439-025-02776-4","url":null,"abstract":"Monogenic liver disorders constitute a major disease burden in pediatric patients presenting with manifestations of liver disease. This is particularly significant in countries with high rates of consanguinity as in Egypt. We recruited 228 infants and children suffering from various forms of liver disease with suspected monogenic background and no conclusive biochemical diagnosis. They presented to the Pediatric Hepatology Unit at Cairo-University-Children’s-Hospital, Egypt, over the period April 2017-June 2023 and were referred for genetic diagnosis by various next-generation-sequencing technologies. One-hundred and eighty-five children (81.1%) had a significant genetic finding. Those included 88 children with a main presentation of organomegaly, 83 with cholestasis, 8 with acute liver failure and 6 with hyperbilirubinemic syndromes. One-hundred seventy-five disease-causing variants (51 pathogenic, 86 likely-pathogenic and 38 of uncertain-significance) in 72 different genes were detected in our cohort, including 85 novel variants in 49 different genes. Variants in AGL (Glycogen storage disease type-III; GSD3), ABCB4 (Progressive familial intrahepatic cholestasis type-III; PFIC3) and ABCB11 (PFIC2) genes were the most common affecting 19, 14 and 13 children, respectively. This study is the first to provide the landscape of pediatric monogenic liver diseases in a homogenous population from the Middle East and Africa, an area notoriously known to be poorly represented in genetic database and literature. Furthermore, our presented data are extremely important for genetic counseling and prenatal diagnosis and will further guide national health care policy makers to prevent or mitigate the effects of such disorders in the future.","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":" ","pages":"1053-1070"},"PeriodicalIF":3.4,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12689692/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145408885","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Polygenic risk scores in healthcare contexts: what's the scope? An interview study of European healthcare providers and researchers' perspectives on ethical challenges. 医疗环境中的多基因风险评分：范围是什么？欧洲医疗保健提供者和研究人员对伦理挑战的看法的访谈研究。

IF 3.4 2区生物学

Human Genetics Pub Date : 2025-12-01 Epub Date: 2025-10-27 DOI: 10.1007/s00439-025-02792-4

Lara Andreoli, Hilde Peeters, Kristel Van Steen, Kris Dierickx

{"title":"Polygenic risk scores in healthcare contexts: what's the scope? An interview study of European healthcare providers and researchers' perspectives on ethical challenges.","authors":"Lara Andreoli, Hilde Peeters, Kristel Van Steen, Kris Dierickx","doi":"10.1007/s00439-025-02792-4","DOIUrl":"10.1007/s00439-025-02792-4","url":null,"abstract":"In the last decade, substantial research efforts have started worldwide to foster the clinical translation of Polygenic Risk Scores (PRS). Understanding the views of key relevant groups becomes timely to critically inform the socio-ethical debate, impact future health policy, and support the development of guidelines for best practices in healthcare contexts. We performed 26 in-depth semi-structured interviews to investigate the perspectives of European researchers and healthcare providers from different specialties (clinical genetics, oncology, cardiology, psychiatry) on the ethical and social implications of PRS uses in healthcare contexts. Findings were conceptualized in four main themes: 1) appropriate clinical use, highlights that PRS should be considered complementary tools aimed at informing a clinical intervention, with notions of appropriateness differing according to clinical goals and condition-type; 2) clinical utility: what's the evidence? captures participants' orientations towards the capability of PRS to improve health outcomes compared to standard care, as well as the barriers, limitations, or emerging areas of utility; 3) balancing risk and responsibility: navigating ethical questions in patient care, addresses classical issues in clinical genetics, including communication and counselling, potential patient harms, relevance of PRS information to family members, and the use of PRS in pediatric settings; 4) searching for standards: clinical guidelines, gathers perspectives on the potential format and content of future clinical guidelines, relevant parties, and contexts of applicability. In conclusion, the present study outlines a framework to define the range of responsible uses in healthcare contexts; however, societal and public health considerations, including priority-setting in national healthcare systems, need to follow for a comprehensive, and contextual, evaluation of PRS.","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":" ","pages":"1229-1244"},"PeriodicalIF":3.4,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145377237","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Clinical validation of artificial intelligence-assisted karyotyping on peripheral blood in a cytogenetic diagnostic laboratory. 细胞遗传学诊断实验室外周血人工智能辅助核型的临床验证。

