Mehawej Cybel, Chouery Eliane, Ghabril Ramy, Tokajian Sima, Megarbane Andre
Department of Human Genetics, Gilbert and Rose-Marie Chagoury School of Medicine, Lebanese American University, Byblos, Lebanon.
Pediatric Nephrology Unit, Department of Clinical Pediatrics, Saint George University Hospital, University of Balamand, Beirut, Lebanon.
Nephron. 2023;147(3-4):229-233. doi: 10.1159/000526841. Epub 2022 Oct 10.
Nephronophthisis (NPHP) is a group of autosomal recessive renal diseases characterized by a reduced ability of the kidneys to concentrate solutes, chronic tubulointerstitial nephritis, and cystic kidney disease. It represents the most common genetic cause of childhood renal failure. To date, around 20 different genes, encoding primary cilia proteins, have been linked to NPHP. These contribute to one-third of cases with NPHP while the majority of patients remain molecularly undiagnosed.
Whole exome sequencing (WES) was carried out on a 2-year-old Lebanese boy with infantile NPHP characterized by multicystic kidney dysplasia, kidney insufficiency, and enlarged kidneys in addition to chronic anemia. The candidate variant, detected by WES, was then tested in the patient and his parents by Sanger sequencing. Copy number variation (CNV) analysis was subsequently performed in the proband.
Our studies enabled the detection of a heterozygous de novo variant in NEK8 (NM_178170: p.Arg45Trp) in the proband. CNV analysis excluded the presence of big deletions or insertions in this gene.
Here we report a de novo heterozygous variant in the NEK8 gene in infantile NPHP. This variant was previously detected at a de novo state in a patient presenting with the same clinical features as the proband. This suggests that autosomal dominant forms of NEK8-linked nephropathies may exist. Reporting further patients with NEK8 mutations is essential to confirm these findings and assess whether dominant forms of the disease are restricted to a specific mutational spot or are linked to variants scattered throughout the NEK8 gene.
肾单位肾痨（NPHP）是一组常染色体隐性遗传性肾脏疾病，其特征为肾脏浓缩溶质的能力下降、慢性肾小管间质性肾炎和多囊肾病。它是儿童肾衰竭最常见的遗传病因。迄今为止，约20种编码初级纤毛蛋白的不同基因已与NPHP相关联。这些基因导致了三分之一的NPHP病例，而大多数患者在分子水平上仍未得到诊断。
对一名2岁的黎巴嫩男孩进行了全外显子组测序（WES），该男孩患有婴儿型NPHP，其特征除慢性贫血外，还包括多囊性肾发育不良、肾功能不全和肾脏肿大。通过WES检测到的候选变异，随后通过桑格测序在患者及其父母中进行检测。随后对先证者进行了拷贝数变异（CNV）分析。
我们的研究在该先证者中检测到NEK8基因（NM_178170：p.Arg45Trp）的杂合新生变异。CNV分析排除了该基因中存在大的缺失或插入。
在此我们报告婴儿型NPHP中NEK8基因的新生杂合变异。该变异先前在一名具有与先证者相同临床特征的患者中以新生状态被检测到。这表明可能存在NEK8相关肾病的常染色体显性形式。报告更多具有NEK8突变的患者对于证实这些发现以及评估该疾病的显性形式是否仅限于特定突变位点或与遍布NEK8基因的变异相关至关重要。
