ESPN 51th Annual Meeting

ESPN 2018


 
Genotype – phenotype correlation in a pediatric ADPKD cohort
STéPHANIE DE RECHTER 1 CAROLINE WEYDERT 1 BERT BAMMENS 2 RUDI VENNEKENS 3 ANNIEK CORVELEYN 4 KOENRAAD DEVRIENDT 4 CLAUDE FEREC 5 MARIE-PIERRE AUDREZET 5 PETER C HARRIS 6 DJALILA MEKAHLI 1

1- KU LEUVEN, DEPARTMENT OF DEVELOPMENT AND REGENERATION, PKD RESEARCH GROUP
2- DEPARTMENT OF INTERNAL MEDICINE, DIVISION OF NEPHROLOGY, UNIVERSITY HOSPITAL OF LEUVEN, LEUVEN, BELGIUM
3- KU LEUVEN, DEPARTMENT OF MOLECULAR AND CELLULAR MEDICINE, LEUVEN, BELGIUM
4- DEPARTMENT OF GENETICS, KU LEUVEN - UNIVERSITY HOSPITAL OF LEUVEN, LEUVEN, BELGIUM
5- DEPARTMENT OF NEPHROLOGY, UNIVERSITY HOSPITAL, BREST, FRANCE
6- DIVISION OF NEPHROLOGY AND HYPERTENSION, MAYO CLINIC COLLEGE OF MEDICINE, ROCHESTER, MINNESOTA, USA
 
Introduction:

The geno-phenotype correlation is well documented in ADPKD adults. PKD2 is milder than PKD1 disease, with ESRD occurring on average 20 years later, and patients with PKD1 truncating mutations have a more severe outcome than PKD1 non truncating mutations. However, pediatric data on this correlation are lacking. We therefore aim to analyse the effect of both PKD1/2 mutations/variants in a large pediatric ADPKD cohort, including the influence of other ciliopathy genes. This genotypic profile will be correlated with disease onset and progression.

Material and methods:

Children diagnosed with ADPKD were eligible for inclusion. Clinical data including renal function and imaging were collected longitudinally, starting at time of diagnosis. PKD genes were analysed by direct sequencing and quantitative fluorescent multiplex PCR on array-comparative genomic hybridization. Also, 136 ciliopathies genes including HNF1B, PKHD1, GANAB, etc will be analysed using next generation sequencing.

Results:

57 ADPKD children from 43 different families were diagnosed at a mean (+/- SD) age of 4.3 (+/-5.1) years, due to screening (56%), symptoms (eg UTI;14%), by coincidence (14%) or prenatally (16%). 88% had a PKD1 mutation (80% truncating, 20% non-truncating), 4% a PKD2 mutation, and 7% non PKD1-PKD2. At last follow-up with a mean (+/-SD) age of 11.4 (+/- 5.8) years, 7% had hypertension, 17% proteinuria/microalbuminuria and 12% both. 25% of the population had unilateral nephromegaly, and another 25% had bilateral nephromegaly. Nine percent of patients were in CKD stage 2 and 2% in stage 3. Ciliopathy gene panel analysis is currently ongoing and we will analyse the effect of present modifier genes on the phenotype.

Conclusions:

We report the first large cohort of genotyped ADPKD children. We aim to describe a correlation between PKD mutations and the onset of disease and modifier mutations and disease progression. These results will contribute to the development of risk stratification criteria from childhood.