Clinical Genetics最新文献

{"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,&nbsp;Pascal de Groote,&nbsp;Erwan Donal,&nbsp;Isabelle Magnin-Poull,&nbsp;Christine Coubes,&nbsp;Xavier Le Guillou Horn,&nbsp;Caroline Rooryck,&nbsp;Patricia Réant,&nbsp;Yann Troadec,&nbsp;Anne-Claire Bréhin,&nbsp;Julie Proukhnitzky,&nbsp;Estelle Gandjbakhch,&nbsp;Philippe Charron,&nbsp;Pascale Richard,&nbsp;Flavie Ader","doi":"10.1111/cge.14679","DOIUrl":"10.1111/cge.14679","url":null,"abstract":"<div>\u0000 \u0000 <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 <i>TTN</i> variant and recorded cardiac and genetic information. The cohort included 332 probands (314 <i>TTNtv</i> probands and 18 probands with <i>in silico</i> predicted in-frame exon skipping probands) and 191 relatives of <i>TTNtv</i> probands including 98 affected family members. Within <i>TTNtv</i> 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 <i>TTN</i>tv patients but lower rate of rhythm disorders (0% vs. 29% respectively). In this work, we extend the genetic spectrum of <i>TTN</i>tv 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>\u0000 </div>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":"107 4","pages":"425-433"},"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}

