Clinical Genetics最新文献

Reduced Penetrance and Variable Expression of Dilated Cardiomyopathy Associated With Homozygous Truncating Variants in NRAP Gene. 与NRAP基因纯合截断变异相关的扩张型心肌病外显率降低和可变表达。

IF 2.3 3区医学

Clinical Genetics Pub Date : 2025-10-01 DOI: 10.1111/cge.70078

Aisha Alqahtani, Sahar Tulbah, Nadiah Alruwaili, Saud Takroni, Maarab Alkorashy, Waleed Manea, Dimpna C Albert Brotons, Abdullah Alwadai, Jehad Alburaiki, Fowzan Alkuraya, Nadiah Al-Hashmi, Samah Zarroug, Zuhair N Al-Hassnan

{"title":"Reduced Penetrance and Variable Expression of Dilated Cardiomyopathy Associated With Homozygous Truncating Variants in NRAP Gene.","authors":"Aisha Alqahtani, Sahar Tulbah, Nadiah Alruwaili, Saud Takroni, Maarab Alkorashy, Waleed Manea, Dimpna C Albert Brotons, Abdullah Alwadai, Jehad Alburaiki, Fowzan Alkuraya, Nadiah Al-Hashmi, Samah Zarroug, Zuhair N Al-Hassnan","doi":"10.1111/cge.70078","DOIUrl":"https://doi.org/10.1111/cge.70078","url":null,"abstract":"Dilated Cardiomyopathy (DCM) is a genetically heterogeneous condition of left ventricular dilation and systolic dysfunction, leading to heart failure. It is mostly inherited in a dominant pattern. Recessive inheritance has been rarely encountered. This study aims to outline the clinical and genetic characteristics associated with recessively inherited NRAP truncating variants in our highly consanguineous population. Twenty-three cases from 12 unrelated consanguineous families were recruited. Cardiological evaluation and genetic testing with exome sequencing (ES) were conducted in all cases, followed by segregation analysis of first-degree relatives. Genetic analysis with ES identified five unique homozygous truncating variants in NRAP in the affected cases. The segregation analysis detected a total of 23 homozygous and 21 heterozygous individuals. Out of the total homozygous cases, three were asymptomatic, while 20 exhibited symptoms with remarkable inter- and intrafamilial variability of the age of onset (range: 9 months to 47 years, median 10 years), seven of whom died (range: 9 months to 28 years, median 7 years). None of the heterozygous individuals showed symptoms. Of note, three homozygous cases underwent heart transplantation. Our findings show that truncating variants in NRAP are associated with reduced penetrance and clinical variability, suggesting a complex mechanism beyond simple Mendelian inheritance.","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":" ","pages":""},"PeriodicalIF":2.3,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145205667","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

IF 2.3 3区医学

Clinical Genetics Pub Date : 2025-09-30 DOI: 10.1111/cge.70085

Sherif F Abdel Ghafar, Amr E Ahmed, Eman T Mohammed, Ghada M H Abdel-Salam, Maha S Zaki, Mohamed S Abdel-Hamid

{"title":"MINPP1-Related Pontocerebellar Hypoplasia in Five New Patients: Identification of Three Novel Variants and Further Phenotype Delineation.","authors":"Sherif F Abdel Ghafar, Amr E Ahmed, Eman T Mohammed, Ghada M H Abdel-Salam, Maha S Zaki, Mohamed S Abdel-Hamid","doi":"10.1111/cge.70085","DOIUrl":"https://doi.org/10.1111/cge.70085","url":null,"abstract":"MINPP1-related pontocerebellar hypoplasia (PCH) is a rare neurodevelopmental disorder characterized by microcephaly, profound developmental delay, and a distinct neuroimaging pattern. To date, only 21 patients from 13 unrelated families have been reported. Herein, we describe five patients from four Egyptian families with homozygous MINPP1 variants. All patients presented with global developmental delay, microcephaly, hypotonia, nystagmus, severe motor impairment, seizures, and intellectual disability. Interestingly, all patients exhibited dysmorphic facies, characterized by a high forehead, long philtrum, smooth philtrum, thin upper lip vermilion, broad chin, and low-set ears. Additional variable findings were optic atrophy, strabismus, feeding difficulties, and genital anomalies. Brain MRI showed cerebellar and pontine hypoplasia, thin corpus callosum, cortical atrophic changes, white matter signal, enlarged ventricles, and striking basal ganglia hypoplasia. Exome sequencing identified four MINPP1 variants, including three novel variants (p.Trp68Ter, p.Trp141Ter, and p.Val434_Gln435dup). All variants are localized within functionally critical domains of the protein and were either absent or extremely rare in public databases. Our study increases the number of affected individuals with MINPP1 variants and reinforces the clinical and brain imaging features of the disorder. In addition, the specific facial gestalt noted in our patients along with the basal ganglia changes appear characteristic and might point to the diagnosis of this type of PCH.","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":" ","pages":""},"PeriodicalIF":2.3,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145191309","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

