Human Mutation最新文献

{"title":"Clinical, Pathologic, and Genetic Spectrum of Collagen VI–Related Disorder in China—A Retrospective Observational Multicenter Study","authors":"Chaoping Hu,&nbsp;Yiyun Shi,&nbsp;Lei Zhao,&nbsp;Wenhua Zhu,&nbsp;Kexin Jiao,&nbsp;Lifei Yu,&nbsp;Xihua Li,&nbsp;Yi Wang","doi":"10.1155/2024/3503253","DOIUrl":"https://doi.org/10.1155/2024/3503253","url":null,"abstract":"<p><b>Background</b>: Collagen VI-related disorder (COLVI-RD) is one of the most common congenital muscular dystrophies. However, data is limited in China.</p><p><b>Methods</b>: We conducted a retrospective study at two tertiary centers. Clinical presentations, lab findings (including serum creatine kinase levels), muscle biopsy, and molecular test results for patients diagnosed with definite COLVI-RD were collected.</p><p><b>Results</b>: A total of 82 patients were enrolled in the study, including 4 with early–severe Ullrich congenital muscular dystrophy (E–S UCMD) (4.8%), 45 with moderate–progressive Ullrich congenital muscular dystrophy (M–P UCMD, 54.9%), 19 with mild UCMD (23.2%), and 14 with Bethlem myopathy (BM, 17.1%). Feeding difficulty, DDH, and neurogenic damage were more common in E–S and M–P UCMD, while contracture of distal joints, atrophic scars, and hyperkeratosis was more prominent in mild UCMD and BM. Seventy patients harbored 64 pathogenic mutations in COLVI-related genes: 28 patients in COL6A1 gene, 25 patients in the COL6A2 gene, and 17 patients in the COL6A3 gene, among which 33 mutations were novel. Missense and splicing mutations were predominant for COL6A1 and COL6A3 genes, which were mostly located in N-terminus of THD, in a dominant pattern, while mutations in the COL6A2 gene were much more polymorphic, which spread throughout the whole length of the gene, in a dominant or recessive pattern. Immunofluorescence dual labeling of Collagen VI/IV in 44 patients showed complete deficiency of Collagen VI in 10 patients (22.7%), sarcolemma-specific Collagen VI deficiency in 25 patients (56.8%), and normal Collagen VI staining in 9 patients (20.5%).</p><p><b>Conclusion</b>: Our study reported the largest cohort of COLVI-RD in China, which showed M–P UCMD was the most common phenotype, followed by mild UCMD and BM. We identified 30 novel mutations and expanded the genetic spectrum. Missense and splicing mutations were predominant for COL6A1 and COL6A3 genes, while mutations in the COL6A2 gene were much more polymorphic. For severe phenotypes, most mutations are sporadic, while some are AD or recessive inherited. For milder phenotypes, sporadic and AD inherited were both common, while only 1 patient with recessive mutations was observed.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2024 1","pages":""},"PeriodicalIF":3.3,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/2024/3503253","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142435434","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genotype/Phenotype Relationship: Lessons From 137 Patients With PMM2-CDG","authors":"Sander Pajusalu,&nbsp;Mari-Anne Vals,&nbsp;Mercedes Serrano,&nbsp;Peter Witters,&nbsp;Anna Cechova,&nbsp;Tomáš Honzik,&nbsp;Andrew C. Edmondson,&nbsp;Can Ficicioglu,&nbsp;Rita Barone,&nbsp;Pascale De Lonlay,&nbsp;Claire-Marine Bérat,&nbsp;Sandrine Vuillaumier-Barrot,&nbsp;Christina Lam,&nbsp;Marc C. Patterson,&nbsp;Mirian C. H. Janssen,&nbsp;Esmeralda Martins,&nbsp;Dulce Quelhas,&nbsp;Jolanta Sykut-Cegielska,&nbsp;Jehan Mousa,&nbsp;Roser Urreizti,&nbsp;Peter McWilliams,&nbsp;Frederique Vernhes,&nbsp;Horacio Plotkin,&nbsp;Eva Morava,&nbsp;Katrin Õunap","doi":"10.1155/2024/8813121","DOIUrl":"https://doi.org/10.1155/2024/8813121","url":null,"abstract":"<p>We report on the largest single dataset of patients with PMM2-CDG enrolled in an ongoing international, multicenter natural history study collecting genetic, clinical, and biological information to evaluate similarities with previous studies, report on novel findings, and, additionally, examine potential genotype/phenotype correlations. A total of 137 participants had complete genotype information, representing 60 unique variants, of which the most common were found to be p.Arg141His in 58.4% (<i>n</i> = 80) of participants, followed by p.Pro113Leu (21.2%, <i>n</i> = 29), and p.Phe119Leu (12.4%, <i>n</i> = 17), consistent with previous studies. Interestingly, six new variants were reported, comprised of five missense variants (p.Pro20Leu, p.Tyr64Ser, p.Phe68Cys, p.Tyr76His, and p.Arg238His) and