{"title":"SNV/Indel and CNV Analysis in Trio-WES for Intellectual and Developmental Disabilities: Diagnostic Yield & Cost-Effectiveness","authors":"Guanhua Qian,&nbsp;Nanyan Yang,&nbsp;Fang Deng,&nbsp;Mingze Zhang,&nbsp;Xin Pan,&nbsp;Bo Tan,&nbsp;Li Liu,&nbsp;Xu Zhang,&nbsp;Hong Yao,&nbsp;Xiaojing Dong","doi":"10.1111/cge.14677","DOIUrl":"10.1111/cge.14677","url":null,"abstract":"<div>\u0000 \u0000 <p>Intellectual and developmental disabilities (IDD) are clinically and genetically heterogeneous disorders of global concern. While whole exome sequencing (WES) is used to identify single nucleotide variants (SNVs) and small insertions/deletions (Indels) in IDD patients, its detection rate is limited. This study evaluated the value of integrating copy number variation (CNV) analysis into traditional SNV/Indel analysis based on trio-WES. One hundred eighty seven patients with IDD in 140 families from southwest China were incorporated into the study cohort. The overall diagnostic rate was 40.11% (75/187), with 33.16% (62/187) from SNV/Indel analysis and 6.95% (13/187) from CNV analysis. SNV/Indel analysis identified 52 variants in 42 genes, including 30 novel and 22 reported variants; CNV analysis identified 11 CNVs, comprising 1 repeat and 10 deletions, with sizes ranging from 1313 to 55 184 kb. 39.29% (55/140) families benefited from this study for their clinical diagnosis, treatment, and reproduction. Furthermore, our strategy, with an incremental cost-effectiveness ratio (ICER) of $2546.22/diagnosis, had demonstrated significant advantages in terms of cost-effectiveness and detection speed compared to previous methods. In general, by incorporating SNV/Indel and CNV analysis based on trio-WES, a robust, cost-effective, and time-saving approach for diagnosing IDD has been developed.</p>\u0000 </div>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":"107 4","pages":"402-412"},"PeriodicalIF":2.9,"publicationDate":"2025-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143001319","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":"Unexpected High Prevalence of Focal Facial Dermal Dysplasia (FFDD) Type IV Is Linked to a Founder Effect in the Belgian Population.","authors":"Aude Beyens, Stefanie Van De Voorde, Marta Guerreiro Santano Ramos Da Silva, Sofie De Meulemeester, Koen Devriendt, Marleen Goeteyn, Sandra Janssens, R Frank Kooy, Toon Rosseel, Sofie Symoens, Frederik Jan Hes, Kathelijn Keymolen, Boyan Dimitrov, Bert Callewaert","doi":"10.1111/cge.14705","DOIUrl":"https://doi.org/10.1111/cge.14705","url":null,"abstract":"<p><p>Focal facial dermal dysplasia (FFDD) type IV is a rare inherited facial defect caused by biallelic variants in CYP26C1. This study reports two novel Belgian FFDD type IV cases, both homozygous for a recurrent CYP26C1 frameshift variant, with a common 700 kb haplotype, indicating a founder effect.</p>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143001322","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":"Haplotype Phasing of Biallelic WNT10B Variants Using Long-Read Sequencing in Split-Hand/Foot Malformation Syndrome.","authors":"Jelena Pozojevic, Naseebullah Kakar, Henrike L Sczakiel, Nathalie Kruse, Kristian Händler, Saranya Balachandran, Varun Sreenivasan, Martin A Mensah, Malte Spielmann","doi":"10.1111/cge.14706","DOIUrl":"https://doi.org/10.1111/cge.14706","url":null,"abstract":"<p><p>Split-hand/foot malformation syndrome (SHFM) is a congenital limb malformation that is both clinically and genetically heterogeneous. Variants in WNT10B are known to cause an autosomal recessive form of SHFM. Here, we report a patient born to unrelated parents who was found to be a compound heterozygote for missense variants in WNT10B: c.994C>T, p.(Arg332Trp) and c.638T>G, p.(Phe213Cys). The variants were identified using long-read PacBio sequencing, which enabled phasing and confirmed that they were located on different alleles. The maternally inherited variant p.(Arg332Trp) has been previously reported, whereas the paternally inherited variant p.(Phe213Cys) is novel and absent from the gnomAD database. Our findings highlight the utility of long-read haplotype phasing, which provides valuable insights in determining the biallelic nature of variants in recessive disorders when parental DNA samples are unavailable.</p>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-01-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143001315","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":"Reanalysis of Exome Sequencing Data in the Indian Undiagnosed Diseases Program: Improving Diagnostic Yield and Ending Diagnostic Odyssey.","authors":"Neha Garg, Pragna Lakshmi, Suzena M Singh, Samarth Kulshreshta, Prajnya Ranganath, Amita Moirangthem, Ashwin Dalal, Aakanksha Gahlot, Ratna Dua Puri","doi":"10.1111/cge.14694","DOIUrl":"https://doi.org/10.1111/cge.14694","url":null,"abstract":"<p><p>In 2021, the Indian Undiagnosed Diseases Program was initiated for patients without a definite diagnosis despite extensive evaluation in four participating sites. Between February 2021 and March 2023, a total of 88 patients were recruited and underwent deep phenotyping. A uniform methodology for data re-analysis was implemented as the first step prior to conducting additional genomic testing. The largest cohort was of 38 patients with neurodevelopmental disorders (NDD). A genetic diagnosis was achieved in 24 of the 88 patients (27.2%), including 7 cases within the NDD cohort. Factors contributing to the increased diagnostic yield included: (a) identification of a novel disease association in DAAM2 gene, and (b) limitations of the standard analysis pipeline, particularly for synonymous variants in SELENOI and KIAA0753 genes, non-frameshift variant in GLRX5 gene, low-coverage variant in GJC2 gene, large deletions in PCNT and PHKG2 genes, and intronic variants in VPS33B and FBN1. Improved phenotyping led to a diagnosis in three cases, while genomic variants missed in the previous bioinformatics analysis were identified in 12 cases. The study also contributed to the development of enhanced bioinformatics scripts for variant prioritization and more refined literature search for novel disease associations. It highlights the importance of incorporating data reanalysis into clinical workflows before pursuing advanced diagnostic tests, particularly in resource-limited settings where healthcare expenses are often borne out of pocket.</p>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142977667","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":"Functional Characterization and In Silico Prediction Tools Improve the Pathogenicity Prediction of Novel Bile Acid Transporter Variants.","authors":"Ziyue Peng, Xin Wang, Ying Li, Yaqiong Ren, Yuhuan Meng, Liwei Sun, Zitong Zhang, Yue Song, Yang Xia, Lei Shi, Shihui Yu, Liang Cheng, Xue Zhang","doi":"10.1111/cge.14704","DOIUrl":"https://doi.org/10.1111/cge.14704","url":null,"abstract":"<p><p>The pathogenicity of cholestatic liver diseases (CLDs) remains insufficiently characterized, hindering definitive diagnosis and timely treatment. The aim of this study was to improve the pathogenicity prediction of novel bile acid (BA) transporter variants in patients with CLDs. We analyzed the clinical characteristics and genetic profiles of a CLD cohort (n = 57) using multiple in silico tools and in vitro functional assays. We identified 78 unique variants in four BA transporter genes. The predominant defects were associated with ABCC2 (57/78, 73.1%), with the most frequent being missense variants (39/78, 50.0%). Using in silico tools, we identified 47 novel variants: 12 mis-splicing, 21 deleterious missense, and 23 with altered protein stability. Of the 34 novel variants in ABCC2 identified through in vitro functional assays, seven incurred aberrant splicing, 11 missense variants resulted in MRP2 reduction, 9 missense variants resulted in abnormal N-glycosylation, 18 variants altered MRP2 localization, and 26 variants reduced organic anion transport activity. These findings indicate that a multidisciplinary approach, integrating bioinformatics and experimental data, significantly enhances the accuracy of genetic-based CLD diagnosis. It serves as a foundational study for BA transport variants pathogenicity reclassification and expands the mutation spectrum of CLDs in China.</p>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142977651","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":"Featured Cover","authors":"Mehmet Burak Mutlu,&nbsp;Taner Karakaya,&nbsp;Hamide Betül Gerik Çelebi,&nbsp;Fahrettin Duymuş,&nbsp;Serhat Seyhan,&nbsp;Sanem Yılmaz,&nbsp;Uluç Yiş,&nbsp;Tahir Atik,&nbsp;Mehmet Fatih Yetkin,&nbsp;Hakan Gümüş","doi":"10.1111/cge.14700","DOIUrl":"https://doi.org/10.1111/cge.14700","url":null,"abstract":"<p>The cover image is based on the article <i>Utility of Optical Genome Mapping in Repeat Disorders</i> by Mehmet Burak Mutlu et al., https://doi.org/10.1111/cge.14633.\u0000\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":"107 2","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cge.14700","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143114463","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}

{"title":"Unusual Co-Occurrence of Multiple Myeloma and AML in a Patient With Germline CEBPA Variant. Expanding the Spectrum of Hereditary Hematologic Malignancies.","authors":"María Noel Spangenberg, Matilde Boada, Carolina Ottati, Lucia Vázquez, Ana Catalán, Sofia Grille","doi":"10.1111/cge.14693","DOIUrl":"https://doi.org/10.1111/cge.14693","url":null,"abstract":"<p><p>Timeline and genetic analysis of a 55-year-old female with a family history of gastric cancer and multiple myeloma, who was diagnosed with AML and a germline CEBPA variant.</p>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142969823","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}