Clinical Genetics最新文献

{"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":"<p><p>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.</p>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":" ","pages":"208-213"},"PeriodicalIF":2.9,"publicationDate":"2025-02-01","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}

{"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":"<p><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>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":" ","pages":"188-195"},"PeriodicalIF":2.9,"publicationDate":"2025-02-01","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}

{"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":"<p><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 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.</p>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":" ","pages":"214-218"},"PeriodicalIF":2.9,"publicationDate":"2025-02-01","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}

{"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":"10.1111/cge.14624","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":" ","pages":"147-156"},"PeriodicalIF":2.9,"publicationDate":"2025-02-01","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}

{"title":"Genetic Analysis of Heterotaxy in a Consanguineous Cohort.","authors":"Maarab Al-Korashy, Hadeel Binomar, Abeer Al-Mostafa, Ibrahim Al-Mogarri, Saud Al-Oufi, Mohamed Al-Admawi, Mansour Al-Jufan, Najmeddine Echahidi, Amal Mokeem, Ahmed Alfares, Khushnooda Ramzan, Sahar Tulbah, Aisha Al-Qahtani, Saud Takroni, Sateesh Maddirevula, Zuhair Al-Hassnan","doi":"10.1111/cge.14641","DOIUrl":"10.1111/cge.14641","url":null,"abstract":"<p><p>Heterotaxy (HTX) is a group of clinical conditions with a shared pathology of dislocation of one or more organs along the left-right axis. The etiology of HTX is tremendously heterogeneous spanning environmental factors, chromosomal aberrations, mono/oligogenic variants, and complex inheritance. However, in the vast majority of cases, the etiology of HTX remains elusive. Here, we sought to describe the yield of genetic analysis and spectrum of variants in HTX in our highly consanguineous population. Twenty-four affected individuals, from 19 unrelated families, were consecutively recruited. Genetic analysis, with exome sequencing, genome sequencing, or multigene panel, detected 9 unique variants, 7 of which were novel, in 8 genes known to be implicated in autosomal recessive form of HTX (C1orf127, CCDC39, CIROP, DNAAF3, DNAH5, DNAH9, MMP21, and MNS1) providing a yield of 42.1%. Of note, 7 of the 9 variants were homozygous, while 2 were inherited in compound heterozygosity, including a heterozygous CNV deletion. A search for candidate genes in negative cases did not reveal a plausible variant. Our work demonstrates a relatively high yield of genetic testing in HTX in a consanguineous population with an enrichment of homozygous variants. The significant genetic heterogeneity observed herewith underscores the complex developmental mechanisms implicated in the pathogenesis of HTX and supports adopting a genome-wide analysis in the diagnostic evaluation of HTX.</p>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":" ","pages":"224-230"},"PeriodicalIF":2.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142603552","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}

{"title":"Genotype-Phenotype Correlations in SYNGAP1-Related Mental Retardation Type 5.","authors":"Liying Hong, Qifeng Yuan","doi":"10.1111/cge.14661","DOIUrl":"10.1111/cge.14661","url":null,"abstract":"<p><p>Variants in the SYNGAP1 gene leading to decreased SynGAP protein expression are critical for the pathogenesis of mental retardation type 5 (MRD5). This study aims to explore the relationship between SYNGAP1 genotype and clinical phenotype through an expanded sample size, thereby enhancing the understanding of the specific mechanisms underlying MRD5. Data from previously published cases of patients with SYNGAP1 mutations were collected, and the relationship between genotype and clinical phenotype was analyzed. A total of 246 MRD5 patients were included in the analysis. Among them, 98.7% (224/227) were diagnosed with intellectual disability (ID), 91.6% (208/227) with epilepsy, and 57.3% (137/239) with autism spectrum disorder (ASD). The clinical phenotypes of MRD5 patients were found to be associated with their genotypes. Variants located in exons 1 to 6 may correlate with milder ID and reduced risk of ASD, yet they are more likely to present as refractory epilepsy.</p>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":" ","pages":"136-146"},"PeriodicalIF":2.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142794507","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}

