背景:Nephronophisis-4(NPHP4)是一种遗传性肾性纤毛病,表现为肾纤维化和肾功能进行性损害。这项研究旨在调查两名伊朗兄弟姐妹中NPHP4的遗传基础和临床表现。
方法:先证者是一名27岁的男性,具有终末期肾病的特征,包括贫血,尿毒症,多尿,和多饮。值得一提的是,他有一个22岁的妹妹,也有类似的介绍。临床诊断程序,比如肾活检,脑成像,血液和尿液检查,心脏评估,眼科检查,和听觉功能评估,进行评估器官受累和潜在的合并症。进行全外显子组测序(WES)和分离分析以鉴定和确认与病症相关的遗传变体。进行计算变体分析以评估候选变体的致病性。此外,使用SWISS-MODEL服务器进行蛋白质建模。
结果:大脑,心脏,眼,听觉功能正常.先证者肾活检显示慢性间质性炎症和纤维化。我们通过WES在NPHP4的外显子21中发现了一个新的纯合7碱基对缺失(c.2999_3005delTGTGTGT/p.Asn1000SerfsTer4)。分离分析证实了受影响个体中NPHP4变体的纯合性和父母中的杂合携带者状态,支持常染色体隐性遗传。3D蛋白质建模表明由于变体引起的显著结构变化。
结论:这项研究扩展了肾单位-4的遗传原因和表型谱,并揭示了遗传分析在诊断和管理罕见遗传性肾脏疾病中的重要性。尤其是那些涉及血缘关系的人。
BACKGROUND: Nephronophthisis-4 (NPHP4) is an inherited renal ciliopathy described by renal fibrosis and progressive impairment of kidney function. This study aimed to investigate the genetic basis and clinical manifestations of NPHP4 in two Iranian siblings.
METHODS: The proband was a 27-year-old male with features of end-stage renal disease, including anemia, uremia, polyuria, and polydipsia. It is worth mentioning that he has a 22-year-old sister with a similar presentation. Clinical diagnosis procedures, such as renal biopsy, brain imaging, blood and urine tests, cardiac evaluation, ophthalmic inspection, and auditory function assessment, were carried out to evaluate organ involvement and potential comorbidities. Whole-exome sequencing (WES) and segregation analysis were performed to identify and confirm genetic variants associated with the condition. Computational variant analysis was conducted to evaluate the pathogenicity of the candidate variant. Furthermore, the SWISS-MODEL server was utilized for protein modeling.
RESULTS: The brain, cardiac, ocular, and auditory functions were normal. Renal biopsy of the proband showed chronic interstitial inflammation and fibrosis. We found a novel homozygous 7-base pair deletion (c.2999_3005delTGTGTGT/ p.Asn1000SerfsTer4) in exon 21 of NPHP4 by WES. Segregation analysis confirmed homozygosity for the NPHP4 variant in affected individuals and heterozygous carrier status in parents, supporting autosomal recessive inheritance. 3D protein modeling indicated significant structural changes due to the variant.
CONCLUSIONS: This study expands the genetic causes and phenotypic spectrum of
nephronophthisis-4 and reveals the importance of genetic analysis in diagnosing and managing rare inherited kidney disorders, particularly those involving consanguinity.