Clinical Genetics最新文献_第3页

Delineating the Clinical and Brain Imaging Characteristics of the Neonatal Form of CSTB-Related Neurodevelopmental Disorders.

IF 2.9 3区医学

Clinical Genetics Pub Date : 2025-02-18 DOI: 10.1111/cge.14720

Mohamed S Abdel-Hamid, Sherif F Abdel-Ghafar, Inas S M Sayed, Maha S Zaki, Ghada M H Abdel-Salam

{"title":"Delineating the Clinical and Brain Imaging Characteristics of the Neonatal Form of CSTB-Related Neurodevelopmental Disorders.","authors":"Mohamed S Abdel-Hamid, Sherif F Abdel-Ghafar, Inas S M Sayed, Maha S Zaki, Ghada M H Abdel-Salam","doi":"10.1111/cge.14720","DOIUrl":"https://doi.org/10.1111/cge.14720","url":null,"abstract":"Cystatin B gene (CSTB) is responsible for the most common childhood onset type of progressive myoclonic epilepsy (EPM1A). More recently, biallelic CSTB variants were described in four patients with a neonatal onset phenotype of microcephaly, diffuse hypomyelination, brain atrophic changes, and dyskinesia. Herein, we describe the clinical and molecular characterization of five additional patients in whom exome sequencing detected a splice variant (c.67-1G>C) in Family I and II and a missense variant (c.10G>C, p.Gly4Arg) in Family III and IV. Interestingly, these variants were described before in patients with EPM1A. However, all our patients had progressive microcephaly, developmental delay, and dyskinesia. In addition, only one patient developed seizures. Brain imaging showed mainly diffuse hypomyelination and progressive cerebral and cerebellar atrophy of variable severity. Interestingly, one patient showed intracranial calcification and another showed congenital distal arthrogryposis. Our findings support the association between CSTB variants and the neonatal form as a distinct neurodevelopmental phenotype. This newly characterized neonatal onset of the CSTB shares many overlapping features with genetic disorders encompassing microcephaly and hypomyelination.","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143448390","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

Intrahepatic Cholestasis of Pregnancy: A Single-Centre Whole-Exome Sequencing Study in a Maltese Cohort.

IF 2.9 3区医学

Clinical Genetics Pub Date : 2025-02-16 DOI: 10.1111/cge.14728

Dorianne Spiteri, Laura Grech, Charles Savona-Ventura, Nikolai Paul Pace

引用次数: 0

A Novel NUP85 Variant Expanding the Phenotypic Spectrum of NUP85-Associated Steroid-Resistant Nephrotic Syndrome.

IF 2.9 3区医学

Clinical Genetics Pub Date : 2025-02-13 DOI: 10.1111/cge.14703

Eda Didem Kurt-Şükür, Emel Timucin, Turgut Baştuğ, Fatih Ozaltin

引用次数: 0

Progressive Cone-Rod Synaptic Dysfunction in Dynamin-1 (DNM1) Related Developmental and Epileptic Encephalopathy: A Distinct Retinal Phenotype in Human.

IF 2.9 3区医学

Clinical Genetics Pub Date : 2025-02-09 DOI: 10.1111/cge.14724

Oliver R Marmoy, Eleanor Hay, Richard Bowman, Dorothy A Thompson

{"title":"Progressive Cone-Rod Synaptic Dysfunction in Dynamin-1 (DNM1) Related Developmental and Epileptic Encephalopathy: A Distinct Retinal Phenotype in Human.","authors":"Oliver R Marmoy, Eleanor Hay, Richard Bowman, Dorothy A Thompson","doi":"10.1111/cge.14724","DOIUrl":"https://doi.org/10.1111/cge.14724","url":null,"abstract":"Dynamin-1 is an essential enzyme involved in the recycling of synaptic vesicles, in particular in the scission of endocytic buds within the pre-synaptic terminal. Heterozygous pathogenic variants in DNM1 result in Developmental and Epileptic Encephalopathy type 31A, where patients exhibit early onset refractory epilepsy, severe-profound intellectual disability and poor visual behaviour. We present data demonstrating that this disorder progressively affects retinal synaptic function which, to our knowledge, is the first report of this phenotype in human. Clinical notes of the proband were reviewed incorporating ophthalmic phenotyping (imaging, electroretinography (ERG), pattern visual evoked potentials (PVEPs) and visual symptoms). Genetic testing was performed using trio whole genome sequencing. Genetic testing confirmed a de-novo pathogenic variant in DNM1, a recurrent heterozygous missense variant, c.709C > T;p.(Arg237Trp). Serial ERG testing at 1, 3, 9 and 12 years old indicated a progressive inner retinal dysfunction affecting both rod and cone synaptic pathways mirroring the abnormalities in the mouse model of dnm1, with normal retinal structure. DNM1 affects retinal synaptic recycling and endocytosis and our findings show likely usefulness of ERG testing in affected individuals. Further work is needed to expand our understanding of how different DNM1 variants affect retinal function.","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143381758","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 Study and Prenatal Diagnosis of Inherited Glycosylphosphatidylinositol Disorders due to Novel Variants in Phosphatidylinositol Glycan Genes.