one frameshift (c.696del p.Ala233Argfs∗100). Patient phenotypes were characterized via the Nijmegen Progression CDG Rating Scale (NPCRS), together with biochemical parameters, the most consistently dysregulated of which were coagulation factors, specifically antithrombin (below normal in 79.5%, 93 of 117), in addition to Factor XI and protein C activity. Patient genotypes were classified based upon the predicted pathogenetic mechanism of disease-associated mutations, of which most were found in the catalysis/activation, folding, or dimerization regions of the PMM2 enzyme. Two different approaches were used to uncover genotype/phenotype relationships. The first characterized genotype only by the predicted pathogenic mechanisms and uncovered associated changes in biochemical parameters, not apparent using only NPCRS, involving catalysis/activation, dimerization, folding, and no protein variants. The second approach characterized genotype by the predicted pathogenic mechanism and/or individual variants when paired with a subset of severe nonfunctioning variants and uncovered correlations with both NPCRS and biochemical parameters, demonstrating that p.Cys241Ser was associated with milder disease, while p.Val231Met, dimerization, and folding variants with more severe disease. Although determining comprehensive genotype/phenotype relationships has previously proven challenging for PMM2-CDG, the larger sample size, plus inclusion of biochemical parameters in the current study, has provided new insights into the interplay of genetics with disease.</p><p><b>Trial Registration:</b>NCT03173300.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2024 1","pages":""},"PeriodicalIF":3.3,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/2024/8813121","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142429225","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Phenotype Correlations With Pathogenic DNA Variants in the MUTYH Gene: A Review of Over 2000 Cases","authors":"Monica Thet,&nbsp;John-Paul Plazzer,&nbsp;Gabriel Capella,&nbsp;Andrew Latchford,&nbsp;Emily A. W. Nadeau,&nbsp;Marc S. Greenblatt,&nbsp;Finlay Macrae","doi":"10.1155/2024/8520275","DOIUrl":"https://doi.org/10.1155/2024/8520275","url":null,"abstract":"<p><i>MUTYH</i>-associated polyposis (MAP) is an autosomal recessive disorder where the inheritance of constitutional biallelic pathogenic <i>MUTYH</i> variants predisposes a person to the development of adenomas and colorectal cancer (CRC). It is also associated with extracolonic and extraintestinal manifestations that may overlap with the phenotype of familial adenomatous polyposis (FAP). Currently, there are discrepancies in the literature regarding whether certain phenotypes are truly associated with MAP. This narrative review is aimed at exploring the phenotypic spectrum of MAP to better characterize the MAP phenotype. Literature search was conducted to identify articles reporting on MAP-specific phenotypes. Clinical data from 2109 MAP patients identified from the literature showed that 1123 patients (53.2%) had CRC. Some patients with CRC had no associated adenomas, suggesting that adenomas are not an obligatory component of MAP. Carriers of the two missense founder variants, and possibly truncating variants, had an increased cancer risk when compared to those who carry other pathogenic variants. It has been suggested that somatic G:C &gt; T:A transversions are a mutational signature of MAP and could be used as a biomarker in screening and identifying patients with atypical MAP, or in associating certain phenotypes with MAP. The extracolonic and extraintestinal manifestations that have been associated with MAP include duodenal adenomas, duodenal cancer, fundic gland polyps, gastric cancer, ovarian cancer, bladder cancer, and skin cancer. The association of breast cancer and endometrial cancer with MAP remains disputed. Desmoid tumors and congenital hypertrophy of the retinal pigment epithelium (CHRPEs) are rarely reported in MAP but have long been seen in FAP patients and thus could act as a distinguishing feature between the two. This collection of MAP phenotypes will assist in the assessment of pathogenic <i>MUTYH</i> variants using the American College of Medical Genetics and the Association for Molecular Pathology (ACMG/AMP) Variant Interpretation Guidelines and ultimately improve patient care.