Clinical Genetics最新文献_第4页

Digenic Inheritance of Monoallelic MUTYH and POLE Germline Variants in Adrenocortical Carcinoma: Implications for Tumorigenesis and Immunotherapy.

IF 2.9 3区医学

Clinical Genetics Pub Date : 2025-02-03 DOI: 10.1111/cge.14721

Jonathan Lopez, Adrien Buisson, Adel Ounnas, Gaelle Tachon, Alain Viari, Florence De Fraipont, Juliette Albuisson, Marc Barritault, Pierre-Paul Bringuier, Jean-Paul Feugeas, Anne Mc Leer, Ahmed Bouras

引用次数: 0

Quantification of Lateralized Overgrowth and Genotype-Driven Tissue Composition.

IF 2.9 3区医学

Clinical Genetics Pub Date : 2025-02-02 DOI: 10.1111/cge.14713

Andrea Gazzin, Giuseppe Reynolds, Damiano Allegro, Davide Rossi, Francesca Sciandra, Hirad Akberi Afkhami, Simona Cardaropoli, Marilidia Piglionica, Nicoletta Resta, Marco Di Stefano, Alessandro Mussa

{"title":"Quantification of Lateralized Overgrowth and Genotype-Driven Tissue Composition.","authors":"Andrea Gazzin, Giuseppe Reynolds, Damiano Allegro, Davide Rossi, Francesca Sciandra, Hirad Akberi Afkhami, Simona Cardaropoli, Marilidia Piglionica, Nicoletta Resta, Marco Di Stefano, Alessandro Mussa","doi":"10.1111/cge.14713","DOIUrl":"https://doi.org/10.1111/cge.14713","url":null,"abstract":"Lateralized overgrowth (LO) is characterized by excessive growth of one side of the body compared to the other. LO can present as isolated (ILO) or within syndromes, like Beckwith-Wiedemann Spectrum (BWSp) and PIK3CA-related overgrowth spectrum (PROS). Currently, the diagnosis of LO relies on clinical evaluation and lacks a standardized method. In this study, we evaluated total body dual-energy X-ray absorptiometry (TB-DXA) as a potential tool for standardizing LO assessment. Patients with LO underwent both clinical evaluation and TB-DXA. TB-DXA data, including total mass, mass of the three main tissue components (adipose, muscle, and bone), total mass discrepancy ratio, relative tissue composition, and discrepancy of relative tissue composition were calculated and compared with clinical findings. Differences between affected regions and the contralateral side were assessed. A total of 46 patients (61% PROS, 24% BWSp, 15% ILO) were included in this study. TB-DXA detected overgrowth regions aligned with clinical evaluation in 91% of cases and was able to identify localized overgrowth even when clinically overlooked. Additionally, TB-DXA revealed differences in tissue composition between affected and unaffected regions for symmetrical body areas, with these differences varying by diagnostic subgroup. Different patterns of tissue composition overgrowth were observed among different conditions, with PROS predominantly showing adipose tissue overgrowth, while BWSp/ILO mainly osteo-muscular overgrowth. TB-DXA is an accurate, safe, and reproducible tool in the clinical setting providing an objective method for identifying and quantifying LO. It offers valuable guidance for clinicians in the diagnosis and management of LO.","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143078588","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 Cryptic CBFB Deletion-Inversion Expands the Mutational Spectrum of Variants Associated With Cleidocranial Dysplasia.

IF 2.9 3区医学

Clinical Genetics Pub Date : 2025-02-02 DOI: 10.1111/cge.14709

Alistair T Pagnamenta, Mona Hashim, Joanna Kennedy, Beth Lawton, Amaka C Offiah, Jenny C Taylor, Sarah F Smithson

{"title":"A Cryptic CBFB Deletion-Inversion Expands the Mutational Spectrum of Variants Associated With Cleidocranial Dysplasia.","authors":"Alistair T Pagnamenta, Mona Hashim, Joanna Kennedy, Beth Lawton, Amaka C Offiah, Jenny C Taylor, Sarah F Smithson","doi":"10.1111/cge.14709","DOIUrl":"https://doi.org/10.1111/cge.14709","url":null,"abstract":"CBFB encodes the core-binding factor β subunit, a small protein which heterodimerises with RUNX1-3 and activates transcription of genes important in bone development. Recently, five families with cleidocranial dysplasia (CCD) were identified harbouring presumed loss of function variants in CBFB. Prompted by a multidisciplinary team review of an affected mother and daughter from the 100 000 Genomes Project with genetically unsolved CCD, we inspected read alignments and identified a deletion-inversion-deletion that removes the first two exons of CBFB. This cryptic variant comprised interlinked deletions of 1310 bp and 1935 bp and had remained undetected by both array-CGH and the Canvas algorithm. The rearrangement was likely mediated by a palindromic AluSx repeat < 1 kb from the transcriptional start site. Due to high GC content and repeats, reduced read depth is observed at one of the breakpoints. Although the clinical presentation of CBFB-related CCD appears to be very similar to RUNX2-related CCD, our patients were of normal stature. The mild developmental delay observed in previously reported cases of CBFB-related CCD was not observed. In conclusion, our data strengthens the evidence linking aberrations of the core-binding factor complex to CCD and extends the mutational spectrum of pathogenic variants.","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143078573","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

