Clinical Genetics最新文献_第3页

Utility of Optical Genome Mapping in Repeat Disorders. 光学基因组图谱在重复性疾病中的应用。

IF 2.9 3区医学

Clinical Genetics Pub Date : 2024-10-22 DOI: 10.1111/cge.14633

Mehmet Burak Mutlu, Taner Karakaya, Hamide Betül Gerik Çelebi, Fahrettin Duymuş, Serhat Seyhan, Sanem Yılmaz, Uluç Yiş, Tahir Atik, Mehmet Fatih Yetkin, Hakan Gümüş

{"title":"Utility of Optical Genome Mapping in Repeat Disorders.","authors":"Mehmet Burak Mutlu, Taner Karakaya, Hamide Betül Gerik Çelebi, Fahrettin Duymuş, Serhat Seyhan, Sanem Yılmaz, Uluç Yiş, Tahir Atik, Mehmet Fatih Yetkin, Hakan Gümüş","doi":"10.1111/cge.14633","DOIUrl":"10.1111/cge.14633","url":null,"abstract":"Genomic repeat sequences are patterns of nucleic acids that exist in multiple copies throughout the genome. More than 60 Mendelian disorders are caused by the expansion or contraction of these repeats. Various specific methods for determining tandem repeat variations have been developed. However, these methods are highly specific to the genomic region being studied and sometimes require specialized tools. In this study, we have investigated the use of Optical Genome Mapping (OGM) as a diagnostic tool for detecting repeat disorders. We evaluated 19 patients with a prediagnosis of repeat disorders and explained the molecular etiology of 9 of them with OGM (5 patients with Facioscapulohumeral Muscular Dystrophy (FSHD), 2 patients with Friedreich's Ataxia (FA), 1 patient with Fragile X Syndrome (FXS), and 1 patient with Progressive Myoclonic Epilepsy 1A (EPM1A)). We confirmed OGM results with more widely used fragment analysis techniques. This study highlights the utility of OGM as a diagnostic tool for repeat expansion and contraction diseases such as FA, FXS, EPM1A, and FSHD.","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142459586","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A Novel PTPRQ c.3697del Variant Causes Autosomal Dominant Progressive Hearing Loss in Both Humans and Mice. 新型 PTPRQ c.3697del 变体导致人类和小鼠常染色体显性进行性听力损失。

IF 2.9 3区医学

Clinical Genetics Pub Date : 2024-10-21 DOI: 10.1111/cge.14634

Yaqi Zhou, Na Yin, Lingchao Ji, Xiaochan Lu, Weiqiang Yang, Weiping Ye, Wenhui Du, Ya Li, Hongyi Hu, Xueshuang Mei

{"title":"A Novel PTPRQ c.3697del Variant Causes Autosomal Dominant Progressive Hearing Loss in Both Humans and Mice.","authors":"Yaqi Zhou, Na Yin, Lingchao Ji, Xiaochan Lu, Weiqiang Yang, Weiping Ye, Wenhui Du, Ya Li, Hongyi Hu, Xueshuang Mei","doi":"10.1111/cge.14634","DOIUrl":"https://doi.org/10.1111/cge.14634","url":null,"abstract":"PTPRQ plays an important role in the development of inner ear hair cell stereocilia. While many autosomal recessive variants in PTPRQ have been identified as the pathogenic cause for nonsyndromic hearing loss (DFNB84A), so far only one autosomal dominant PTPRQ variant, c.6881G>A (p.Trp2294*), has been reported for late-onset, mild-to-severe hearing loss (DFNA73). By using targeted next-generation sequencing, this study identified a novel PTPRQ truncating pathogenic variant, c.3697del (p.Leu1233Phefs*11), from a Chinese Han family that co-segregated with autosomal dominant, postlingual, progressive hearing loss. A Ptprq-3700del knock-in mouse model was generated by CRISPR-Cas9 and characterized for its hearing function and inner ear morphology. While the homozygous knock-in mice exhibit profound hearing loss at all frequencies at the age of 3 weeks, the heterozygous mutant mice resemble the human patients in mild, progressive hearing loss from age 3 to 12 weeks, primarily affecting high frequencies. At this stage, the homozygous knock-in mice have a normal hair cell count but disorganized stereocilia. Cochlear proteosome analysis of the homozygous mutant mice revealed differentially expressed genes and pathways involved in oxidative phosphorylation, regulation of angiogenesis and synaptic vesicle cycling. Our study provides a valuable animal model for further functional studies of the pathogenic mechanisms underlying DFNA73.","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142459563","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Modified Rules for Classification of Variants Associated With Disorders of Somatic Mosaicism. 体细胞嵌合紊乱相关变异分类的修正规则