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2024 1","pages":""},"PeriodicalIF":3.3,"publicationDate":"2024-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/2024/8520275","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142328560","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Long-Read Sequencing Identified a PKD1 Gene Conversion in ADPKD Rather Than the False-Positive Exon Deletion Indicated by WES and MLPA","authors":"Xueping Qiu,&nbsp;Xin Jin,&nbsp;Jin Li,&nbsp;Yuanzhen Zhang,&nbsp;Jianhong Ma,&nbsp;Fang Zheng","doi":"10.1155/2024/7225526","DOIUrl":"https://doi.org/10.1155/2024/7225526","url":null,"abstract":"<p>Whole exome sequencing (WES) has become an increasingly common technique for identifying the genetic cause of Mendelian genetic diseases. However, it may fail to detect the complex regions of the genome. Here, we investigated the genetic etiology of a pedigree with autosomal dominant polycystic kidney disease (ADPKD) using a combination of WES, multiplex ligation-dependent probe amplification (MLPA), Sanger sequencing, and long-read sequencing (LRS). Initially, WES of the proband revealed a heterozygous variant c.7391G&gt;C in <i>PKD1</i> Exon 18, along with a heterozygous deletion of the 17th and 18th exons of <i>PKD1</i> detected by exome-based copy number variation (CNV) analysis. MLPA confirmed the <i>PKD1</i> heterozygous deletion of Exon 18. Except for c.7391G&gt;C, Sanger sequencing identified four other heterozygous variants (c.7278T&gt;C, c.7288C&gt;T, c.7344C&gt;G, and c.7365C&gt;T) in Exon 18 of <i>PKD1</i>. Subsequently, LRS uncovered seven clustered substitution variants (c.7209+28C&gt;T, c.7210-16C&gt;T, c.7278T&gt;C, c.7288C&gt;T, c.7344C&gt;G, c.7365C&gt;T, and c.7391G&gt;C), with six of them omitted by WES due to interference from <i>PKD1</i> pseudogenes. Combining LRS results with cosegregation of the pedigree analysis, we found these variants were in <i>cis</i> and converted from <i>PKD1</i> pseudogenes, covering a region of at least 282 bp. Notably, the paralogous sequence variants of c.7288C&gt;T introduced a premature stop codon of <i>PKD1</i>, leading to a function loss, and were classified as pathogenic (PVS1+PS4+PM2) according to the ACMG/AMP guideline. Our study highlights the limitations of WES/MLPA and the importance of utilizing complementary tools like LRS for comprehensive variant detection in <i>PKD1</i>.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2024 1","pages":""},"PeriodicalIF":3.3,"publicationDate":"2024-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/2024/7225526","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142275040","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Constitutional BRCA1 Epimutations: A Key for Understanding Basal-Like Breast and High-Grade Serous Ovarian Cancer","authors":"Per E. Lønning,&nbsp;Oleksii Nikolaienko,&nbsp;Stian Knappskog","doi":"10.1155/2024/7353984","DOIUrl":"https://doi.org/10.1155/2024/7353984","url":null,"abstract":"<p>Germline pathogenic genetic variants in the <i>BRCA1</i> and <i>BRCA2</i> genes are the most frequent causes of familial breast and ovarian cancer. Contrasting <i>BRCA2,</i> epimutations in the <i>BRCA1</i> gene are frequently detected in tissue from triple-negative breast (TNBC) and high-grade serous ovarian cancers (HGSOC). While studies over the last decade have reported <i>BRCA1</i> epimutations in white blood cells (WBC) from breast and ovarian cancer patients, the potential hazard ratio for incident TNBC and HGSOC was not formally assessed until recently.</p><p>Conducting a prospective nested case-control study on women participating in the American Women’s Health Initiative Study, we provided firm evidence that mosaic WBC <i>BRCA1</i> epimutations, even at allele frequencies &lt; 0.1%, are associated with a significantly increased risk of both incident HGSOC and TNBC &gt; 5 years after WBC collection. In a second study assessing <i>BRCA1</i> epimutations in WBC and matched tumor samples from TNBC, our results indicated such epimutations to be the underlying cause of around 20% of TNBC, far exceeding the percentage of cases carrying <i>BRCA1</i> germline pathogenic genetic variants.</p><p>We detected primary constitutional <i>BRCA1</i> epimutations in tissues derived from all three germ layers. They occur independently of <i>BRCA1</i> promoter haplotypes but are present on the same allele in all WBC within affected individuals. Moreover, epimutations are consistently found on the same allele in normal and tumor breast tissue as well as in WBC. This finding, together with <i>BRCA1</i> epimutations detected in WBC from newborns, strongly indicates an early embryonic event with clonal expansion affecting all germ layers.