Pathogenic Deep Intronic PCSK1 Variant Causes Proprotein Convertase 1/3 Deficiency in a Family.

IF 2.9 3区医学

Clinical Genetics Pub Date : 2025-02-01 DOI: 10.1111/cge.14717

Leah M Huber, Aslı Subaşıoğlu, Dorota Garczarczyk-Asim, Taras Valovka, Thomas Müller, Rüdiger Adam, Andreas R Janecke

{"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":"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.","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}

引用次数: 0

Genomic Testing in Adults With Undiagnosed Rare Conditions: Improvement of Diagnosis Using Clinical Exome Sequencing as a First-Tier Approach.

IF 2.9 3区医学

Clinical Genetics Pub Date : 2025-02-01 DOI: 10.1111/cge.14715

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

{"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":"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.","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}

引用次数: 0

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.

IF 2.9 3区医学

Clinical Genetics Pub Date : 2025-01-31 DOI: 10.1111/cge.14712

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

{"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":"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.","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}

引用次数: 0

Identification of Novel SCMC Gene Variants Associated With Early Embryonic Arrest.

IF 2.9 3区医学

Clinical Genetics Pub Date : 2025-01-29 DOI: 10.1111/cge.14696

Changlong Zhang, Shuai Zhao, Honghui Zhang, Wei Su, Yang Wang, Ying Cui, Bohan Yang, Yikun Wang, Han Zhao

{"title":"Identification of Novel SCMC Gene Variants Associated With Early Embryonic Arrest.","authors":"Changlong Zhang, Shuai Zhao, Honghui Zhang, Wei Su, Yang Wang, Ying Cui, Bohan Yang, Yikun Wang, Han Zhao","doi":"10.1111/cge.14696","DOIUrl":"https://doi.org/10.1111/cge.14696","url":null,"abstract":"The subcortical maternal complex (SCMC) is crucial for the oocyte-to-embryo transition, and genetic variants in SCMC genes have been associated with early embryonic arrest (EEA). In this study, we performed whole-exome sequencing on 303 independent females with EEA and identified 16 patients with biallelic pathogenic variants in SCMC genes (NLRP2, NLRP5, PADI6, and TLE6), accounting for 5.3% of EEA cases. NLRP5 had the highest prevalence, with 7 out of 16 cases (43.8%). A total of 23 novel variants were identified, including 13 missense, eight loss-of-function, one in-frame insertion, and one large 6.9 kb deletion. Functional predictions using mCSM indicated that nine missense variants destabilize SCMC structure. Additionally, RT-PCR and cDNA sequencing demonstrated that the synonymous variant in TLE6 (c.180G>A) impacts splicing and induces nonsense-mediated decay. Taken together, our findings revealed that novel biallelic variants in SCMC genes were associated with human EEA, which expands the spectrum of genetic causes and facilitates the genetic diagnosis of female infertility with EEA.","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":"143063864","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

Toe Polydactyly and Supernumerary Nipple: Broadening the Phenotypic Spectrum of STAR Syndrome.

IF 2.9 3区医学

Clinical Genetics Pub Date : 2025-01-29 DOI: 10.1111/cge.14711

Omar Zgheib, Léa Jacques, Louise Frizon, Gabriela Windisch, Siv Fokstuen

引用次数: 0

Revealing Molecular Diagnosis With Whole Exome Sequencing in Patients With Inherited Retinal Disorders.

IF 2.9 3区医学

Clinical Genetics Pub Date : 2025-01-24 DOI: 10.1111/cge.14708

Cuneyd Yavas, Yunus Emre Arvas, Mustafa Dogan, Alper Gezdirici, Elif Sibel Aslan, Murat Karapapak, Savas Barıs, Recep Eroz

{"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":"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.","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}

引用次数: 0

Balanced Translocation t(3;12) Disrupting HMGA2 and NAALADL2 Genes in Twins With Silver-Russell Syndrome and Intellectual Disability.

IF 2.9 3区医学

Clinical Genetics Pub Date : 2025-01-23 DOI: 10.1111/cge.14699

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

引用次数: 0