Clinical Genetics最新文献_第10页

PERCC1-Related Congenital Enteropathy 与 PERCC1 相关的先天性肠病

IF 2.9 3区医学

Clinical Genetics Pub Date : 2024-10-29 DOI: 10.1111/cge.14638

Lena S. Kerle, Pia Karlsland Åkeson, Thomas Müller, Andreas R. Janecke

引用次数: 0

Recognisable Neuroradiological Findings in Five Neurogenetic Disorders 五种神经遗传性疾病中可识别的神经放射学发现。

IF 2.9 3区医学

Clinical Genetics Pub Date : 2024-10-27 DOI: 10.1111/cge.14637

Jessica Rosenblum, Marije Meuwissen, Anna C. Jansen, Renske Oegema, Nihaal Reddy, Kshitij Mankad, Sniya Sudhakar

{"title":"Recognisable Neuroradiological Findings in Five Neurogenetic Disorders","authors":"Jessica Rosenblum, Marije Meuwissen, Anna C. Jansen, Renske Oegema, Nihaal Reddy, Kshitij Mankad, Sniya Sudhakar","doi":"10.1111/cge.14637","DOIUrl":"10.1111/cge.14637","url":null,"abstract":"<div>\u0000 \u0000 <p>The rate of discovery and increased understanding of genetic causes for neurodevelopmental disorders has peaked over the past decade. It is well recognised that some genes show marked variability in neuroradiological phenotypes, and inversely, some radiological phenotypes are associated with several different genetic conditions. However, some readily recognisable brain magnetic resonance imaging (MRI) patterns, especially in the context of corresponding associated clinical findings, should prompt consideration of a pathogenic variant in a specific gene or gene pathway. As these conditions can often prove challenging to diagnose, a clinical suspicion of a specific disorder may be invaluable to guide and interpret genetic testing. This review focuses on five neurogenetic syndromes with recognisable brain findings that radiologists, paediatric neurologists, geneticists, and other specialists involved in neurodevelopmental disorders should be able to recognise in order to pinpoint the gene or gene groups involved and delve into their molecular mechanisms. The comprehensively reviewed conditions include <i>DDX3X</i>-related neurodevelopmental disorder, Van Maldergem syndrome, NMDAR-related disorders, <i>EML1</i>-associated disorder and <i>ARFGEF2</i>-related periventricular nodular heterotopia with microcephaly.</p>\u0000 </div>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":"107 1","pages":"13-22"},"PeriodicalIF":2.9,"publicationDate":"2024-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142496294","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

Genetic Variants Supporting the Diagnosis of Primary Ciliary Dyskinesia in Japan 日本支持原发性睫状肌运动障碍诊断的基因变异。

IF 2.9 3区医学

Clinical Genetics Pub Date : 2024-10-27 DOI: 10.1111/cge.14640

Minako Hijikata, Kozo Morimoto, Masashi Ito, Keiko Wakabayashi, Akiko Miyabayashi, Hiroyuki Yamada, Naoto Keicho

{"title":"Genetic Variants Supporting the Diagnosis of Primary Ciliary Dyskinesia in Japan","authors":"Minako Hijikata, Kozo Morimoto, Masashi Ito, Keiko Wakabayashi, Akiko Miyabayashi, Hiroyuki Yamada, Naoto Keicho","doi":"10.1111/cge.14640","DOIUrl":"10.1111/cge.14640","url":null,"abstract":"<div>\u0000 \u0000 <p>Primary ciliary dyskinesia (PCD; OMIM 244400) is a rare genetic disorder affecting motile cilia and is characterized by impaired mucociliary clearance in the airway epithelium that leads to chronic oto-sinopulmonary manifestations. To date, over 50 PCD-causing genes have been identified, with these genes and their variants varying globally across populations. We performed targeted resequencing of 42 PCD-causative genes in 150 Japanese patients suspected of having PCD and identified pathogenic or likely pathogenic variants in 51 patients. Among these, 24 patients exhibited a homozygous deletion of <i>DRC1</i> exons 1–4, the most common cause of PCD in Japan. The allele frequency of this deletion was estimated at 0.0034 (95% CI: 0.0025–0.0044), based on bioinformatic analysis of 7906 whole-genome sequences from the general Japanese population. Additionally, RNA sequencing of nasal samples supplemented in silico variant predictions, aiding in the identification of causative variants. Considering potential ethnic differences, it is essential to accumulate global data on these variants and their functional impacts.</p>\u0000 </div>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":"107 2","pages":"219-223"},"PeriodicalIF":2.9,"publicationDate":"2024-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142496292","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