IF 2.9 3区医学

Clinical Genetics Pub Date : 2024-10-21 DOI: 10.1111/cge.14636

Fernando Zazueta Leon-Quintero, Kevin M Bowling, Alexa Dickson, Meagan M Corliss, Molly C Schroeder, Julie A Neidich, Jonathan W Heusel, Kilannin Krysiak, Katarzyna Polonis, Bijal A Parikh, Yang Cao

{"title":"Modified Rules for Classification of Variants Associated With Disorders of Somatic Mosaicism.","authors":"Fernando Zazueta Leon-Quintero, Kevin M Bowling, Alexa Dickson, Meagan M Corliss, Molly C Schroeder, Julie A Neidich, Jonathan W Heusel, Kilannin Krysiak, Katarzyna Polonis, Bijal A Parikh, Yang Cao","doi":"10.1111/cge.14636","DOIUrl":"https://doi.org/10.1111/cge.14636","url":null,"abstract":"Disorders of somatic mosaicism (DoSMs) are rare genetic disorders arising from postzygotic alteration leading to segmental/nonsegmental disease. Current professional guidelines for standardized variant interpretation focus on germline and cancer variants, making them suboptimal for DoSM variant interpretation. The Brain Malformations Variant Curation Expert Panel (BMVCEP) modified existing guidelines to account for brain-specific disorders of somatic mosaicism, but applicability to other DoSM presentations is limited. At Washington University in St. Louis School of Medicine, we have adopted the BMVCEP interpretation framework but suggested alterations that make it more suitable for generalized DoSM variant classification. These modifications include (1) expanding applicability beyond genes associated with brain malformations, (2) introduction of a criterion to interpret truncating variants at the C-terminus of gain of function genes, (3) establishment of a variant allele fraction (VAF) cutoff for applying de novo criteria, and (4) demonstration that in silico prediction tools are relevant to interpretation of gain of function missense variants. Furthermore, modifications to BMVCEP guidelines reduce the number of variants classified as uncertain. The variant classification considerations that we propose have the potential to improve the accuracy of somatic variant classification, better inform clinical care, and may benefit clinical laboratories also conducting DoSM testing.","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142459582","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A Frameshift Variant in ANKRD24 Implicates Its Role in Human Non-Syndromic Hearing Loss. ANKRD24 中的一个帧移位变异暗示了它在人类非突发性听力损失中的作用。

IF 2.9 3区医学

Clinical Genetics Pub Date : 2024-10-21 DOI: 10.1111/cge.14635

Negar Kazemi, Raziye Rezvani Rezvandeh, Farzane Zare Ashrafi, Ebrahim Shokouhian, Masoud Edizadeh, Kevin T A Booth, Kimia Kahrizi, Hossein Najmabadi, Marzieh Mohseni

{"title":"A Frameshift Variant in ANKRD24 Implicates Its Role in Human Non-Syndromic Hearing Loss.","authors":"Negar Kazemi, Raziye Rezvani Rezvandeh, Farzane Zare Ashrafi, Ebrahim Shokouhian, Masoud Edizadeh, Kevin T A Booth, Kimia Kahrizi, Hossein Najmabadi, Marzieh Mohseni","doi":"10.1111/cge.14635","DOIUrl":"https://doi.org/10.1111/cge.14635","url":null,"abstract":"Hearing loss (HL) is the most prevalent sensorineural disorders, affecting about one in 1000 newborns. Over half of the cases are attributed to genetic factors; however, due to the extensive clinical and genetic heterogeneity, many cases remain without a conclusive genetic diagnosis. The advent of next-generation sequencing methodologies in recent years has greatly helped unravel the genetic etiology of HL by identifying numerous genes and causative variants. Despite this, much remains to be uncovered about the genetic basis of sensorineural hearing loss (SNHL). Here, we report an Iranian consanguineous family with postlingual, moderate-to-severe autosomal recessive SNHL. After first excluding plausible variants in known deafness-causing genes using whole exome sequencing, we reanalyzed the data, using a gene/variant prioritization pipeline established for novel gene discovery for HL. This approach identified a novel homozygous frameshift variant c.1934_1937del; (p.Thr645Lysfs*52) in ANKRD24, which segregated with the HL phenotype in the family. Recently, ANKRD24 has been shown to be a pivotal constituent of the stereocilia rootlet in cochlea hair cells and interacts with TRIOBP, a protein already implicated in human deafness. Our data implicate for the first time, ANKRD24 in human nonsyndromic HL (NSHL) and expands the genetic spectrum of HL.","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142459562","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