IF 3.6 2区生物学

Human Genetics Pub Date : 2025-12-01 Epub Date: 2025-11-10 DOI: 10.1007/s00439-025-02789-z

Yujie Zhu, Matthew Hoi Kin Chau, Huilin Wang, Ning Song, Ran Wei, Kin Wah Suen, Anna Chi Sum Chan, Wan Ching Hung, Ye Cao, Zirui Dong, Tak Yeung Leung, Sau Wai Cheung, Kwong Wai Choy

{"title":"Clinical validation of artificial intelligence-assisted karyotyping on peripheral blood in a cytogenetic diagnostic laboratory.","authors":"Yujie Zhu, Matthew Hoi Kin Chau, Huilin Wang, Ning Song, Ran Wei, Kin Wah Suen, Anna Chi Sum Chan, Wan Ching Hung, Ye Cao, Zirui Dong, Tak Yeung Leung, Sau Wai Cheung, Kwong Wai Choy","doi":"10.1007/s00439-025-02789-z","DOIUrl":"10.1007/s00439-025-02789-z","url":null,"abstract":"G-banded chromosome analysis, also known as G-banded karyotyping, remains a fundamental and irreplaceable diagnostic modality in clinical genetic testing. G-banded karyotypes provide whole genome visualization through chromosome banding patterns at the single-cell resolution for the diagnosis of chromosomal disorders. However, this method is labor-intensive and requires specialized expertise to manually analyze and karyotype metaphase spreads. In recent years, artificial intelligence (AI) algorithms have been utilized to automate karyotyping and assist with chromosome analysis. Despite this progress, there is a scarcity of studies evaluating the utility of artificial intelligence-assisted (AI-assisted) karyotyping analysis in cytogenetics diagnostic laboratories. This study highlights promising applications of AI-assisted karyotyping analysis in a cytogenetics diagnostic laboratory through a combination of a literature review, our data, and experience from a retrospective cohort study. This study also discusses important considerations of the use of AI-assisted karyotyping analysis in a cytogenetic diagnostic laboratory and outlines a two-stage framework for its implementation into clinical workflows. This approach aims to utilize the accuracy and efficiency of AI-assisted karyotyping analysis, potentially benefiting personalized patient care and contributing to advancements in the health system.","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":" ","pages":"1269-1276"},"PeriodicalIF":3.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12689769/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145482042","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Analysis of blood-based DNA methylation signatures of aging and disease progression in inflammatory bowel disease. 炎症性肠病中衰老和疾病进展的血液DNA甲基化特征分析。

IF 3.6 2区生物学

Human Genetics Pub Date : 2025-12-01 Epub Date: 2025-09-29 DOI: 10.1007/s00439-025-02779-1

Trevor Doherty, Edel McDermott, Sarah Jane Delany, Hugh Mulcahy, Therese M Murphy