The Genetic Defects of N-DRC in Male Infertility. 男性不育症中N-DRC的遗传缺陷。

IF 2.3 3区医学

Clinical Genetics Pub Date : 2025-09-29 DOI: 10.1111/cge.70081

Jiao Qin, Jinyu Wang, Dingming Li, Fuping Li

{"title":"The Genetic Defects of N-DRC in Male Infertility.","authors":"Jiao Qin, Jinyu Wang, Dingming Li, Fuping Li","doi":"10.1111/cge.70081","DOIUrl":"https://doi.org/10.1111/cge.70081","url":null,"abstract":"The nexin-dynein regulatory complex (N-DRC) is a large protein complex composed of at least 11 subunits (DRC1-DRC11) and plays a crucial role in ciliary and flagellar motility. It links adjacent doublets of microtubules (DMTs) between A and B microtubules, regulating dynein motor activity. Genetic defects in N-DRC subunits lead to primary ciliary dyskinesia (PCD) and abnormal flagellar motility. In recent years, an increasing number of genetic mutations in N-DRC subunits have been reported, associated with male infertility, characterized by multiple morphological abnormalities of the flagella (MMAF) and asthenozoospermia. Therefore, genetic diagnosis of N-DRC defects in male infertility is of significant clinical importance, impacting the reproductive health of patients and the well-being of their offspring. In this review, we summarize the gene mutations of N-DRC subunits reported in the literature concerning male infertility, analyze the phenotypes of affected patients, and outline the functions and mechanisms of N-DRC in sperm flagellar motility. Furthermore, we provide an overview of gene knockout (KO) mouse models of N-DRC and their associated phenotypes. Finally, we summarize the outcomes of assisted reproductive technology (ART) in both patients and KO mice, offering references for the diagnosis and treatment of clinical male infertility caused by N-DRC genetic factors.","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":" ","pages":""},"PeriodicalIF":2.3,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145191366","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

Clinical, Biochemical and Molecular Characterisation of Newborns With Fatty Acid β-Oxidation Disorders: Novel Variants in the ACADM, ACADVL and SLC22A5 Genes. 新生儿脂肪酸β氧化障碍的临床、生化和分子特征：ACADM、ACADVL和SLC22A5基因的新变异

IF 2.3 3区医学

Clinical Genetics Pub Date : 2025-09-29 DOI: 10.1111/cge.70083

Irene Hidalgo Mayoral, Amanda Herranz Cecilia, Carmen Rodríguez-Jiménez, Ana Carazo Álvarez, Ana Bergua Martínez, José David Andrade Guerrero, Ana Moráis López, Sonia Rodríguez-Nóvoa

{"title":"Clinical, Biochemical and Molecular Characterisation of Newborns With Fatty Acid β-Oxidation Disorders: Novel Variants in the ACADM, ACADVL and SLC22A5 Genes.","authors":"Irene Hidalgo Mayoral, Amanda Herranz Cecilia, Carmen Rodríguez-Jiménez, Ana Carazo Álvarez, Ana Bergua Martínez, José David Andrade Guerrero, Ana Moráis López, Sonia Rodríguez-Nóvoa","doi":"10.1111/cge.70083","DOIUrl":"https://doi.org/10.1111/cge.70083","url":null,"abstract":"In this study, we aimed to assess clinical, laboratory and molecular features of newborns with clinical suspicion for systemic primary carnitine deficiency (CUD), medium-chain acyl-CoA dehydrogenase deficiency (MCADD) and very long-chain acyl-CoA dehydrogenase deficiency (VLCADD). The implementation of newborn screening programs for fatty acid β-oxidation disorders (FAODs) has changed the natural course of these diseases, facilitating the initiation of preventive or therapeutic measures for affected newborns shortly after birth. This study included 94 newborns who were admitted between 2016 and 2023 because of biochemical signs of CUD, MCADD and VLCADD, and provided clinical, biochemical and genotypic data. Definitive molecular diagnosis confirmed that 16/94 newborns (17%) were true positives of the NBS, and 17 novel variants were detected in SLC22A5, ACADM and ACADVL genes. We assessed the clinical evolution of patients over time. This study expands the genotypic spectrum of SLC22A5, ACADM and ACADVL and highlights the role of genetics in identifying and correctly characterising FAODs.","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":" ","pages":""},"PeriodicalIF":2.3,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145191322","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