</p><p>Future work in the field must lead to an understanding of exactly when and how the <i>BRCA1</i> epimutations occur and, most importantly, whether primary constitutional epimutations in genes other than <i>BRCA1</i> may cause an elevated risk of other cancer types.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2024 1","pages":""},"PeriodicalIF":3.3,"publicationDate":"2024-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/2024/7353984","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142234019","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical and Genetic Characteristics of Two Cases With Developmental and Epileptic Encephalopathy 93 Caused by Novel ATP6V1A Mutations and Literature Review","authors":"Jian Ma,&nbsp;Hongwei Zhang,&nbsp;Yuqiang Lv,&nbsp;Min Gao,&nbsp;Zhongtao Gai,&nbsp;Yi Liu","doi":"10.1155/2024/4678670","DOIUrl":"https://doi.org/10.1155/2024/4678670","url":null,"abstract":"<p>Developmental and epileptic encephalopathy 93 (DEE93) is a new defined autosomal dominant neurologic disorder caused by heterozygous mutations in the <i>ATP6V1A</i> gene on chromosome 3q13. DEE93 is characterized by developmental delay, early-onset refractory seizures, hypotonia, and intellectual disability. So far, merely 31 cases caused by <i>ATP6V1A</i> gene mutation have been reported in literature worldwide, and early genetic detection is required for differential diagnosis. Here, we analyze the clinical and genetic features of two patients with two novel <i>ATP6V1A</i> mutations (c.1061G&gt;T/p.(Trp354Leu) and c.746C&gt;T/p.(Pro249Leu)) and expound the therapeutic schedule for epilepsy. We also review the reported mutations and genotypes associated with the disorder. Our study expands the clinical and genetic spectrum of <i>ATP6V1A</i> mutation-associated DEE93, which provides a basis for the diagnosis, treatment, and genetic counseling of the disorder.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2024 1","pages":""},"PeriodicalIF":3.3,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/2024/4678670","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142100469","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Estimating the Prevalence of GNE Myopathy Using Population Genetic Databases","authors":"Alexa Derksen,&nbsp;Rachel Thompson,&nbsp;Madeeha Shaikh,&nbsp;Sally Spendiff,&nbsp;Theodore J. Perkins,&nbsp;Hanns Lochmüller","doi":"10.1155/2024/7377504","DOIUrl":"https://doi.org/10.1155/2024/7377504","url":null,"abstract":"<p>GNE myopathy (GNEM) is a rare autosomal recessive disorder characterized by progressive skeletal muscle wasting starting in early adulthood. The prevalence of GNEM is estimated to range between one and nine cases per million individuals, but the accuracy of these estimates is limited by underdiagnosis, misdiagnosis, and bias introduced by founder allele frequencies. As GNEM is a recessive disorder, unaffected carriers of single damaging variants can be expected to be found in the healthy population, providing an alternative method for estimating prevalence. We aim to estimate the prevalence of GNEM using allele frequencies obtained from healthy population genetic databases. We performed a review to establish a complete list of all known pathogenic GNEM variants from both literature and variant databases. We then developed standardized filtering steps using in silico tools to predict the pathogenicity of unreported <i>GNE</i> variants of uncertain clinical significance and validated our pathogenicity inferences using Mendelian Approach to Variant Effect pRedICtion built in Keras (MAVERICK) and AlphaMissense. We calculated conservative and liberal disease prevalence estimates using allele frequencies from the Genome Aggregation Database (gnomAD) population database by employing methodologies based on the assumptions of the Hardy–Weinberg Equilibrium. We additionally calculated estimates for disease prevalence removing the contribution of unique variant combinations that either do not cause myopathy in humans or result in embryonic lethality. We present the most comprehensive list of reported pathogenic <i>GNE</i> variants to date, together with additional variants predicted as pathogenic by in silico methods. We provide additional pathogenicity scores for these variants using new pathogenicity prediction tools and present a set of estimates for GNEM prevalence based on the different assumptions. Our most conservative estimate suggested a prevalence of 18.46 cases per million, while our most liberal estimate places the prevalence at 95.42 cases per million. When accounting for variant severity, this range drops to 11.00–87.68 cases per million. Our findings indicate that the true global prevalence of GNEM is greater than previous predictions underscoring that this condition is considerably more widespread than previously believed.