IF 2.9 3区医学

Clinical Genetics Pub Date : 2025-02-09 DOI: 10.1111/cge.14716

Zi-Xi Zhao, Jing-Lin Zhou, Qi Wang, Songmin Peng, Yao Peng, Yu-Rong Wang, Liang Hu, Rejima Aiyitahong, Lin Peng, Feng Gu, Guang-Xiu Lu, Ge Lin, Song Chen, Yue-Qiu Tan, Juan Du, Wen-Bin He

{"title":"Genetic Study and Prenatal Diagnosis of Inherited Glycosylphosphatidylinositol Disorders due to Novel Variants in Phosphatidylinositol Glycan Genes.","authors":"Zi-Xi Zhao, Jing-Lin Zhou, Qi Wang, Songmin Peng, Yao Peng, Yu-Rong Wang, Liang Hu, Rejima Aiyitahong, Lin Peng, Feng Gu, Guang-Xiu Lu, Ge Lin, Song Chen, Yue-Qiu Tan, Juan Du, Wen-Bin He","doi":"10.1111/cge.14716","DOIUrl":"https://doi.org/10.1111/cge.14716","url":null,"abstract":"Inherited glycosylphosphatidylinositol deficiency disorders (IGDs) are a group of rare recessive genetic conditions characterised by developmental delays and an early onset epilepsy caused by disruptions in the glycosylphosphatidylinositol-anchored biosynthetic pathway. In this study, we identified eight variants in phosphatidyl inositol glycan (PIG) genes from four IGDs families through whole-exome sequencing (WES). The variants included one in PIGA, two in PIGW and five in PIGN, with five being novel variants. Functional analysis confirmed the pathogenicity of the PIGN (c.1117-12C>G) and PIGW (c.1112delT and c.659T>G) variants. According to ACMG/AMP guidelines, four novel variants were classified as pathogenic or likely pathogenic. Families I and III successfully delivered healthy children after prenatal diagnosis. This study identified the pathogenic causes of four IGD pedigrees, expanded the mutation spectrum of PIG genes and provided a theoretical basis for reproductive interventions in such families.","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143381757","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

Genome-Wide Association Study Reveals Genetic Architecture of Common Epilepsies.

IF 2.9 3区医学

Clinical Genetics Pub Date : 2025-02-04 DOI: 10.1111/cge.14710

Sarita Thakran, Debleena Guin, Priyanka Singh, Bharathram Uppili, Srinivasan Ramachandran, Suman S Kushwaha, Ritushree Kukreti

{"title":"Genome-Wide Association Study Reveals Genetic Architecture of Common Epilepsies.","authors":"Sarita Thakran, Debleena Guin, Priyanka Singh, Bharathram Uppili, Srinivasan Ramachandran, Suman S Kushwaha, Ritushree Kukreti","doi":"10.1111/cge.14710","DOIUrl":"https://doi.org/10.1111/cge.14710","url":null,"abstract":"Epilepsy, affecting approximately 50 million individuals worldwide, exhibits a genetic heritability of 32%. While several genes/loci associated with epilepsy have been identified through candidate and genome-wide association studies (GWAS), exploration of population-specific markers remains underexplored. We conducted the first GWAS in north Indian population (~1500 samples) to identify genetic variants/loci associated with epilepsy risk, validated using targeted next-generation sequencing (NGS). Our GWAS revealed 30 variants across seven loci associated with epilepsy risk, including six novel loci. Subtype analysis based on etiology and seizure types, identified 57 variants across 11 loci, 10 of which are novel. Gene-set analysis unveiled enrichment in genes associated with glutathione synthesis and recycling and regulation of dopaminergic neuron differentiation pivotal in epilepsy pathophysiology. Furthermore, PRS analysis revealed a significant genetic contribution to the epilepsy with an R2 of 0.00573. Additionally, targeted NGS showed ~95% concordance with GSA genotypes. Our study highlights six novel loci rs17031055/4q31.3(DCHS2), rs73182224/3q27.2(DGKG), rs9322462/6q25.2(CNKSR3), rs75328617/8q24.23(RNU1-35P), rs2938010/10q26.13(CTBP2) and rs11652575/17p11.2(SLC5A10) associated with epilepsy risk. These findings offer valuable insights into the genetic landscape of epilepsy in the north Indian population, providing foundation for future exploratory studies.","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143188525","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

Two Novel Protein-Truncating Variants in NLRP2 and Their Functional Impacts on the Subcortical Maternal Complex.