Novel MBTPS1 Variants and Cutis Laxa Phenotype in the 8th Reported Case of Spondyloepiphyseal Dysplasia, Kondo-Fu Type. 8例脊柱骨骺发育不良（近藤-富型）的新MBTPS1变异和皮肤松弛表型

IF 2.3 3区医学

Clinical Genetics Pub Date : 2025-09-29 DOI: 10.1111/cge.70084

Elsa Lucas-Castro, Francisca Diaz-González, Silvia Modamio-Høybjor, Manuel Parrón-Pajares, Sonia Pajares, Laura Gort, Julián Nevado, Pablo Lapunzina, Antonio Leiva-Gea, Karen E Heath

引用次数: 0

IF 2.3 3区医学

Clinical Genetics Pub Date : 2025-09-28 DOI: 10.1111/cge.70077

Burak Altintas, Andrea Stacy, Katie Gettinger, David B Wilson, Marwan S Shinawi

引用次数: 0

Mapping the Prevalence of Lynch Syndrome in the Ceará-Northeast of Brazil. 绘制巴西Ceará-Northeast Lynch综合征患病率图。

IF 2.3 3区医学

Clinical Genetics Pub Date : 2025-09-27 DOI: 10.1111/cge.70082

Maria Claudia Dos Santos Luciano, Paulo Goberlanio de Barros Silva, Rosane Oliveira de Sant'Ana, Clarissa Gondim Picanço de Albuquerque, Francisca Fernanda Barbosa Oliveira, Flavio da Silveira Bitencourt, Isabelle Joyce de Lima Silva Fernandes, José Fernando Bastos Moura, Maria Júlia Barbosa Bezerra

{"title":"Mapping the Prevalence of Lynch Syndrome in the Ceará-Northeast of Brazil.","authors":"Maria Claudia Dos Santos Luciano, Paulo Goberlanio de Barros Silva, Rosane Oliveira de Sant'Ana, Clarissa Gondim Picanço de Albuquerque, Francisca Fernanda Barbosa Oliveira, Flavio da Silveira Bitencourt, Isabelle Joyce de Lima Silva Fernandes, José Fernando Bastos Moura, Maria Júlia Barbosa Bezerra","doi":"10.1111/cge.70082","DOIUrl":"https://doi.org/10.1111/cge.70082","url":null,"abstract":"Lynch syndrome (LS) is an autosomal dominant hereditary disorder that increases the risk of various cancers, especially colorectal (CRC) and endometrial cancer (EC). It results from pathogenic variants in mismatch repair (MMR) genes-primarily MLH1, MSH2, MSH6, and PMS2. Population-specific variant frequencies emphasize the need for localized genetic studies. Methods This study investigated LS prevalence in Ceará, Northeast Brazil, analyzing 150 patients: 130 with CRC, 13 with endometrial cancer, and 7 with other tumors but a family history of LS-associated cancers. Researchers used next-generation sequencing (NGS) to examine 131 genes linked to hereditary cancer syndromes. Variants were classified as Lynch-syndrome associated (MMR genes) or non-Lynch-associated (non-MMR genes). Detection rates varied from 1.18 to 5.07 per 100,000 people; pathogenic variant prevalence ranged from 0 to 1.96 per 100,000 across microregions. Overall, the prevalence of MMR variants was 0.56 per 100,000, and 0.34 for non-MMR variants. MSH2 showed the highest number of pathogenic or likely pathogenic variants, followed by MSH6, PMS2, and MLH1. The study found a particular geographic distribution of LS-related variants. One novel MSH6 variant and two unreported non-Lynch variants (APC and SMAD4) were identified. Conclusions These findings highlight three novel variants in MSH6, APC, and SMAD4, and indicate that Ceará has a higher diversity and a unique spectrum of variants. This reinforces the importance of regional genetic screening and suggests the need to expand testing access, especially in high-risk areas, to improve the early detection and prevention of hereditary cancers in Northeast Brazil.","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":" ","pages":""},"PeriodicalIF":2.3,"publicationDate":"2025-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145174028","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