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2024 1","pages":""},"PeriodicalIF":3.3,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/2024/7377504","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142099980","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genome Sequencing Unveils the Role of Copy Number Variants in Hearing Loss and Identifies Novel Deletions With Founder Effect in the DFNB1 Locus","authors":"Zibin Lin,&nbsp;Jiale Xiang,&nbsp;Xiangzhong Sun,&nbsp;Nana Song,&nbsp;Xiaozhou Liu,&nbsp;Qinming Cai,&nbsp;Jing Yang,&nbsp;Haodong Ye,&nbsp;Jiangfan Xu,&nbsp;Hongfu Zhang,&nbsp;Jiguang Peng,&nbsp;Yu Sun,&nbsp;Zhiyu Peng","doi":"10.1155/2024/9517114","DOIUrl":"https://doi.org/10.1155/2024/9517114","url":null,"abstract":"<p>Sensorineural hearing loss is a prevalent disorder with significant genetic involvement, which is often challenging to diagnose due to genetic heterogeneity. Exome sequencing (ES) has been a standard diagnostic tool for sensorineural hearing loss, but its limitations in detecting copy number variants (CNVs) and intronic variants have prompted the exploration of genome sequencing (GS) for improved diagnostic yield. We conducted GS on 46 hearing loss families with previously negative ES results and an additional cohort of 36 patients with a monoallelic pathogenic variant in <i>GJB2</i> (the most common deafness gene). Additionally, the impact of a previously unrecognized novel 125-kb deletion in the DFNB1 locus on <i>GJB2</i> expression was assessed using quantitative polymerase chain reaction (qPCR), and haplotype analysis was performed to characterize the deletion. GS diagnosed eight cases (17%, 8/46) in the ES-negative cohort, primarily attributed to CNVs (6/8). Notably, a previously unrecognized 125 kb deletion in the DFNB1 region was identified, affecting <i>GJB2</i> expression and characterizing it as a founder effect in East Asian. In 47 patients with a monoallelic <i>GJB2</i> variant, 15% (95% CI, 7.4%–28%) were diagnosed with DFNB1 deletions. Analysis of the gnomAD database revealed the prevalence and ethnic diversity of DFNB1 deletions, with the novel 125 kb deletion emerging as a prominent pathogenic variant in East Asian, non-Finnish European, and admixed American populations. Our study highlights the utility of GS in diagnosing sensorineural hearing loss. The identification of DFNB1 deletions underscores their significant contribution to hearing loss etiology, advocating for their inclusion in routine diagnostic testing. We propose GS as a primary genetic testing approach for patients with hearing loss, offering comprehensive genomic analysis and the potential for improved diagnostic accuracy.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2024 1","pages":""},"PeriodicalIF":3.3,"publicationDate":"2024-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/2024/9517114","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141966985","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel Pathogenic Variants in POLR3K Cause POLR3-Related Leukodystrophy","authors":"Stefanie Perrier,&nbsp;Julia Macintosh,&nbsp;Agata D. Misiaszek,&nbsp;Gabrielle Lambert,&nbsp;Kether Guerrero,&nbsp;Luan T. Tran,&nbsp;Christoph W. Müller,&nbsp;Tomi Pastinen,&nbsp;Gustavo H. B. Maegawa,&nbsp;Isabelle Thiffault,&nbsp;Geneviève Bernard","doi":"10.1155/2024/8807171","DOIUrl":"https://doi.org/10.1155/2024/8807171","url":null,"abstract":"<p>POLR3-related hypomyelinating leukodystrophy (POLR3-HLD) is a rare inherited neurological disorder caused by biallelic pathogenic variants in specific genes encoding subunits of RNA polymerase III (Pol III). Here, we report the third patient worldwide with pathogenic variants in <i>POLR3K</i> and clinical features consistent with POLR3-HLD. The female patient presented with mild intellectual and behavioural disturbances in childhood, as well as growth delay, with brain MRI revealing diffuse hypomyelination and a pattern consistent with POLR3-HLD. In adolescence, she manifested minor motor