In conclusion, we describe a patient affected by a complex clinical phenotype resolved by WES carrying multiple molecular pathogenic variants, including a de novo inactivating USP7 variant, compound heterozygosity for a major cystic fibrosis-causing variant and a modifier allele, IVS8-5T, determining a CFTR-RD condition, and a maternally inherited truncating PKD2 variant predisposing to adult-onset autosomal dominant polycystic kidney disease. Here, USP7 is linked to cystic fibrosis.