NEK8-Associated Nephropathies: Do Autosomal Dominant Forms Exist?

Abstract

<b><i>Introduction:</i></b> 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. <b><i>Materials and Methods:</i></b> 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. <b><i>Results:</i></b> Our studies enabled the detection of a heterozygous de novo variant in <i>NEK8</i> (NM_178170: p.Arg45Trp) in the proband. CNV analysis excluded the presence of big deletions or insertions in this gene. <b><i>Conclusion:</i></b> Here we report a de novo heterozygous variant in the <i>NEK</i>8 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 <i>NEK8</i> 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 <i>NEK8</i> gene.

The dominant findings of a recessive man: from Mendel’s kid pea to kidney

“…While their biallelic loss-of-function variants cause Mainzer-Saldino syndrome [ 16 ], renal-hepatic-pancreatic dysplasia [ 17 – 19 ], or steroid-resistant nephrotic syndrome [ 20 ], respectively, monoallelic variants of IFT140 and NEK8 were found causal in rare forms of ADPKD [ 21 – 23 ] and those of NPHS2 in focal segmental glomerulosclerosis (FSGS) [ 24 ]. The monoallelic variants were specific in NEK8 (i.e., p.R45W) [ 21 , 22 ] and in NPHS2 (p.L330Vfs*15 with a premature stop in the last exon) [ 24 ], suggesting a dominant negative effect [ 21 ], but the IFT140 variants in mild ADPKD are intriguingly loss-of-function variants [ 23 ]. Such transformations of dominant or recessive phenotypes would have reversed the two forms of a trait in Mendel’s experiment, but would not have changed the 3:1 ratio of the dominant and recessive forms in the second generation.…”