High Concordance of Copy Number Variants Detected by Chromosomal Microarray and Exome Sequencing in Clinical Diagnostics. 染色体微阵列和外显子组测序检测拷贝数变异在临床诊断中的高一致性

IF 2.3 3区医学

Clinical Genetics Pub Date : 2025-09-27 DOI: 10.1111/cge.70079

Rivka Birnbaum, Maya Slovik, Shamir Zenvirt, Ilana Livyatan, Israel Altman, Shiri Gershon, Jonathan Rips, Hagit Daum, Chaggai Rosenbluh, Orly Elpeleg, Vardiella Meiner, Ayala Frumkin, Hagar Mor-Shaked, Tamar Harel

{"title":"High Concordance of Copy Number Variants Detected by Chromosomal Microarray and Exome Sequencing in Clinical Diagnostics.","authors":"Rivka Birnbaum, Maya Slovik, Shamir Zenvirt, Ilana Livyatan, Israel Altman, Shiri Gershon, Jonathan Rips, Hagit Daum, Chaggai Rosenbluh, Orly Elpeleg, Vardiella Meiner, Ayala Frumkin, Hagar Mor-Shaked, Tamar Harel","doi":"10.1111/cge.70079","DOIUrl":"https://doi.org/10.1111/cge.70079","url":null,"abstract":"Exome sequencing (ES), originally developed to detect single nucleotide variants (SNVs), has been increasingly leveraged to detect copy number variants (CNVs) through read-depth analysis, enhancing diagnostic yield with minimal computational overhead. However, chromosomal microarray (CMA) testing remains widely used. To evaluate the utility of ES as a first-tier clinical diagnostic test, we compared the sensitivity of CNV detection by ES to that of CMA in individuals who underwent both tests, and developed triploidy screening based on ES data. ES identified most clinically relevant CNVs, with a 98.91% concordance for regions adequately captured. A retrospective analysis of CNVs detected from ES over a ~3-year period, comprising 1563 prenatal and 4884 postnatal cases, revealed CNVs in 3.8% of prenatal and 4.4% of postnatal samples. The relatively low percentage stems from the fact that most cases underwent CMA before ES. Pathogenic or likely pathogenic variants constituted 78.7% and 78.0% of these subgroups, with the remainder classified as variants of unknown significance. We highlight clinically relevant examples of CNVs across a range of sizes, including cases involving both CNVs and SNVs. The high consanguinity rate of the cohort allowed for systematic analysis of homozygous CNVs. Additionally, we demonstrate that ES can capture other diagnostic utilities traditionally associated with CMA, specifically uniparental disomy (UPD) and triploidy. Overall, our findings support ES as a robust, cost-effective alternative to CMA and advocate for its broader use as a first-tier diagnostic test for neurodevelopmental delay and congenital malformations, particularly until whole genome sequencing becomes more accessible and affordable.","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":" ","pages":""},"PeriodicalIF":2.3,"publicationDate":"2025-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145173976","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 Further Case Supporting BORCS8 as a Cause of an Infantile-Onset Neurodegenerative Disorder. 支持BORCS8作为婴儿发病神经退行性疾病病因的又一病例

IF 2.3 3区医学

Clinical Genetics Pub Date : 2025-09-24 DOI: 10.1111/cge.70075

Mohamed S Abdel-Hamid, Samer H ElKhayat, Ghada M H Abdel-Salam

引用次数: 0

Genetic Etiology of 46, XY Disorders of Sex Development in Chinese Patients: Insights From Whole-Exome Sequencing. 中国46，xy性发育障碍的遗传病因学：来自全外显子组测序的见解

IF 2.3 3区医学

Clinical Genetics Pub Date : 2025-09-21 DOI: 10.1111/cge.70068

Hui Jing, Zixuan Wang, Yu Mao, Yunman Tang, Yuhan Chen, Li Cao, Yuwei Chen-Zhang, Jiyun Yang

引用次数: 0