IF 2.9 3区医学

Clinical Genetics Pub Date : 2024-10-21 DOI: 10.1111/cge.14628

Jessica Rosenblum, Diane Beysen, Anna C Jansen, Marjan De Rademaeker, Edwin Reyniers, Katrien Janssens, Marije Meuwissen

引用次数: 0

Biallelic PIGM Coding Variant Causes Intractable Epilepsy and Intellectual Disability Without Thrombotic Events. 双倍拷贝 PIGM 编码变异导致难治性癫痫和智力障碍，但无血栓事件。

IF 2.9 3区医学

Clinical Genetics Pub Date : 2024-10-19 DOI: 10.1111/cge.14629

Gali Heimer, Ben Pode-Shakked, Dina Marek-Yagel, Helly Vernitsky, Michal Tzadok, Ortal Barel, Eran Eyal, Bruria Ben-Zeev, Gil Atzmon, Yair Anikster

{"title":"Biallelic PIGM Coding Variant Causes Intractable Epilepsy and Intellectual Disability Without Thrombotic Events.","authors":"Gali Heimer, Ben Pode-Shakked, Dina Marek-Yagel, Helly Vernitsky, Michal Tzadok, Ortal Barel, Eran Eyal, Bruria Ben-Zeev, Gil Atzmon, Yair Anikster","doi":"10.1111/cge.14629","DOIUrl":"https://doi.org/10.1111/cge.14629","url":null,"abstract":"During the past two decades, an emerging group of genes coding for proteins involved in glycosylphosphatidylinositol (GPI) anchor biosynthesis are being implicated in early-infantile epileptic encephalopathy. Amongst these, a hypomorphic promoter mutation in the mannosyltransferase-encoding PIGM gene was described in seven patients to date, exhibiting intractable absence epilepsy, portal and cerebral vein thrombosis and intellectual disability (ID). We describe here three siblings exhibiting intractable epilepsy and ID, found to harbor a homozygous c.224G>A p.(Arg75His) missense variant in PIGM, which segregated with the disease in the family. The variant is evolutionary conserved, extremely rare in general population databases and predicted to be deleterious. Structural modeling of the PIGM protein and the p.(Arg75His) variant indicates that it is located in a short luminal region of the protein, predicted to be hydrophilic. Functional prediction suggests that the entire local region is sensitive to mutations, with the p.(Arg75His) variant in particular. This is the first report of a PIGM coding variant, and the second variant altogether to be described affecting this gene. This phenotype differs from that of patients with the shared PIGM promoter mutation by lack of thrombotic events and no decrease in PIGM cDNA levels or CD59 expression on red blood cells.","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2024-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142459579","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Exome Sequencing of Consanguineous Pashtun Families With Familial Epilepsy Reveals Causative and Candidate Variants in TSEN54, MOCS2, and OPHN1. 家族性癫痫近亲普什图族的外显子组测序发现 TSEN54、MOCS2 和 OPHN1 的致病变异和候选变异。

IF 2.9 3区医学

Clinical Genetics Pub Date : 2024-10-14 DOI: 10.1111/cge.14627

Afrasiab Khan, Anees Muhammad, Hidayat Ullah, Hina Ambreen, Abeed Ullah, Patrick May, Holger Lerche, Tobias B Haack, Shoaib Ur Rehman, Josua Kegele