{"title":"Analysis of blood-based DNA methylation signatures of aging and disease progression in inflammatory bowel disease.","authors":"Trevor Doherty, Edel McDermott, Sarah Jane Delany, Hugh Mulcahy, Therese M Murphy","doi":"10.1007/s00439-025-02779-1","DOIUrl":"10.1007/s00439-025-02779-1","url":null,"abstract":"Inflammatory bowel diseases (IBDs) are chronic inflammatory disorders influenced by environmental factors and characterised by a dysregulated immune response. DNA methylation (DNAm) a key epigenetic mechanism plays a role in the etiology of complex diseases like IBD. Epigenetic clocks which estimate biological aging through DNAm patterns have also been linked to various health states, including IBD. Previously, we profiled DNA methylation in peripheral blood from adult IBD patients and controls using the Illumina 450K microarray (n = 184). We now expand this dataset with 8-year clinical follow-up data, including disease progression and treatment response. Additionally, we generate second and third-generation epigenetic clock measures in this cohort to investigate if IBD patients exhibit epigenetic age acceleration compared to healthy controls. We identified one CpG site (cg03583111) significantly differentially methylated in IBD patients with long-term clinical recurrence (after the first year of study) compared to non-recurrence (no treatment escalation after 8 years). We assessed DNAm aging signatures in IBD patients versus controls, finding evidence of significant epigenetic age acceleration, as measured by three epigenetic clocks (GrimAge, GrimAge2, and DunedinPACE), in IBD patients compared to controls. These associations were replicated in two independent IBD cohorts: adult (GSE87648, n = 377) and paediatric (GSE112611, n = 238). Moreover, we observed higher age acceleration (GrimAge, U = 669, p = 0.003) and a faster pace of aging (DunedinPACE, t = 3.233, p = 0.002) in patients with active UC compared to inactive disease, but not for CD. These findings suggest that blood-based DNAm signatures could serve as biomarkers for detecting, monitoring, and classifying IBD.","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":" ","pages":"1079-1095"},"PeriodicalIF":3.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12689681/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145185725","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Evolution of the Japanese Y chromosome by analysis of the haplogroups and the deletion of the gene in the AZFc region. 日本人Y染色体的单倍群分析和AZFc区域基因的缺失。

IF 3.4 2区生物学

Human Genetics Pub Date : 2025-12-01 Epub Date: 2025-10-13 DOI: 10.1007/s00439-025-02787-1

Kenshiro Nii, Atsushi Tada, Yusuke Nakagawa, Youichi Sato

{"title":"Evolution of the Japanese Y chromosome by analysis of the haplogroups and the deletion of the gene in the AZFc region.","authors":"Kenshiro Nii, Atsushi Tada, Yusuke Nakagawa, Youichi Sato","doi":"10.1007/s00439-025-02787-1","DOIUrl":"10.1007/s00439-025-02787-1","url":null,"abstract":"The Y chromosome is classified into haplogroups based on its nucleotide polymorphisms. There are multiple amplicon genes in the azoospermia factor c (AZFc) region of the Y chromosome, and combinations of copy numbers of these genes diversify the Y chromosome structure. In this study, we investigated the evolution of the Y chromosome in a Japanese population based on the relationship between the Y chromosome haplogroup and the deletion patterns of genes in the AZFc region. Haplogroup branch markers were determined by PCR, PCR restriction fragment length polymorphism (PCR–RFLP), Sanger sequencing, and TaqMan PCR in 2,157 Japanese men. Single nucleotide variants (SNVs) on DAZ, BPY2, CDY1, TTTY4, and GOLGA2P2Y gene copies were analyzed for deletions by PCR–RFLP. Haplogroups D1a2a1a, D1a2a1c, and D1a2a2 showed the same AZFc deletion patterns. Haplogroups C and O1b2a showed a common AZFc deletion, with some exceptions. Therefore, it is possible that they diverged into subgroups following the occurrence of a common AZFc deletion pattern. Haplogroups O2a2 and O2a1b showed a common AZFc deletion pattern with some exceptions; however, after dividing into their respective downstream haplogroups, they showed several more deletion patterns. Thus, several additional deletion patterns may have occurred because of the divergence of downstream haplogroups. Haplogroups O1a and O1b1a1a exhibited several AZFc deletion patterns. Thus, each haplogroup may have originated from a different ancestor. This study provides further insights into the relationship between Y chromosome haplogroups and the deletion patterns of genes in the AZFc region, which is important for understanding the evolution of the Y chromosome.","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":" ","pages":"1207-1214"},"PeriodicalIF":3.4,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145280019","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Most males in modern Poland carry Y-chromosomal lineages from clades that have recently expanded over Central, Eastern and South-Eastern Europe. 现代波兰的大多数男性携带的y染色体谱系来自最近在中欧、东欧和东南欧扩展的分支。

IF 3.6 2区生物学

Human Genetics Pub Date : 2025-12-01 Epub Date: 2025-10-06 DOI: 10.1007/s00439-025-02781-7

