A Possible Founding PKD2 Mutation Associated With Variable Phenotypes of ADPKD in Bergamo Province

Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited disease of the kidney. It occurs in adulthood but is also rarely diagnosed in early childhood. The majority of the disease-causing variants observed in ADPKD patients are located in two genes: PKD1 and PKD2. They account for 78% and 13% of ADPKD cases, respectively, while in approximately 6-9% of clinically diagnosed patients other genes have been shown to contribute to the disease. Most ADPKD mutations are private and so far no hot-spot mutations have been reported in PKD1 and PKD2. On average, renal survival of patients with PKD2 mutations is 20 years longer than in patients with PKD1 mutations. However, there is a high degree of clinical variability among patients as well as within families, with different rates of progression towards end-stage renal disease (ESRD), partially driven by genetic factors. Few reports are available about possible founding mutations in ADPKD. We have recently reported the results of genetic analysis for PKD1 and PKD2 by Sanger sequencing and Multiplex Ligation-dependent Probe Amplification (MLPA) in a large Italian cohort of ADPKD patients who were referred to our center for genetic analysis through the Italian National Health Service. MLPA is a method for detecting copy number variation (CNV) of a specific DNA segment within the genome, suggestive of duplications, deletions or other structural variants that may affect long DNA stretches. The exact characterization of the extent of the structural variant identified by MLPA, however, requires subsequent analyses. In 4 families (6 patients) who were negative at Sanger sequencing, MLPA analysis of PKD2 revealed a novel heterozygous copy number variation (CNV) indicative of a deletion of at least 11,000 base pairs (bp) and spanning exons 1-2. These families are formally not related, but they live in the same geographical area including three small villages in Bergamo province (Torre de Roveri, Albano S. Alessandro, Scanzorosciate), suggesting a potential founder effect. More recently, we detected the same PKD2 CNV in 3 additional families (4 patients) from the same geographical area, further strengthening this hypothesis. Most affected subjects in these families have mild disease, as expected for PKD2 mutations, but one patient experienced early ESRD and another one presents congenital anomalies of the kidney and the urinary tract (CAKUT) in addition to the typical ADPKD phenotype, indicating a different expressivity of the disease or the possible presence of other genetic factors affecting the clinical phenotype. Further in depth analyses were needed to investigate the deletion of at least 11,000 base pairs (bp) and spanning exons 1-2 to find the breakpoint site in the 10 patients for diagnostic purpose. We found the same breakpoint sites across all the patients pointing to a common origin, and similar disease expressivity.