{"title":"Exome Sequencing of Consanguineous Pashtun Families With Familial Epilepsy Reveals Causative and Candidate Variants in TSEN54, MOCS2, and OPHN1.","authors":"Afrasiab Khan, Anees Muhammad, Hidayat Ullah, Hina Ambreen, Abeed Ullah, Patrick May, Holger Lerche, Tobias B Haack, Shoaib Ur Rehman, Josua Kegele","doi":"10.1111/cge.14627","DOIUrl":"https://doi.org/10.1111/cge.14627","url":null,"abstract":"Next-generation sequencing is advancing in low- and middle-income countries, but accessibility remains limited. In Pakistan, many members of the Pashtun population practice familial marriage and maintain distinct socio-cultural traditions, isolating them from other ethnic groups. As a result, they may harbor genetic variants that could unveil new gene-disease associations. To investigate the genetic basis of epilepsy in the Pashtun community we recently established a collaboration between Bannu University and the University of Tuebingen. Here we report our first results of exome sequencing of four families with presumed monogenetic epilepsy and Mendelian inheritance pattern. In Family #201, we identified distinct disease-causing variants. One had a homozygous pathogenic missense variant in TSEN54 (c.919G > T, p.(Ala307Ser)), linked to Pontocerebellar Hypoplasia Type 2A. The second individual had a homozygous class IV missense variant in MOCS2 (c.226G > A, p.(Gly76Arg)) which is associated with Molybdenum cofactor deficiency. In family EP02, one affected individual carried a heterozygous class III variant in OPHN1 (c.1490G > A, p.(Arg497Gln)), related to syndromic X-linked intellectual disability with epilepsy. Our small study demonstrates the promise of next-generation sequencing in genetic epilepsies among the Pashtun population. Diagnostic next-generation sequencing should be established in Pakistan as soon as possible, and if not feasible, genetic research projects may pioneer this path.","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142459580","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

ME2 Deficiency Is Associated With Recessive Neurodevelopmental Disorder. ME2缺陷与隐性神经发育障碍有关

IF 2.9 3区医学

Clinical Genetics Pub Date : 2024-10-14 DOI: 10.1111/cge.14632

Naif A M Almontashiri, Essa Alharby, Mohammed Saleh, Mohamed Abu-Farha, Ali Alasmari, Marinella Gebbia, Charlotte Hiesl, Roy W A Peake, Sami Samir Amr, Eckhard Boles, Frederick P Roth, Jehad Abubaker

{"title":"ME2 Deficiency Is Associated With Recessive Neurodevelopmental Disorder.","authors":"Naif A M Almontashiri, Essa Alharby, Mohammed Saleh, Mohamed Abu-Farha, Ali Alasmari, Marinella Gebbia, Charlotte Hiesl, Roy W A Peake, Sami Samir Amr, Eckhard Boles, Frederick P Roth, Jehad Abubaker","doi":"10.1111/cge.14632","DOIUrl":"https://doi.org/10.1111/cge.14632","url":null,"abstract":"Malate is an important dicarboxylic acid produced from fumarate in the tricarboxylic acid cycle. Deficiencies of fumarate hydrolase (FH) and malate dehydrogenase (MDH), responsible for malate formation and metabolism, respectively, are known to cause recessive forms of neurodevelopmental disorders (NDDs). The malic enzyme isoforms, malic enzyme 1 (ME1) and 2 (ME2), are required for the conversion of malate to pyruvate. To date, there have been no reports linking deficiency of either malic enzyme isoforms to any Mendelian disease in humans. We report a patient presenting with NDD, subtle dysmorphic features, resolved dilated cardiomyopathy, and mild blood lactate elevation. Whole exome sequencing (WES) revealed a homozygous frameshift variant (c.1379_1380delTT, p.Phe460fs*22) in the malic enzyme 2 (ME2) gene resulting in truncated and unstable ME2 protein in vitro. Subsequent deletion of the yeast ortholog of human ME2 (hME2) resulted in growth arrest, which was rescued by overexpression of hME2, strongly supporting an important role of ME2 in mitochondrial function. Our results also support the pathogenicity and candidacy of the ME2 gene and variant in association with NDD. To our knowledge, this is the first report of a Mendelian human disease resulting from a biallelic variant in the ME encoding gene. Future studies are warranted to confirm ME2-associated recessive NDD.","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142459581","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The p. S178L mutation in Tbc1d24 disrupts endosome-mediated synaptic vesicle trafficking of cochlear hair cells and leads to hearing impairment in mice. Tbc1d24的p. S178L突变会破坏耳蜗毛细胞内膜介导的突触囊泡贩运，导致小鼠听力受损。