Michał Milewski, Mateusz Dawidziuk

{"title":"Most males in modern Poland carry Y-chromosomal lineages from clades that have recently expanded over Central, Eastern and South-Eastern Europe.","authors":"Michał Milewski, Mateusz Dawidziuk","doi":"10.1007/s00439-025-02781-7","DOIUrl":"10.1007/s00439-025-02781-7","url":null,"abstract":"Previous studies on Y-chromosomal haplogroup diversity in Poland have been focused mainly on macro-haplogroups. Consequently, younger subclades have rarely been explored to elucidate the relatively recent history of the Polish population. Here we present the results of deep genotyping of 598 chromosome Y sequences from modern Poland and demonstrate that about 60% of Polish males can be assigned to subhaplogroups that are both relatively young and widely distributed among different Slavic populations, thus supporting the scenario in which Early Slavic mass migration and territorial expansion took place in the first millennium of the common era. While most of those young Slavic-associated subclades are part of haplogroup R1a, other haplogroups, including I2a, R1b and E1b, are also represented by specific subclades, which together may constitute an important clue when trying to identify the location of the Proto-Slavic homeland based on ancient DNA data. Additionally, we have identified two specifically Polish subclades (I-Y6343 and R-Z17913, from haplogroups I1a and R1b, respectively) that likely descend from Late Ancient or Early Medieval founders representing the local Pre-Slavic population of the Roman period.","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":" ","pages":"1115-1125"},"PeriodicalIF":3.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12689765/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145232362","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The spectrum of pathogenic NF1 variants in participants enrolling on clinical trials of MEK inhibitors for plexiform neurofibroma. 参与网状神经纤维瘤MEK抑制剂临床试验的参与者的致病性NF1变异谱

IF 3.4 2区生物学

Human Genetics Pub Date : 2025-12-01 Epub Date: 2025-10-15 DOI: 10.1007/s00439-025-02786-2

Chelsea Kotch, Alicia Gomes, Krista S Schatz, Eva Dombi, Symone Brown, Andrea M Gross, Mélanie Alves, Sébastien Perreault, Sabine Mueller, Alyssa T Reddy, Carlos Romo, Miriam Bornhorst, James Tonsgard, Brian D Weiss, Brigitte Widemann, Michael J Fisher

{"title":"The spectrum of pathogenic NF1 variants in participants enrolling on clinical trials of MEK inhibitors for plexiform neurofibroma.","authors":"Chelsea Kotch, Alicia Gomes, Krista S Schatz, Eva Dombi, Symone Brown, Andrea M Gross, Mélanie Alves, Sébastien Perreault, Sabine Mueller, Alyssa T Reddy, Carlos Romo, Miriam Bornhorst, James Tonsgard, Brian D Weiss, Brigitte Widemann, Michael J Fisher","doi":"10.1007/s00439-025-02786-2","DOIUrl":"10.1007/s00439-025-02786-2","url":null,"abstract":"Patients with neurofibromatosis type 1 (NF1) enrolled on interventional clinical trials of a mitogen activated protein kinase (MEK) inhibitor for a plexiform neurofibroma (PN) are required to have inoperable, progressive and/or symptomatic tumor as per protocol inclusion criteria. Thus, the represented germline pathogenic NF1 variants of these clinical trial participants may correlate with increased risk for symptomatic and/or progressive PN. However, the spectrum of pathogenic NF1 variants of participants enrolled on interventional clinical trials has not been previously described. Herein, we report 39 individuals with a diagnosis of NF1 per the National Institutes of Health consensus criteria who received treatment with a MEK inhibitor through a clinical trial for a morbid and/or progressive PN. Truncating variants were the most common variant (N = 14; 36.8%), followed by frameshift (N = 10; 26.3%) and canonical splice/intronic (N = 7; 18.4%); only 1 participant had a NF1 microdeletion (2.5%). Three variants were noted to be recurrent in the study population (c.6789_6792del (p.Tyr2264Thrfs*5), c.4537 C > T (p.Arg1513*), and c.3826 C > T (p.Arg1276*)); there were no related study participants. There was no significant difference in rates of PN response to MEK inhibition across NF1 variant subtype (P = 0.616). In summary, the reported NF1 germline variants may represent those associated with an increased likelihood of symptomatic PN, however sample size limits inference regarding correlation. Contribution of this study’s findings to the literature may support future development of more accurate risk stratification for PN in individuals with NF1.","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":" ","pages":"1199-1206"},"PeriodicalIF":3.4,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13409318/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145292022","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Genetic differences between diagnosed and undiagnosed Celiac disease: a population-based study. 确诊和未确诊乳糜泻的遗传差异：一项基于人群的研究