IF 2.9 3区医学

Clinical Genetics Pub Date : 2025-02-04 DOI: 10.1111/cge.14718

Zeynep Yalcin, Zheng Gao, Ibrahim M Abdelrazek, Eric Bareke, Jacek Majewski, Ebtesam Abdalla, Seang-Lin Tan, Lei Li, Rima Slim

{"title":"Two Novel Protein-Truncating Variants in NLRP2 and Their Functional Impacts on the Subcortical Maternal Complex.","authors":"Zeynep Yalcin, Zheng Gao, Ibrahim M Abdelrazek, Eric Bareke, Jacek Majewski, Ebtesam Abdalla, Seang-Lin Tan, Lei Li, Rima Slim","doi":"10.1111/cge.14718","DOIUrl":"https://doi.org/10.1111/cge.14718","url":null,"abstract":"Female infertility is a prevalent reproductive disorder with high genetic heterogeneity. Previous reports have demonstrated the causal role of biallelic pathogenic variants in the Subcortical Maternal Complex (SCMC) genes in female reproductive failure with some leading to infertility, early embryonic loss, and molar pregnancies, while others are compatible with live birth with and without multilocus imprinting disorders (MLID). Here, we report two deleterious protein-truncating variants, c.1326delG, p.Leu443Phefs*78 and c.2802_2803del, p.Arg935Metfs*15, in heterozygous state in the NLRP2 gene of a patient with primary infertility, four early miscarriages, and one failed attempt of intracytoplasmic sperm injection. We show that the two variants mediate mRNA decay in EBV-transformed lymphoblastoid cells from the patient, lead to decreased NLRP2 protein levels, and alter NLRP2 interactions with other members of the SCMC in vitro. This study emphasizes the importance of performing clinical exomes for patients with recurrent reproductive failure and reporting their variants and reproductive histories to improve patient counseling.","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143188608","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

Whole Genome Sequencing to Identify Novel Germline Fumarate Hydratase Mutation in Child With Bilateral Renal Cell Carcinoma.

IF 2.9 3区医学

Clinical Genetics Pub Date : 2025-02-04 DOI: 10.1111/cge.14723

Christopher Kershaw, Leigh Demain, Eleanor Baker, George Burghel, Miranda Durkie, Claire Forde, Guy Makin, Edmund Cheesman, Anne Warren, David Gokhale, Helene Schlecht, Eamonn Maher, Pedro Oliveira, Emma Woodward

引用次数: 0

Rare Cause 5q SMA: Molecular Genetic and Clinical Analyses of Intragenic Subtle Variants in the SMN Locus.

IF 2.9 3区医学

Clinical Genetics Pub Date : 2025-02-04 DOI: 10.1111/cge.14714

Kristina Mikhalchuk, Viktoria Zabnenkova, Svetlana Braslavskaya, Alena Chukhrova, Nina Ryadninskaya, Elena Dadaly, Galina Rudenskaya, Inna Sharkova, Inga Anisimova, Ludmila Bessonova, Irina Mishina, Svetlana Repina, Marina Petukhova, Peter Sparber, Anna Kuchina, Dmitry Saushev, Svetlana Artemieva, Sergey Kurbatov, Ilya Kanivets, Vera Zarubina, Daria Barykova, Ekaterina Lisakonova, Alexander Polyakov, Olga Shchagina

{"title":"Rare Cause 5q SMA: Molecular Genetic and Clinical Analyses of Intragenic Subtle Variants in the SMN Locus.","authors":"Kristina Mikhalchuk, Viktoria Zabnenkova, Svetlana Braslavskaya, Alena Chukhrova, Nina Ryadninskaya, Elena Dadaly, Galina Rudenskaya, Inna Sharkova, Inga Anisimova, Ludmila Bessonova, Irina Mishina, Svetlana Repina, Marina Petukhova, Peter Sparber, Anna Kuchina, Dmitry Saushev, Svetlana Artemieva, Sergey Kurbatov, Ilya Kanivets, Vera Zarubina, Daria Barykova, Ekaterina Lisakonova, Alexander Polyakov, Olga Shchagina","doi":"10.1111/cge.14714","DOIUrl":"https://doi.org/10.1111/cge.14714","url":null,"abstract":"Spinal muscular atrophy 5q (5q SMA) is one of the most prevalent autosomal recessive disorders globally. The underlying cause of 5q SMA is attributed to variants in SMN1. Exon 7 of SMN1 is not detectable in major of probands with 5q SMA, and minor of probands have a combination of the deletion and an intragenic subtle variant in the second allele. From 1991 to 2023, DNA samples from 2796 probands representing unrelated families were analyzed at the Research Centre for Medical Genetics for the diagnosis of 5q SMA. The copy number of Exon 7 of SMN1 and SMN2 was determined for all probands by MLPA. Subsequently, direct automated Sanger sequencing was employed to perform intragenic subtle variant screenings in all 116 probands with one copy of Exon 7 of SMN1. The diagnosis of 5q SMA was confirmed in 1495 probands. Among the 41 probands with one copy of Exon 7 of SMN1 from the initial 116 tested, 24 intragenic subtle variants in SMN1/SMN2 were documented. The aim of this study was to identify and characterize intragenic subtle variants in SMN1 and analyze their relationship with clinical manifestations in probands with 5q SMA in the Russian cohort.","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143188607","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

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