IF 2.9 3区医学

Clinical Genetics Pub Date : 2024-10-14 DOI: 10.1111/cge.14620

Penghui Chen, Shule Hou, Gen Li, Yuzhe Lin, Jiawen Lu, Lei Song, Geng-Lin Li, Xiuhong Pang, Hao Wu, Tao Yang

{"title":"The p. S178L mutation in Tbc1d24 disrupts endosome-mediated synaptic vesicle trafficking of cochlear hair cells and leads to hearing impairment in mice.","authors":"Penghui Chen, Shule Hou, Gen Li, Yuzhe Lin, Jiawen Lu, Lei Song, Geng-Lin Li, Xiuhong Pang, Hao Wu, Tao Yang","doi":"10.1111/cge.14620","DOIUrl":"https://doi.org/10.1111/cge.14620","url":null,"abstract":"The ribbon synapses of cochlear inner hair cells (IHCs) employ efficient vesicle resupply to enable fast and sustained release rates. However, the molecular mechanisms of these physiological activities remain unelucidated. Previous studies showed that the RAB-specific GTPase-activating protein TBC1D24 controls the endosomal trafficking of the synaptic vesicles (SVs) in Drosophila and mammalian neurons, and mutations in TBC1D24 may lead to non-syndromic hearing loss or hearing loss associated with the DOORS syndrome in humans. In this study, we generated a knock-in mouse model for the p. S178L mutation in TBC1D24, which leads to autosomal dominant non-syndromic hearing loss (DFNA65). The p.S178L mutant mice show mild hearing loss and progressively declined wave I amplitude of the auditory brainstem responses. Despite the normal gross and cellular morphology of the cochlea, transmission electron microscopy reveals accumulation of endosome-like vacuoles and a lower-than-normal number of SVs directly associated with the ribbons in the IHCs. Consistently, patch clamp of the IHCs shows reduced exocytosis under prolonged stimulus. ARF6, a TBC1D24-interacting protein also involved in endosomal membrane trafficking, was underexpressed in the cochleae of the mutant mouse and has weakened in vitro interaction with the p.S178L mutant TBC1D24. Our results suggest an important role of TBC1D24 in maintaining endosomal-mediated vesicle recycling and sustained exocytosis of hair cell ribbon synapses.","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142459585","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

PathVar: A Customisable NGS Variant Calling Algorithm Implicates Novel Candidate Genes and Pathways in Hemiplegic Migraine. PathVar：可定制的 NGS 变异调用算法揭示了偏瘫性偏头痛的新型候选基因和通路。

IF 2.9 3区医学

Clinical Genetics Pub Date : 2024-10-12 DOI: 10.1111/cge.14625

Mohammed M Alfayyadh, Neven Maksemous, Heidi G Sutherland, Rodney A Lea, Lyn R Griffiths

{"title":"PathVar: A Customisable NGS Variant Calling Algorithm Implicates Novel Candidate Genes and Pathways in Hemiplegic Migraine.","authors":"Mohammed M Alfayyadh, Neven Maksemous, Heidi G Sutherland, Rodney A Lea, Lyn R Griffiths","doi":"10.1111/cge.14625","DOIUrl":"https://doi.org/10.1111/cge.14625","url":null,"abstract":"The exponential growth of next-generation sequencing (NGS) data requires innovative bioinformatics approaches to unravel the genetic underpinnings of diseases. Hemiplegic migraine (HM), a debilitating neurological disorder with a genetic basis, is one such condition that warrants further investigation. Notably, the genetic heterogeneity of HM is underscored by the fact that approximately two-thirds of patients lack pathogenic variants in the known causal ion channel genes. In this context, we have developed PathVar, a novel bioinformatics algorithm that harnesses publicly available tools and software for pathogenic variant discovery in NGS data. PathVar integrates a suite of tools, including HaplotypeCaller from the Genome Analysis Toolkit (GATK) for variant calling, Variant Effect Predictor (VEP) and ANNOVAR for variant annotation, and TAPES for assigning the American College of Medical Genetics and Genomics (ACMG) pathogenicity labels. Applying PathVar to whole exome sequencing data from 184 HM patients, we detected 648 variants that are probably pathogenic in multiple patients. Moreover, we have identified several candidate genes for HM, many of which cluster around the Rho GTPases pathway. Future research can leverage PathVar to generate high quality, candidate pathogenic variants, which may enhance our understanding of HM and other complex diseases.","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2024-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142459583","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0