Autosomal dominant polycystic kidney disease (ADPKD) is the most common monogenic renal disease and is mainly caused by pathogenic variants in the PKD1 and PKD2 genes. Biallelic IFT140 variants cause a rare severe early-onset ciliopathy with renal failure in childhood (prevalence < 1/ 50 000). Recently, monoallelic loss-of-function (LoF) variants in the IFT140 gene have been described as a cause of atypical ADPKD.
Our objective was to explore the prevalence of LoF IFT140 variants in a large cohort of ADPKD patients.

A total of 768 index patients with suspected ADPKD were analyzed using a custom-designed renal disease gene panel sequenced with a high depth of coverage (>400x).

Monoallelic LoF variants in IFT140 were detected in 8 of the 768 patients with suspected ADPKD. The 8 patients had a mean age of 50 years (range: 34 to 78 years) and all had normal renal function (estimated glomerular filtration rate > 60 ml/min/1.73 m2). They had asymmetrically enlarged kidneys with few large renal cysts and no or few hepatic cysts. Three IFT140 patients had hypertension. Three of the 8 IFT140 variants identified consisted of deletion of one or more exons.

Identification of a monoallelic LoF IFT140 variant is diagnostic of an atypical form of ADPKD, characterized by asymmetrically enlarged kidneys with voluminous cysts, preserved renal function or mild renal insufficiency, hypertension, and few or no liver cysts. The IFT140 gene is the cause of approximately 1% of patients with ADPKD.