The genotype distribution in a single-centre cohort of patients with polycystic kidney disease

Abstract Background and Aims Polycystic kidney disease (PKD) is one of the most common causes of chronic kidney disease (CKD) and could lead to the end-stage kidney disease (ESKD) both in adulthood and in childhood. In the last few years many genes were discovered to be associated with PKD beyond the classical genes PKD1 and PKD2, that account for the majority of patients with ADPKD (Autosomal Dominant Polycystic Kidney Disease), and PKHD1 and DZIPIL that are responsible of ARPKD (Autosomal Recessive Polycystic Kidney Disease). The new genes are associated with different type of extra-renal involvement and with variable chance to develop CKD or ESKD. Thus, it is important for clinicians to define what mutation is involved in each patient to improve care in a context of precision medicine. We here describe a cohort of 65 consecutive patients followed at our PKD outpatient clinic who underwent the genetic analysis. Method We conducted a retrospective study of patients followed at our PKD outpatient clinic who underwent a genetic test for clinical reasons. We recorded why test was performed, with which modality and what was the result. If the analysis was positive we analyzed if only one or more genes were found mutated and if they belong to new genes described as being involved in PKD or if they are usually described in association with different diseases. Then, we collected demographic and clinical information (age, sex, renal function/presence of absence of ESKD) and the radiological description of kidneys in order to distinguish between typical and atypical PKDs. Results Among the 65 patients of our cohort 28 (43%) were males and 37 (57%) were females, the mean age was 56±18.6 years old; 20% had ESKD. They underwent genetic analysis for different reasons: 31 because of atypical PKD forms, 6 to define a suspected de novo mutation, 14 as a familiar screening and 14 for a better prognosis definition or when they approached the kidney transplant. The genetic analysis was conducted in two main ways: sequencing of PKD1 and PKD2 genes according to modern standards or exome sequencing. The first type of analysis was used for typical ADPKD forms whereas the second type was used when patients displayed an atypical presentation for both cysts distribution and kidney diameter (usually not enlarged kidneys with multiple bilateral cysts) and in two patients in which PKD1 and PKD2 sequencing was negative despite the PKD phenotype. We found that 25% of patients were negative, and the others are almost equally distributed between typical gene mutations and mutations in other genes (40% and 35% respectively) (Figure 1A). Of those with typical mutation, 81% was PKD1 positive and 19% PKD2 positive, a distribution that reflects that of literature (Figure 1B). Of those with other genes positivity: 52% had a DNAJB11 mutation, 17% a mutations in other PKD genes (ALG8, LRP5, PKHD1, COL4A1, IFT140), 32% had a mutation in genes usually associated with CAKUT (congenital anomalies of kidney and urinary tract) or with syndromic or extra-renal diseases (Figure 1C). 18 patients presented with multiple mutations, usually 2, in one case three and in another 4. Of them, the 22% had a double PKD1 mutation, while the others showed mutations in different genes associated with syndromic or extra-renal diseases (Figure 1D). Conclusion Our cohort revealed a wide variety of genetic mutations and also an almost equal distribution between typical genes and atypical/other genes. This could be the result of the small number of patients involved and of the monocentric design of the study (we have a cluster of patients with DNAJB11 belonging to the same small geographical area), but also of the larger inclusion of patients presenting with atypical PKDs. Unfortunately a 25% of patients remained genetically unresolved despite the use of exome sequencing.