Clinical Genetics最新文献

{"title":"Pathogenic Deep Intronic PCSK1 Variant Causes Proprotein Convertase 1/3 Deficiency in a Family.","authors":"Leah M Huber, Aslı Subaşıoğlu, Dorota Garczarczyk-Asim, Taras Valovka, Thomas Müller, Rüdiger Adam, Andreas R Janecke","doi":"10.1111/cge.14717","DOIUrl":"https://doi.org/10.1111/cge.14717","url":null,"abstract":"<p><p>Proprotein convertase 1/3 (PC1/3), encoded by PCSK1, is expressed in neuronal and endocrine cell types, where it activates a number of protein precursors that play roles in energy homeostasis. Biallelic PCSK1 loss-of-function mutations cause a polyendocrinopathy; a total of 34 patients were reported. An infant with congenital malabsorptive diarrhea of all carbohydrates underwent exome sequencing (ES), with particular consideration of PC1/3 deficiency, but no mutations were found. The onset of obesity in the second year of life increased suspicion of PC1/3 deficiency in the proband, as well as in his equally affected cousin. Transcript analysis revealed minor amounts of an aberrant PCSK1 transcript containing intron 9 sequence and encoding a premature stop codon (p.Pro400Valfs*35). A deep intronic PCSK1 variant, NG_021161.1(NM_000439.5):c.1196+2681T>A, was found to segregate in the proband's family with the disease. A minigene approach demonstrated that the identified deep-intronic variant underlies pseudo-exon inclusion of the intron 9 sequence in the transcript. The characteristic phenotype of PC1/3 deficiency might require extended genetic testing to make a timely diagnosis.</p>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143074058","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":"Genomic Testing in Adults With Undiagnosed Rare Conditions: Improvement of Diagnosis Using Clinical Exome Sequencing as a First-Tier Approach.","authors":"Roberta Petillo, Ilaria De Maggio, Carmelo Piscopo, Massimiliano Chetta, Marina Tarsitano, Luigi Chiriatti, Elvira Sannino, Serena Torre, Marcella D'Antonio, Paola D'Ambrosio, Marco Rambaldi, Maria Cioce, Valentina De Stefano, Maria Rita Parisi, Antonella Telese, Maria Oro, Maria Rivieccio, Francesca Clementina Radio, Cecilia Mancini, Marcello Niceta, Viviana Cordeddu, Alessandro Bruselles, Corrado Mammì, Adele Dattola, Tiziana Fioretti, Gabriella Esposito, Antonio Novelli, Alessandro Tessitore, Alessandra Tessa, Filippo Maria Santorelli, Achille Iolascon, Matteo Della Monica, Marco Tartaglia, Manuela Priolo","doi":"10.1111/cge.14715","DOIUrl":"https://doi.org/10.1111/cge.14715","url":null,"abstract":"<p><p>Adult patients with undiagnosed genetic disorders suffer most from diagnostic delay and seldom appear in cohort studies investigating the diagnostic yield in medical genetic clinical practice. Here we present the results of the diagnostic activity performed in a referral center on 654 consecutive, unselected adult subjects presenting with molecularly unsolved conditions. More than 50% of the referred individuals were affected by syndromic or isolated intellectual disability. Different molecular approaches, including clinical/whole exome sequencing (CES/WES), chromosomal microarray analysis (CMA), and/or targeted gene or gene panel sequencing were used to analyze patients' DNA. Definitive diagnosis was obtained in over 30% of individuals. The most sensitive methodology was CES/WES, which allowed us to reach a diagnosis in over 50% of the 162 solved cases. Despite the great variety of clinical presentations, our results represent a reliable picture of the \"real world\" daily routine in an outpatient medical genetics clinic dedicated to diagnostic activity, and contribute to better understand the great value of a definitive molecular diagnosis in adults, either for the affected individuals and their families. This retrospective analysis demonstrates the importance of adopting a genomic-first approach within the diagnostic process for adults affected with unsolved rare conditions.</p>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143074055","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":"Integrating Prenatal Exome Sequencing and Ultrasonographic Fetal Phenotyping for Assessment of Congenital Malformations: High Molecular Diagnostic Yield and Novel Phenotypic Expansions in a Consanguineous Cohort.","authors":"Sara H El-Dessouky, Wessam E Sharaf-Eldin, Mona M Aboulghar, Hatem A Mousa, Maha S Zaki, Reza Maroofian, Sameh M Senousy, Maha M Eid, Hassan M Gaafar, Alaa Ebrashy, Ahmed Z Shikhah, Ahmed N Abdelfattah, Ahmed Ezz-Elarab, Mohamed I Ateya, Adel Hosny, Youssef Mohamed Abdelfattah, Rana Abdella, Mahmoud Y Issa, Lova S Matsa, Nahla Abdelaziz, Ahmed K Saad, Shahryar Alavi, Homa Tajsharghi, Ebtesam M Abdalla","doi":"10.1111/cge.14712","DOIUrl":"https://doi.org/10.1111/cge.14712","url":null,"abstract":"<p><p>To evaluate the diagnostic yield of prenatal exome sequencing (pES) in fetuses with structural anomalies detected by