{"title":"Balanced Translocation t(3;12) Disrupting HMGA2 and NAALADL2 Genes in Twins With Silver-Russell Syndrome and Intellectual Disability.","authors":"Vanessa Sodré de Souza, Halinna Dornelles Wawruk, Mana M Mehrjouy, Mads Bak, Gabriela Corassa Rodrigues da Cunha, Ana Caroline Gabriel Gonçalves, Mara Santos Cordoba, Niels Tommerup, Juliana F Mazzeu","doi":"10.1111/cge.14699","DOIUrl":"https://doi.org/10.1111/cge.14699","url":null,"abstract":"<p><p>Silver-Russell Syndrome (SRS) is a genetic disorder characterized by intrauterine and postnatal growth restriction. Most cases are caused by an imprinting error either with hypomethylation of the Imprinted Control Region 1 at 11p15.5, or maternal uniparental disomy of chromosome 7. Approximately 40% of the cases have unknown etiology, thus distinct mechanisms have been described in association with the syndrome. Here, we present a case of monozygotic twin sisters with a clinical diagnosis of SRS, mild intellectual disability and epilepsy who carry a balanced translocation between chromosomes 3 and 12 that interrupts the NAALADL2 and HMGA2 genes, respectively. Disruption of HMGA2, a gene previously described as causative of SRS, confirms the initial diagnosis. NAALADL2 gene has been recently proposed as a candidate for intellectual disability and could partially contribute to our patient's phenotype.</p>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143021600","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}

{"title":"Exploring the Familial Phenotypic Variability Associated With TTN Truncating Variants in Cardiomyopathies: Variant Spectrum, Genotype-Phenotype Correlation and Consequences in Genetic Counseling.","authors":"Marie Massier, Pascal de Groote, Erwan Donal, Isabelle Magnin-Poull, Christine Coubes, Xavier Le Guillou Horn, Caroline Rooryck, Patricia Réant, Yann Troadec, Anne-Claire Bréhin, Julie Proukhnitzky, Estelle Gandjbakhch, Philippe Charron, Pascale Richard, Flavie Ader","doi":"10.1111/cge.14679","DOIUrl":"https://doi.org/10.1111/cge.14679","url":null,"abstract":"<p><p>Titin truncating variants (TTNtv) are the main genetic cause of dilated cardiomyopathies (DCMs). The phenotype and prognosis of probands have been evaluated in several large cohorts. However, few data are available on intrafamilial expressivity. To evaluate the phenotypical variability, we selected probands and family members carrying a unique TTN variant and recorded cardiac and genetic information. The cohort included 332 probands (314 TTNtv probands and 18 probands with in silico predicted in-frame exon skipping probands) and 191 relatives of TTNtv probands including 98 affected family members. Within TTNtv families, 96% of the affected relatives presented the same cardiomyopathy subtype as the proband, and 60% shared severity criteria (heart transplantation, implantable cardioverter-defibrillator, personal sudden death). Furthermore, we reported 18 probands that carry predicted in-frame exon skipping variants; they presented DCM (84%) as TTNtv patients but lower rate of rhythm disorders (0% vs. 29% respectively). In this work, we extend the genetic spectrum of TTNtv associated with DCM and show that within a family, and the cardiomyopathy phenotype is homogenous but the expressivity could vary. Such results are helpful for appropriate genetic counseling to better predict and manage the phenotype of mutation carriers.</p>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143022136","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}