IF 3.6 2区生物学

Human Genetics Pub Date : 2025-12-01 Epub Date: 2025-09-29 DOI: 10.1007/s00439-025-02778-2

Mohammad Sayeef Alam, Brooke N Wolford, Kristian Hveem, Knut E A Lundin, Sebo Withoff, Iris H Jonkers, Ludvig M Sollid, Rebecka Hjort, Eivind Ness-Jensen

{"title":"Genetic differences between diagnosed and undiagnosed Celiac disease: a population-based study.","authors":"Mohammad Sayeef Alam, Brooke N Wolford, Kristian Hveem, Knut E A Lundin, Sebo Withoff, Iris H Jonkers, Ludvig M Sollid, Rebecka Hjort, Eivind Ness-Jensen","doi":"10.1007/s00439-025-02778-2","DOIUrl":"10.1007/s00439-025-02778-2","url":null,"abstract":"A large proportion of individuals with celiac disease (CeD) remain undiagnosed, often presenting at an older age of onset or with non-classical symptoms compared to diagnosed cases. Such heterogeneity might be related to genetic factors. The aim was to utilize a CeD-screened adult population to compare the genetic variants in known and newly diagnosed cases. In the fourth wave of the population-based Trøndelag Health Study (HUNT4) 826 CeD and 51,516 non-CeD individuals were included. Medical registries identified 361 previously diagnosed cases, while screening identified 465 new cases. A validated polygenic risk score (PRS) was used to assess the genetic risk of CeD among the two case groups versus non-CeD individuals. Additional genetic variants not included in the PRS were also analyzed. The PRS distinguished cases from non-cases with high accuracy (AUROC: 85% for known cases, 83% for new cases). The genetic variation explained by the PRS was similar for known and new cases (17.1% versus 14.5%). The odds ratio for being in the highest genetic risk group (top 10%) was 22.7 (95% CI 14.1-36.4) for known cases and 18.6 (95% CI 12.4-27.9) for new cases versus the median group (40%-60%). Differences in effect size among specific genome-wide variants were observed but were not significantly associated with CeD. A validated PRS showed significant genetic difference between CeD cases and the general population, with similar association in both known and newly diagnosed cases. This suggests that genetic architectures of the two groups are comparable, implying that other non-genetic factors may drive CeD in adults.","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":" ","pages":"1071-1078"},"PeriodicalIF":3.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12689682/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145185774","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Investigation of GSDME results in the identification of the first pathogenic synonymous variants and genotype-phenotype correlations. GSDME的研究结果鉴定了第一个致病同义变异体和基因型-表型相关性。

IF 3.6 2区生物学

Human Genetics Pub Date : 2025-12-01 Epub Date: 2025-09-29 DOI: 10.1007/s00439-025-02782-6

Joseph J Chin, W Daniel Walls, Kai Wang, Amanda M Odell, Diana L Kolbe, Kevin T A Booth, Hela Azaiez, Richard J H Smith

