Revue des polykystoses rénales sans mutation identifiée des gènes PKD1 ou PKD2

Details

Supervisors

Demoulin, Nathalie

Faculty

Faculté de médecine et médecine dentaire

Degree label

Master [180] en médecine

Abstract

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is the most frequent inherited kidney disease, and the cause of end stage renal disease in 5 to 10% of patients. Mutations in PKD1 and PKD2 genes are responsible for most cases of ADPKD, in 85% and 15% of cases respectively. Approximately 5 to 10% of ADPKD patients genotyped for PKD1-PKD2 mutations will however remain genetically undiagnosed. This may result from limitations of sequencing techniques used and existence of other causal genes (polycystic liver disease genes (such as ALG8, SEC63, GANAB), DNAJB11). The objectives of our study were to (i) analyse and classify ADPKD patients and families for whom genetic sequencing by Sanger method did not reveal mutations in PKD1 or PKD2; and (ii) study the contribution of next generation sequencing (NGS) techniques eventually performed in these cases. We reviewed all cases of patients of the CUSL ADPKD cohort (881 patients, 531 families). Of the genotyped families (519 patients, 249 families, Sanger sequencing), 169 (68%) had PKD1 causal variants (59% non-truncating), 54 (22%) had PKD2 variants, 6 (2%) were being genotyped and 20 (8%) had no PKD1 or PKD2 variant. We reviewed these 20 families and added 3 others with cystic kidneys and no PKD1-PKD2 variant found by Sanger sequencing. We classified them into five groups according to the (i) typical vs atypical aspect of the renal cysts, (ii) the presence vs absence of hepatic cysts and (iii) positive vs negative family history. We then analysed results of NGS targeted panels (62 potentially causal ‘cystic’ genes) performed in 14 of the 23 families. In the typical cystic groups, NGS panel performed in 7/10 families revealed causal PKD1-PKD2 variants in 3 families (2 due to drop allele effect and 1 due to improved knowledge of PKD1 structure over time), a PKD1 mosaicism in 1 patient (with negative familial history), a GANAB variant of unknown clinical significance in 1 patient and absence of causal variant in 2 patients. In the atypical cystic group, NGS panel performed in 7/13 families showed causal ALG8 variants in 2 families, a NEK8 variant of unknown clinical significance in 1 patient and absence of causal variant in 4 families. Limits of our study include incomplete genotyping of the entire ADPKD cohort, little family segregation analysis and heterogeneity of the cohort (typical and atypical phenotypes). Altogether, targeted NGS panel helped in genetic diagnosis in 5/7 (71%) typical ADPKD families with negative Sanger sequencing of PKD1-PKD2, vs 3/7 (43%) families with atypical renal cystic presentations. Variants need to be looked for in affected relatives (family segregation) and RNA analysis is underway for the GANAB variant. In conclusion, NGS techniques may be contributive in ADPKD families which are genetically unresolved using Sanger sequencing of PKD1-PKD2, especially in those with a typical cystic phenotype.