prenatal ultrasound in a consanguineous population. This was a prospective study of 244 anomalous fetuses from unrelated consanguineous Egyptian families. Detailed phenotyping was performed throughout pregnancy and postnatally, and pES data analysis was conducted. Genetic variants were prioritized based on the correlation of their corresponding human phenotype ontology terms with the ultrasound findings. Analyses were carried out to determine the diagnostic efficiency of pES and its correlation to the organ systems involved. The largest clinical category of fetuses referred for pES was those manifesting multisystem anomalies (104/244, 42.6%). pES provided a definitive diagnosis explaining the fetal anomalies in 47.1% (115/244) of the cases, with the identification of 122 pathogenic or likely pathogenic variants completely fitting with the phenotype. Variants of uncertain significance associated with the fetal phenotypes were detected in 84 fetuses (34%), while 18.44% (45/244) had negative results. Positive consanguinity is associated with a high diagnostic yield of ES. The novel variants and new fetal manifestations, described in our cohort, further expand the mutational and phenotypic spectrum of a wide variety of genetic disorders presenting with congenital malformations.</p>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143074057","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":"Toe Polydactyly and Supernumerary Nipple: Broadening the Phenotypic Spectrum of STAR Syndrome.","authors":"Omar Zgheib, Léa Jacques, Louise Frizon, Gabriela Windisch, Siv Fokstuen","doi":"10.1111/cge.14711","DOIUrl":"https://doi.org/10.1111/cge.14711","url":null,"abstract":"<p><p>STAR syndrome is a very rare X-linked dominant disorder characterized by the association of toe syndactyly, facial dysmorphism including telecanthus and a broad nasal tip, and anogenital and renal malformations. We hereby report a patient with a novel frameshift mutation in CCNQ, the STAR syndrome causative gene. More importantly, the patient presented hitherto unreported clinical features, namely toe polydactyly in addition to syndactyly, and a supernumerary nipple. This nineteenth reported case further broadens the phenotypic spectrum of STAR syndrome.</p>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143063865","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":"Revealing Molecular Diagnosis With Whole Exome Sequencing in Patients With Inherited Retinal Disorders.","authors":"Cuneyd Yavas, Yunus Emre Arvas, Mustafa Dogan, Alper Gezdirici, Elif Sibel Aslan, Murat Karapapak, Savas Barıs, Recep Eroz","doi":"10.1111/cge.14708","DOIUrl":"https://doi.org/10.1111/cge.14708","url":null,"abstract":"<p><p>Inherited retinal diseases (IRDs) constitute a heterogeneous group of clinically and genetically diverse conditions, standing as a primary cause of visual impairment among individuals aged 15-45, with an estimated incidence of 1:2000. Our study aimed to comprehensively evaluate the genetic variants underlying IRDs in the Turkish population. This study included 50 unrelated Turkish IRD patients and their families. Genomic DNA was extracted from each participant, and candidate variants were identified via next-generation sequencing to determine their pathogenicity. We detected variants in 58% of the patients, of which six novel variants were identified. Among these, 16 cases exhibited variants associated with retinitis pigmentosa and Stargardt disease, while 13 presented variants linked to other retinal diseases. The spectrum of identified variants included 21 homozygous cases and five compound heterozygous variants, both indicative of autosomal recessive inheritance. Three cases revealed heterozygous variants suggestive of autosomal dominant inheritance, and two cases featured hemizygous variants suggestive of X-linked inheritance. Importantly, no matches with copy number variants were detected in our analysis. This study comprehensively portrays clinical and genetic profiles within the Turkish population affected by IRDs. Identifying novel variants and delineating inheritance patterns contribute to a deeper understanding of the genetic diagnosis of IRDs, paving the way for more precise diagnostic and therapeutic interventions.</p>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143045228","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}

{"title":"SNV/Indel and CNV Analysis in Trio-WES for Intellectual and Developmental Disabilities: Diagnostic Yield & Cost-Effectiveness.","authors":"Guanhua Qian, Nanyan Yang, Fang Deng, Mingze Zhang, Xin Pan, Bo Tan, Li Liu, Xu Zhang, Hong Yao, Xiaojing Dong","doi":"10.1111/cge.14677","DOIUrl":"https://doi.org/10.1111/cge.14677","url":null,"abstract":"<p><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>","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":"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}