{"title":"Investigation of GSDME results in the identification of the first pathogenic synonymous variants and genotype-phenotype correlations.","authors":"Joseph J Chin, W Daniel Walls, Kai Wang, Amanda M Odell, Diana L Kolbe, Kevin T A Booth, Hela Azaiez, Richard J H Smith","doi":"10.1007/s00439-025-02782-6","DOIUrl":"10.1007/s00439-025-02782-6","url":null,"abstract":"Despite advances in the genetic diagnosis of hearing loss, there remains room for improvement. One way to improve the genetic diagnostic rate is the proper assessment of synonymous variants that are often bioinformatically filtered out. We used GSDME as a model to demonstrate the importance of assessing synonymous variants. Variants in the gene GSDME (also known as DFNA5) are associated with autosomal dominant nonsyndromic hearing loss. The hearing loss is typically progressive and downsloping. All reported causative variants of GSDME-related hearing loss involve the skipping of exon 8, which results in the expression of a constitutively active, but truncated protein that induces apoptosis of cochlear hair cells. A retrospective search of previously tested patients identified 3 novel pathogenic synonymous GSDME variants. The functional impact of these variants was confirmed in vitro via a minigene splicing assay. We also observed variant-dependent differences in the levels of aberrant splicing, leading us to hypothesize that partial loss of splicing will result in a less severe hearing loss phenotype as compared to complete loss of splicing. Audiometric analysis found an association between complete loss of splicing and greater initial and/or more quickly progressing hearing loss as compared to partial loss of splicing. Over the course of the study, we also found limited correlation between in silico prediction and in vitro observed effects of a variant on splicing, indicating the need to cautiously apply in silico prediction tools in the context of genetic diagnosis.","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":" ","pages":"1127-1138"},"PeriodicalIF":3.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12689683/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145185806","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Development and validation of an MPS-based 513-Plex SNP identity panel for degraded forensic samples. 基于mps的513-Plex SNP鉴定面板的开发和验证，用于降解法医样品。

IF 3.4 2区生物学

Human Genetics Pub Date : 2025-12-01 Epub Date: 2025-10-27 DOI: 10.1007/s00439-025-02785-3

Linyu Shi, Xiaoxiao Feng, Mengyang Zhao, Anjie Wei, Jiarong Zhang, Piao Yuan, Haoliang Fan, Jiangwei Yan

{"title":"Development and validation of an MPS-based 513-Plex SNP identity panel for degraded forensic samples.","authors":"Linyu Shi, Xiaoxiao Feng, Mengyang Zhao, Anjie Wei, Jiarong Zhang, Piao Yuan, Haoliang Fan, Jiangwei Yan","doi":"10.1007/s00439-025-02785-3","DOIUrl":"10.1007/s00439-025-02785-3","url":null,"abstract":"Degraded samples pose a challenge in routine forensic practice. The commonly used short tandem repeat markers are not optimally suitable for the analysis of degraded samples because of their structural complexity and locus length. By contrast, single nucleotide polymorphisms (SNPs), characterised by their single base mutation feature, enable the design of short amplification fragments, conferring an advantage in detecting mutations in degraded samples. Hence, our team has developed a multiplex amplification system for individual identification of degraded samples, encompassing 507 autosomal SNP loci, five Y-InDel loci, and one amelogenin sex determination locus. The amplification fragment lengths in this multiplex system range from 81 to 116 bp. The forensic applicability of this panel was validated through sequencing analysis of 201 samples. Among these were 30 degraded samples (simulated degraded samples: heat degradation and ultrasonic fragmentation; formalin-fixed, paraffin-embedded samples). The results indicated that the genotyping accuracy of all loci included in this panel remained at 100% for samples with 0.1 ng of DNA input and severe degradation. Sensitivity experiments revealed that at a DNA input of only 31.25 pg, the locus detection rate reached 100%, with genotype accuracy of 92.5%. Based on population data analysis, the total discrimination power of this system reached 1-5.513 × 10-143. Furthermore, we included forensic case samples encompassing semen, saliva, menstrual blood, 10-year-old bloodstain cards, and 12-year-old bloodstain cards in the validation studies. The results demonstrated 100% genotyping accuracy across all sample types. Additional, validation data confirmed the system's species specificity (Homo sapiens-specific) and tolerance to inhibitors including humic acid, heme, ethylene diamine tetraacetic acid and indigo (up to 200 µM). In conclusion, this system can serve as a novel tool for the analysis of degraded samples in forensic work.","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":" ","pages":"1181-1198"},"PeriodicalIF":3.4,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145377214","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

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