Clinical Genetics最新文献_第2页

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":null,"pages":null},"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":null,"pages":null},"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":null,"pages":null},"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":null,"pages":null},"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":null,"pages":null},"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

Hidden Aberrant Transcripts in TTC37 Cause Trichohepatoenteric Syndrome. TTC37 中隐藏的异常转录本会导致三肠管综合征。

IF 2.9 3区医学

Clinical Genetics Pub Date : 2024-10-10 DOI: 10.1111/cge.14630

José Francisco da Silva Franco, Raquel Leão Neves, Alef Nascimento Menezes, Beatriz Ribeiro Nogueira, Caio Perez Gomes, João Bosco Pesquero

引用次数: 0

A Strong Candidate Gene for Nonsyndromic Intellectual Disability Phenotype: SGSM3. 非综合症智障表型的强候选基因：SGSM3。

IF 2.9 3区医学

Clinical Genetics Pub Date : 2024-10-10 DOI: 10.1111/cge.14631

Ayberk Turkyilmaz, Kubra Adanur Saglam, Mustafa Yilmaz, Alper Han Cebi

引用次数: 0

Chromosome 8p Syndromes Clinical Presentation and Management Guidelines. 染色体 8p 综合征临床表现和处理指南。

IF 2.9 3区医学

Clinical Genetics Pub Date : 2024-10-10 DOI: 10.1111/cge.14626

Kourtney Santucci, Kristina E Malik, Katie Angione, Dana Bennink, Andrea Gerk, Drew Mancini, Megan Stringfellow, Tristen Dinkel, Scott Demarest, Andrea S Miele, Margarita Saenz

引用次数: 0

A Novel Homozygous Missense ZP1 Variant Result in Human Female Empty Follicle Syndrome. 导致人类女性空卵泡综合征的新型同卵缺义 ZP1 变异基因

IF 2.9 3区医学

Clinical Genetics Pub Date : 2024-10-08 DOI: 10.1111/cge.14624

Pei He, Siping Liu, Xiao Shi, Chuyu Huang, Wenfeng Li, Jiamin Wu, Huixi Li, Junting Liu, Yuyuan Wen, Weiqing Zhang, Zhuolin Qiu, Chen Luo, Rui Hua

{"title":"A Novel Homozygous Missense ZP1 Variant Result in Human Female Empty Follicle Syndrome.","authors":"Pei He, Siping Liu, Xiao Shi, Chuyu Huang, Wenfeng Li, Jiamin Wu, Huixi Li, Junting Liu, Yuyuan Wen, Weiqing Zhang, Zhuolin Qiu, Chen Luo, Rui Hua","doi":"10.1111/cge.14624","DOIUrl":"https://doi.org/10.1111/cge.14624","url":null,"abstract":"Empty follicle syndrome (EFS) is a disorder characterised by the unsuccessful retrieval of oocytes from matured follicles following ovarian stimulation for in vitro fertilisation (IVF). Genetic factors significantly contribute to this pathology. To date, an increasing number of genetic mutations associated with GEFS have been documented, however, some cases still remain unexplained by these previously reported mutations. Here, we identified a novel homozygous missense ZP1 variant (c.1096 C > T, p.Arg366Trp) in a female patient with GEFS from a consanguineous family who failed to retrieve any oocytes during two cycles of IVF treatment. We conducted a molecular dynamics simulation analysis on the mutant ZP1 model, revealing that the mutant ZP1 protein has an altered 3D structure, lower fluctuation, higher compactness and higher instability than wild-type ZP1. Immunostaining, immunoblotting and co-immunoprecipitation results showed that the homozygous missense mutation in ZP1 impaired protein secretion and weakened interactions between ZP1 and other ZP proteins, which may affect the ZP assembly. This study contributes to a more comprehensive understanding of the genetic aetiopathogenesis of GEFS.","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":null,"pages":null},"PeriodicalIF":2.9,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142388535","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

Consolidating the Role of Mutated ATP2B2 in Neurodevelopmental and Cerebellar Pathologies. 巩固突变 ATP2B2 在神经发育和小脑疾病中的作用

IF 2.9 3区医学

Clinical Genetics Pub Date : 2024-10-05 DOI: 10.1111/cge.14622

Antonia M Stehr, Jerica Lenberg, Jennifer Friedman, Dries Dobbelaere, Apolline Imbard, Jonathan Levy, Sarah Donoghue, Nicolas Derive, Radka Stoeva, Paul Gueguen, Michael Zech

{"title":"Consolidating the Role of Mutated ATP2B2 in Neurodevelopmental and Cerebellar Pathologies.","authors":"Antonia M Stehr, Jerica Lenberg, Jennifer Friedman, Dries Dobbelaere, Apolline Imbard, Jonathan Levy, Sarah Donoghue, Nicolas Derive, Radka Stoeva, Paul Gueguen, Michael Zech","doi":"10.1111/cge.14622","DOIUrl":"10.1111/cge.14622","url":null,"abstract":"Plasma membrane calcium ATPases (PMCAs) encoded by ATP2B genes have been implicated in Mendelian diseases with ataxia, dystonia, and intellectual disability. Work to date has shown that ATP2B2 (encoding PMCA2) is required for synaptic function and Purkinje-cell integrity in the cerebellum. A recent case series has linked ATP2B2 to a novel entity, characterized by neurodevelopmental and movement phenotypes, in only seven individuals. We called for collaboration to collect five unpublished families affected by the new rare ATP2B2-related condition. Exome-/genome sequencing-identified genotypes included four likely pathogenic/pathogenic heterozygous de novo missense variants and one dominantly inherited end-truncating frameshift allele. The six affected individuals shared features with the described patients including developmental delay, cognitive disturbances, epilepsy, autistic traits, and motor disorders. Striking cerebellar atrophy was observed in one affected individual. In association with hearing loss and movement abnormalities, we report a recurrent p.(Glu457Lys) substitution, previously documented in a neurologically impaired ATP2B2 mouse mutant. Our study further delineates the mutational spectrum and presentation of a human syndrome caused by ATP2B2 variants, confirming the importance of PMCA2 in neurotypical and cerebellar development.","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":null,"pages":null},"PeriodicalIF":2.9,"publicationDate":"2024-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142379173","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