AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE (ADPKD): PKD1 AND PKD2 MUTATIONAL SCREENING IN 100 ITALIAN PATIENTS

INTRODUCTION AND AIMS: Autosomal dominant polycystic kidney disease (ADPKD), the most common inherited kidney disorder with an incidence of 1 in 400 to 1 in 1000 individuals, is characterized by the development and progressive enlargement of renal cysts leading to end-stage renal failure. ADPKD is typically diagnosed by imaging such as ultrasonography, computed tomography, or magnetic nuclear resonance. However, a diagnosis by imaging may be uncertain, expecially in young individuals (<30 years) and in individuals with a negative family history. ADPKD is caused by mutations in PKD1 or PKD2 genes. The molecular diagnosis of ADPKD is complicated by extensive allelic heterogeneity and particularly by the presence of six highly homologous sequences of PKD1 exons 1–33. Although, clinical studies and case reports describing one or few families have been reported in Italian population, to date a comprehensive molecular study of ADPKD is still lacking. Here, we report our comprehensive mutation analysis of PKD1 And PKD2 genes in 100 Italian ADPKD patients. METHODS: PKD1 and PKD2 genes were analyzed in 100 ADPKD Italian patients - the largest Italian cohort analyzed to date in a single study - by direct sequencing, Multiplex Ligation-dependent Probe Amplification (MLPA) and RNA analysis. The potential pathogenicity of the newly identified missense variants was evaluated by combining different methods: PolyPhen, Sorting Intolerant from Tolerant (SIFT) and Mutation Taster. RESULTS: We identified the largest number of pathogenic mutations (n = 50) reported in a single study in Italian population. The mutations are of all different type (17 missense, 10 nonsense, 8 splice site, 15 small deletions and insertions) and are spread over the exons of the PKD1 gene. Twenty PKD1 mutations have not been previously described, expanding the spectrum of known ADPKD pathogenic mutations, and 10 were de novo, described in sporadic ADPKD patients, providing in such cases a definitive diagnosis of ADPKD. Of the 20 different novel PKD1 mutations 3 were found in ≥2 unrelated patients in our cohort. Notably, all of these recurrent mutations were found in patients from Southern Italy, a sign of founder mutations. CONCLUSIONS: In summary, we performed a comprehensive mutation screening of PKD1 and PKD2 genes in Italian population. Our study represents a significant advance in the molecular diagnosis of ADPKD Italian patients because it (1) analyze the largest Italian cohort to date and report the largest number of new mutations in a single Italian study; (2) describe for the first time new potential founder mutations in ADPKD patients from Southern Italy and 3) emphasize the important role of molecular genetic screening in ADPKD young individuals and sporadic patients for the definitive diagnosis.