{"title":"A Homozygous Variant in HSD17B1 Identified in Women With Poor Ovarian Response.","authors":"Jingyi Ren, Yan Ouyang, Shuangyao Wang, Fei Gong, Guangxiu Lu, Ge Lin, Jing Guo","doi":"10.1111/cge.14707","DOIUrl":"https://doi.org/10.1111/cge.14707","url":null,"abstract":"<p><p>An increasing number of patients utilizing in vitro fertilization (IVF) and assisted reproductive technology (ART) are characterized as impaired or poor ovarian responders (PORs). Owing to its unclear molecular etiology, the management of patients with age-related ovarian characteristics remains a controversial and complex clinical concern. Therefore, it is important to identify and understand the etiological causes behind POR to develop more effective and efficient management strategies for these patients. In this study, we report a homozygous HSD17B1 (accession number: NM_000413.4) variant (c.718-1G>C) in a patient with POR from a consanguineous family. The proband, a 33-years-old woman, exhibited poor ovarian reserve prestimulation parameters (antral follicle count < 5; anti-Müllerian hormone = 0.386 ng/mL), resulting in the classification of this patient as patient oriented strategies encompassing individualized oocyte number (POSEIDON) group three according to the POSEIDON criteria. Additionally, this patient displayed impaired estradiol production and reduced 17-ketosteroids secretion and multiple ovarian cysts, which differed from previously reported POR cases. Overall, our findings provide valuable insights for researchers and clinicians into the relationships between the phenotype and genotype of POR and the HSD17B1 gene.</p>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143001306","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}

{"title":"Comprehensive Clinical and Genetic Characterization of a Spanish Cohort of 22 Patients With Bainbridge-Ropers Syndrome.","authors":"Laura Trujillano, Irene Valenzuela, Mar Costa-Roger, Ivon Cuscó, Paula Fernandez-Alvarez, Anna Cueto-González, Amaia Lasa-Aranzasti, Bárbara Masotto, Anna Abulí, Marta Codina-Solà, Miguel Del Campo, Juan Antonio Ruiz Moreno, Cristina Pardo Domínguez, Carmen Palma Milla, Rubén Pérez de la Fuente, Juan Francisco Quesada-Espinosa, Noemí Núñez-Enamorado, Blanca Gener, María Juliana Ballesta-Martínez, Alejandro J Brea-Fernández, Montse Fernández-Prieto, Juan Pablo Trujillo-Quintero, Anna Ruiz, Fernando Santos-Simarro, Mónica Rosello, Carmen Orellana, Francisco Martinez, Antonio F Martinez-Monseny, Dídac Casas-Alba, Mercedes Serrano, María Palomares-Bralo, Emi Rikeros-Orozco, María Ángeles Gómez-Cano, Pilar Tirado-Requero, Juan Pié Juste, Feliciano J Ramos, Elena García-Arumí, Eduardo F Tizzano","doi":"10.1111/cge.14701","DOIUrl":"https://doi.org/10.1111/cge.14701","url":null,"abstract":"<p><p>Bainbridge-Ropers Syndrome (BRPS) is a genetic condition resulting from truncating variants in the ASXL3 gene. The clinical features include neurodevelopmental and language impairments, behavioral issues, hypotonia, feeding difficulties, and distinctive facial features. In this retrospective study, we analyzed 22 Spanish individuals with BRPS, aiming to perform a detailed clinical and molecular description and establish a genotype-phenotype correlation. We identified 19 ASXL3 variants, nine of which are novel. We documented recurrence in nontwin siblings due to parental mosaicism. The predominant prenatal finding was intrauterine growth restriction (35%) followed, after birth, by feeding difficulties (90.5%), hypotonia (85.7%), and gastroesophageal reflux disease (82.4%). Later in life, intellectual disability, language impairment, autism spectrum disorder (75%), and joint laxity (73.7%) were noted. Individuals with variants in the 3' mutational cluster region (MCR) of exon 12 exhibited more perinatal feeding problems, and those with variants in the 5' MCR of exon 11 displayed lower percentiles in height and occipitofrontal circumference, as well as higher frequency of arched eyebrows. This study is the first characterization of a Spanish BRPS cohort, with more than 50 clinical features analyzed, representing the most detailed phenotypic analysis to date.</p>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143001309","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}