Monoallelic IFT140 Variants Causing Childhood-Onset Autosomal Dominant Polycystic Kidney Disease.

Abstract

IFT140 is a component of the intraflagellar transport-complex A involved in retrograde ciliary trafficking of proteins into primary cilia. Monoallelic IFT140 variants have been identified as an important cause of adult-onset autosomal dominant polycystic kidney disease (ADPKD), accounting for ∼2% of prevalent cases. Patients with ADPKD-IFT140 usually present in later life with small numbers of large cysts and rarely develop kidney failure. Here, we report 3 genetically resolved cases of ADPKD-IFT140 diagnosed in childhood or infancy from 3 unrelated pedigrees with ages at presentation ranging from in utero to 14 years. Each pedigree had a different familial IFT140 variant, with no evidence of a second ADPKD gene variant on whole genome sequencing. All 3 children had normal kidney function and normal blood pressure, although 1 child presented initially with a high cyst burden in utero and had impaired function on a DMSA scan. Despite the negative family history, cascade screening of first-degree relatives revealed previously undiagnosed ADPKD with features typical of adult-onset ADPKD-IFT140. Our findings highlight the need to consider IFT140 as a potential cause of childhood early-onset ADPKD and expand the phenotypic spectrum of ADPKD-IFT140.