Clinical Spectrum and Prognosis of Atypical Autosomal Dominant Polycystic Kidney Disease Caused by Monoallelic Pathogenic Variants of IFT140.

RATIONALE & OBJECTIVE: Monoallelic predicted loss-of-function (pLoF) variants in IFT140 have recently been associated with an autosomal dominant polycystic kidney disease (ADPKD)-like phenotype. This study enhanced the characterization of this phenotype.

STUDY DESIGN

Case series.

SETTING & PARTICIPANTS: Seventy-five among 2,797 European individuals with ADPKD-like phenotypes who underwent genetic testing that revealed pLoF IFT140-variants.

FINDINGS

The 75 individuals (median age 56 years, 53.3% females) were from 61 families and were found to have 41 different monoallelic pLoF IFT140-variants. The majority of individuals presented with large, exophytic kidney cysts (median total kidney volume, 688mL [IQR, 201-4,139]), and 90.2% were classified using the Mayo Imaging Classification as Mayo Class 2A. Arterial hypertension was present in 50.7% of the individuals (median age at diagnosis, 59 years [IQR, 29-73]). Only 1 patient developed kidney failure (at age 69 years). A significant difference was observed in the age-adjusted estimated glomerular filtration rate (eGFR) between the male and female patients (P<0.001), and 56.3% of the individuals over the age of 60 years had an eGFR of<60mL/min/1.73m. The estimated genetic prevalence of monoallelic pLoF IFT140 variants was 19.76 (95% CI, 18.8-20.7) and 27.89 (95% CI, 23.8-31.9) per 10,000 in the Genome Aggregation Database and the 100,000 Genomes Project (100kG), respectively. Only cystic kidney disease (ICD-10 Q61) was associated with pLoF IFT140 variants (P = 2.9 × 10, odds ratio = 5.6 (95% CI, 3.3-9.2) in 100kG.

STUDY LIMITATIONS

Retrospective study; IFT140-related cystic kidney disease may not be diagnosed in younger patients or patients with milder forms.

CONCLUSIONS

Individuals with monoallelic IFT140 pLoF variants are likely to develop kidney cysts atypical of classic ADPKD and generally have a favorable kidney prognosis.

PLAIN-LANGUAGE SUMMARY: Monoallelic pathogenic variants in IFT140 have been linked to a spectrum of kidney disease clinically similar to autosomal dominant polycystic kidney disease (ADPKD). This article describes a case series of 75 individuals with ADPKD-IFT140. Affected individuals typically presented with an atypical imaging pattern, had fewer but larger kidney cysts compared with classic ADPKD, and rarely developed liver cysts. Although the kidney prognosis appeared better than in classic ADPKD, 56.3% of individuals over 60 years of age had stage 3 or more severe CKD. Individuals with ADPKD-IFT140 variants are likely to develop kidney cyst patterns atypical of ADPKD. Their kidney prognosis appears favorable.