96 - Monoallelic NEK8 Pathogenic Variants Cause Very Early Onset Polycystic Kidney Disease

Poster Number: 96
Publication Number: 96.138

Christian Hanna, Mayo Clinic Children's Center, Rochester, MN, United States; Sarah R. Senum, The Mayo Clinic, Rochester, MN, United States; Carl Cramer, Mayo Clinic Children's Center, Rochester, MN, United States; Charles D. Madsen, Mayo Clinic Children's Center, Rochester, MN, United States; Peter C. Harris, Mayo Clinic, Rochester, MN, United States

Background: There is broad genetic heterogeneity underlying polycystic kidney disease (PKD) in children, including autosomal recessive polycystic disease (ARPKD) and ciliopathies with more syndromic involvement. Ciliopathies are often traced to pathogenic variants in genes encoding ciliary proteins. Biallelic pathogenic variants to NEK8, which encodes the cilia associated protein NEK8, cause renal-hepatic-pancreatic dysplasia with multiorgan involvement, while monoallelic carriers are usually asymptomatic.

Objective: We have used broader genetic screening approaches to analyze genetically unresolved childhood PKD families.

Design/Methods: Genetic testing in childhood PKD patients was performed at Mayo Clinic PKD Research Center employing a PKD/ciliopathy gene panel including 357 genes.

Results: Here we report 3 families with a specific monoallelic NEK8 missense variant, c.133C >T (p.Arg45Trp), presenting as very early onset PKD and kidney failure during childhood. Each family is heterozygous for the NEK8 variant, a substitution in the kinase region of NEK8. In one family, PKD was diagnosed in 3 generations: the mother and daughter had kidney failure at 3 and 6 years, respectively, while the grandmother, who was a mosaic for the NEK8 variant, experienced kidney failure at 48 years. In the second family, the son had kidney failure at 8 years and genetic analysis showed that the pathogenic change occurred de novo. Clinical details and variant segregation of the third case with childhood PKD are pending.Conclusion(s): A specific monoallelic NEK8 pathogenic variant causes early onset PKD with childhood kidney failure and should be considered in unresolved ARPKD and other childhood PKD patients with a negative or positive family history.