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":"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。","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":null,"url":null,"abstract":"<p><p>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.</p>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":" ","pages":""},"PeriodicalIF":2.3000,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"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\":null,\"url\":null,\"abstract\":\"<p><p>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.</p>\",\"PeriodicalId\":10354,\"journal\":{\"name\":\"Clinical Genetics\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":2.3000,\"publicationDate\":\"2025-10-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Clinical Genetics\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1111/cge.70078\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"GENETICS & HEREDITY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Clinical Genetics","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1111/cge.70078","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"GENETICS & HEREDITY","Score":null,"Total":0}
Reduced Penetrance and Variable Expression of Dilated Cardiomyopathy Associated With Homozygous Truncating Variants in NRAP Gene.
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.
期刊介绍:
Clinical Genetics links research to the clinic, translating advances in our understanding of the molecular basis of genetic disease for the practising clinical geneticist. The journal publishes high quality research papers, short reports, reviews and mini-reviews that connect medical genetics research with clinical practice.
Topics of particular interest are:
• Linking genetic variations to disease
• Genome rearrangements and disease
• Epigenetics and disease
• The translation of genotype to phenotype
• Genetics of complex disease
• Management/intervention of genetic diseases
• Novel therapies for genetic diseases
• Developmental biology, as it relates to clinical genetics
• Social science research on the psychological and behavioural aspects of living with or being at risk of genetic disease