Identification of Two Novel Missense Variants in BNC1 in Han Chinese Patients With Non-syndromic Premature Ovarian Insufficiency 在非综合征性卵巢早衰的中国汉族患者中发现 BNC1 的两个新型错义变异基因

IF 2.9 3区医学

Clinical Genetics Pub Date : 2024-10-27 DOI: 10.1111/cge.14639

Yuncheng Pan, Jitong Mo, Shuting Ren, Yifei Zhang, Feng Zhang, Xiaojin Zhang, Yanhua Wu

引用次数: 0

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":"<div>\u0000 \u0000 <p>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.</p>\u0000 </div>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":"107 2","pages":"188-195"},"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":"10.1111/cge.14634","url":null,"abstract":"<div>\u0000 \u0000 <p>\u0000 <i>PTPRQ</i> plays an important role in the development of inner ear hair cell stereocilia. While many autosomal recessive variants in <i>PTPRQ</i> have been identified as the pathogenic cause for nonsyndromic hearing loss (DFNB84A), so far only one autosomal dominant <i>PTPRQ</i> 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 <i>PTPRQ</i> truncating pathogenic variant, c.3697del (p.Leu1233Phefs*11), from a Chinese Han family that co-segregated with autosomal dominant, postlingual, progressive hearing loss. A <i>Ptprq</i>-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.</p>\u0000 </div>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":"107 2","pages":"208-213"},"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":"10.1111/cge.14636","url":null,"abstract":"<div>\u0000 \u0000 <p>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.</p>\u0000 </div>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":"107 3","pages":"261-270"},"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":"10.1111/cge.14635","url":null,"abstract":"<div>\u0000 \u0000 <p>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 <i>ANKRD24</i>, 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, <i>ANKRD24</i> in human nonsyndromic HL (NSHL) and expands the genetic spectrum of HL.</p>\u0000 </div>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":"107 2","pages":"214-218"},"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

{"title":"RNU4-2-Related Neurodevelopmental Disorder Is Associated With a Recognisable Facial Gestalt","authors":"Jessica Rosenblum, Diane Beysen, Anna C. Jansen, Marjan De Rademaeker, Edwin Reyniers, Katrien Janssens, Marije Meuwissen","doi":"10.1111/cge.14628","DOIUrl":"10.1111/cge.14628","url":null,"abstract":"<div>\u0000 \u0000 <p>De novo heterozygous variants in <i>RNU4-2</i>, a component of the major spliceosome, were recently found to cause a novel neurodevelopmental disorder. Preliminary evidence suggests that this newly discovered syndrome is one of the most common monogenic causes of neurodevelopmental disorders. It is characterised by developmental delay and intellectual disability, microcephaly, short stature and hypotonia. However, much remains to be elucidated regarding the phenotype of the affected individuals. We report on four novel individuals affected by the condition, two of which were identified following targeted sequencing based solely on the facial features that were similar to those of the first patient we identified. This strongly suggests that this syndrome entails a recognisable morphological phenotype, which is particularly relevant for resource-limited regions where whole genome sequencing is not readily available, and in view of retro-active selection/prioritisation of individuals with hitherto negative genetic testing.</p>\u0000 </div>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":"107 1","pages":"104-112"},"PeriodicalIF":2.9,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142459584","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

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":"10.1111/cge.14629","url":null,"abstract":"<p>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 <i>PIGM</i> 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 <i>PIGM</i>, 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 <i>PIGM</i> coding variant, and the second variant altogether to be described affecting this gene. This phenotype differs from that of patients with the shared <i>PIGM</i> promoter mutation by lack of thrombotic events and no decrease in PIGM cDNA levels or CD59 expression on red blood cells.</p>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":"107 2","pages":"179-187"},"PeriodicalIF":2.9,"publicationDate":"2024-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11725556/pdf/","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0