Oumayma Taroua, O. Askander, Hakima Rhou, A. Bouhouche
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Case Presentation: Here we report a Moroccan consanguineous family with an 18-year-old girl who presented with advanced renal failure and microscopic hematuria. Her audiometry revealed hearing impairment. Urinalysis performed in all the asymptomatic family members showed microscopic hematuria in the mother and younger sister, while computed tomography excluded a urologic cause. Using next-generation sequencing analysis, we identified in the proband a nonsense homozygous variant in the COL4A3 gene (c.4114C>T, p.Gln1372Ter) that was never reported in the literature, and which is considered pathogenic according to the ACMG classification. Segregation analysis in the family showed that the parents were heterozygous like the elder brother, whereas the younger sister was mutated homozygous, and the other brother was homozygous normal. Conclusion: We report a novel nonsense pathogenic variant in COL4A3 that expends the allelic spectrum in AS. Clinical exploration and genetic testing of all the family members revealed intrafamilial clinical variability, suggesting a pseudo-dominant inheritance and a reduced penetrance.","PeriodicalId":48566,"journal":{"name":"Molecular Syndromology","volume":null,"pages":null},"PeriodicalIF":0.9000,"publicationDate":"2024-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"A Novel Loss-of-Function Variant in COL4A3 in a Consanguineous Moroccan Family Displaying the Alport Syndrome with Variable Clinical Expression\",\"authors\":\"Oumayma Taroua, O. Askander, Hakima Rhou, A. Bouhouche\",\"doi\":\"10.1159/000540122\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"Introduction: Alport syndrome (AS) is a rare genetic disorder characterized by abnormalities in the kidneys, ears, and eyes. Its clinical presentation typically manifests in childhood or adolescence and varies widely among affected individuals, ranging from isolated hematuria to end-stage renal disease. The genetic causes of AS primarily involve mutations in the genes encoding type IV collagen COL4A3, COL4A4, and COL4A5, which play essential roles in maintaining the structural integrity of the glomerular basement membrane in the kidney, the cochlea, and the retina. They can be transmitted in autosomal dominant, autosomal recessive, and X-linked recessive. Case Presentation: Here we report a Moroccan consanguineous family with an 18-year-old girl who presented with advanced renal failure and microscopic hematuria. Her audiometry revealed hearing impairment. Urinalysis performed in all the asymptomatic family members showed microscopic hematuria in the mother and younger sister, while computed tomography excluded a urologic cause. Using next-generation sequencing analysis, we identified in the proband a nonsense homozygous variant in the COL4A3 gene (c.4114C>T, p.Gln1372Ter) that was never reported in the literature, and which is considered pathogenic according to the ACMG classification. Segregation analysis in the family showed that the parents were heterozygous like the elder brother, whereas the younger sister was mutated homozygous, and the other brother was homozygous normal. Conclusion: We report a novel nonsense pathogenic variant in COL4A3 that expends the allelic spectrum in AS. 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引用次数: 0
摘要
简介阿尔波特综合征(AS)是一种罕见的遗传性疾病,以肾脏、耳朵和眼睛的异常为特征。其临床表现通常出现在儿童或青少年时期,受影响的个体差异很大,从孤立性血尿到终末期肾病不等。强直性脊柱炎的遗传原因主要涉及编码 IV 型胶原 COL4A3、COL4A4 和 COL4A5 的基因突变,这些基因在维持肾小球基底膜、耳蜗和视网膜结构完整性方面发挥着重要作用。它们可通过常染色体显性、常染色体隐性和 X 连锁隐性遗传。病例介绍:我们在此报告一个摩洛哥近亲家庭中的一名 18 岁女孩,她出现晚期肾衰竭和镜下血尿。她的听力测定显示有听力障碍。对所有无症状的家庭成员进行的尿液分析表明,母亲和妹妹出现了镜下血尿,而计算机断层扫描排除了泌尿系统病因。通过新一代测序分析,我们在该患者的 COL4A3 基因中发现了一个无义同源变异(c.4114C>T, p.Gln1372Ter),该变异在文献中从未报道过,根据 ACMG 的分类,该变异被认为是致病性的。该家族的分离分析表明,父母与哥哥一样是杂合子,而妹妹是突变的同合子,另一个哥哥是正常的同合子。结论我们报告了COL4A3中的一种新型无义致病变体,它扩大了强直性脊柱炎的等位基因谱。对所有家族成员进行的临床研究和基因检测发现,家族内部存在临床变异,这表明该基因具有假显性遗传性和较低的渗透性。
A Novel Loss-of-Function Variant in COL4A3 in a Consanguineous Moroccan Family Displaying the Alport Syndrome with Variable Clinical Expression
Introduction: Alport syndrome (AS) is a rare genetic disorder characterized by abnormalities in the kidneys, ears, and eyes. Its clinical presentation typically manifests in childhood or adolescence and varies widely among affected individuals, ranging from isolated hematuria to end-stage renal disease. The genetic causes of AS primarily involve mutations in the genes encoding type IV collagen COL4A3, COL4A4, and COL4A5, which play essential roles in maintaining the structural integrity of the glomerular basement membrane in the kidney, the cochlea, and the retina. They can be transmitted in autosomal dominant, autosomal recessive, and X-linked recessive. Case Presentation: Here we report a Moroccan consanguineous family with an 18-year-old girl who presented with advanced renal failure and microscopic hematuria. Her audiometry revealed hearing impairment. Urinalysis performed in all the asymptomatic family members showed microscopic hematuria in the mother and younger sister, while computed tomography excluded a urologic cause. Using next-generation sequencing analysis, we identified in the proband a nonsense homozygous variant in the COL4A3 gene (c.4114C>T, p.Gln1372Ter) that was never reported in the literature, and which is considered pathogenic according to the ACMG classification. Segregation analysis in the family showed that the parents were heterozygous like the elder brother, whereas the younger sister was mutated homozygous, and the other brother was homozygous normal. Conclusion: We report a novel nonsense pathogenic variant in COL4A3 that expends the allelic spectrum in AS. Clinical exploration and genetic testing of all the family members revealed intrafamilial clinical variability, suggesting a pseudo-dominant inheritance and a reduced penetrance.
期刊介绍:
''Molecular Syndromology'' publishes high-quality research articles, short reports and reviews on common and rare genetic syndromes, aiming to increase clinical understanding through molecular insights. Topics of particular interest are the molecular basis of genetic syndromes, genotype-phenotype correlation, natural history, strategies in disease management and novel therapeutic approaches based on molecular findings. Research on model systems is also welcome, especially when it is obviously relevant to human genetics. With high-quality reviews on current topics the journal aims to facilitate translation of research findings to a clinical setting while also stimulating further research on clinically relevant questions. The journal targets not only medical geneticists and basic biomedical researchers, but also clinicians dealing with genetic syndromes. With four Associate Editors from three continents and a broad international Editorial Board the journal welcomes submissions covering the latest research from around the world.