Identifying new genes in ADPKD-like pedigrees

Objectives:

• To analyse whole exome sequencing data from individuals with ADPKD who remained genetically unresolved after application of a cystic kidney gene panel, in order to identify new cystic gene candidates and cystic kidney phenocopies.
• To assess the clinical and radiological features of genetically unresolved individuals with ADPKD in conjunction with family history and genetic findings.
• To explore the genetic prevalence and penetrance of ADPKD-linked genes using population-based databases (gnomAD) and large patient-based genomic datasets (Genomics England 100k Genomes Project).
• To analyse the clinical phenotype of patients with presentations atypical of classical ADPKD (e.g., ADPKD related to monoallelic pathogenic variants in IFT140, ALG5, and ALG6).

Results:

• ADPKD and the ADPKD-like spectrum represent a genetically heterogeneous group of diseases, involving more than 20 genes (10 cystic genes and over 10 ADPKD phenocopies).
• Predicted loss-of-function monoallelic variants in IFT140are the third most common genetic cause of ADPKD, typically associated with an atypical presentation and a favourable kidney prognosis.
• Monoallelic variants in an ongoing candidate gene under phenotypic characterization may also cause ADPKD with atypical features reminiscent of IFT140-associated disease.