dysfunction. Next-generation sequencing revealed a paternally inherited missense variant in <i>POLR3K</i> (c.322G&gt;T; p.D108Y) and a maternally inherited large deletion, spanning approximately 17.8 kb from chr16:30,362-48,162. The missense variant is located at the C-terminus position of the protein and is predicted to impair residue interactions and cause steric interference in enzyme conformational changes. The large deletion encompasses the third and last exon of <i>POLR3K</i>, leading to a likely amorphic truncated protein product lacking the final 42 amino acids from the total 108 amino acid–length protein. Studies of RNA-level expression showed a significant reduction in the levels of <i>POLR3K</i> RNA in the patient compared to the control. In considering whether the transcriptional function of Pol III was affected, the expression of several Pol III-transcribed RNAs was measured, where the levels of several distinct tRNAs were significantly reduced in the patient while the expression of other RNA transcripts was not decreased, suggesting that Pol III retains partial function. This study provides further evidence for the association of pathogenic variants in <i>POLR3K</i> with POLR3-HLD, expanding the spectrum of pathogenic variants in genes encoding for Pol III subunits associated with this disease.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2024 1","pages":""},"PeriodicalIF":3.3,"publicationDate":"2024-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/2024/8807171","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141968403","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Application of Targeted Y-Chromosomal Capture Enrichment to Increase the Resolution of Native American Haplogroup Q","authors":"Zehra Köksal,&nbsp;Claus Børsting,&nbsp;Graciela Bailliet,&nbsp;Germán Burgos,&nbsp;Elizeu Carvalho,&nbsp;Andrea Casas-Vargas,&nbsp;Adriana Castillo,&nbsp;Marilia Brito Gomes,&nbsp;Beatriz Martínez,&nbsp;Humberto Ossa,&nbsp;María Laura Parolin,&nbsp;Alfredo Quiroz,&nbsp;Ulises Toscanini,&nbsp;William Usaquén,&nbsp;Irina F. Velázquez,&nbsp;Carlos Vullo,&nbsp;Leonor Gusmão,&nbsp;Vania Pereira","doi":"10.1155/2024/3046495","DOIUrl":"https://doi.org/10.1155/2024/3046495","url":null,"abstract":"<p>Y-chromosomal haplogroups and the Y-SNPs defining them are relevant for the exploration of male lineages, inference of paternal ancestry, and reconstruction of migration pathways, to name a few. Currently, over 300,000 Y-SNPs have been reported, defining 20 main haplogroups. However, ascertainment bias in the investigations has led to some haplogroups being overlooked, which hinders a representative depiction of certain populations and their migration events. For migration pattern analyses of the first settlers of the Americas, the Native American main founding lineage Q-M3 needs to be further investigated to allow clear genetic differentiation of individuals of different ethnogeographic origins. To increase the resolution within this haplogroup, a total of 7.45 Mb of the Y chromosome of 59 admixed South Americans of haplogroup Q was targeted for sequencing using hybridization capture enrichment. Data were combined with 218 publicly available sequences of Central and South Americans of haplogroup Q. After rigorous data processing, variants not meeting the quality criteria were excluded and 4128 reliable Y-SNPs were reported. A total of 2224 Y-SNPs had previously unknown positions in the phylogenetic tree, and 1291 of these are novel. The phylogenetic relationships between the Y-SNPs were established using the software SNPtotree in order to report a redesigned phylogenetic tree containing 300 branches, defined by 3400 Y-SNPs. The new tree introduces 117 previously undescribed branches and is the most comprehensive phylogenetic tree of the Native American haplogroup Q lineages to date. The 214 sequences were assigned to 135 different low- to high-resolution branches, while in the previous phylogenetic tree, only 195 sequences could be sorted into 14 low-resolution branches with the same quality criteria. The improved genetic differentiation of subhaplogroup Q-M3 has a great potential to resolve migration patterns of Native Americans.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2024 1","pages":""},"PeriodicalIF":3.3,"publicationDate":"2024-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/2024/3046495","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141967119","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}