ESPN 53rd Annual Meeting

ESPN 2021


 
Genotype-phenotype correlations in 304 patients with autosomal recessive polycystic kidney disease (ARPKD) and PKHD1 variants
KATHRIN BURGMAIER 1 LEONIE BRINKER 1 FLORIAN ERGER 2 BODO BECK 2 MARCUS BENZ 3 CARSTEN BERGMANN 4 OLIVIA BOYER 5 LAURE COLLARD 6 CLAUDIA DAFINGER 7 MARC FILA 8 CLAUDIA KOWALEWSKA 9 BäRBEL LANGE-SPERANDIO 10 LAURA MASSELLA 11 ANTONIO MASTRANGELO 12 DJALILA MEKAHLI 13 MONIKA MIKLASZEWSKA 14 NADINA ORTIZ-BRUECHLE 15 LUDWIG PATZER 16 LARISA PRIKHODINA 17 BRUNO RANCHIN 18 NADEJDA RANGUELOV 19 RAPHAEL SCHILD 20 TOMAS SEEMAN 21 LALE SEVER 22 PRZEMYSLAW SIKORA 23 MARIA SZCZEPANSKA 24 ANA TEIXEIRA 25 JULIA THUMFART 26 BARBARA UETZ 27 LUTZ T. WEBER 1 ELKE WÜHL 28 KLAUS ZERRES 15 JÖRG DÖTSCH 1 FRANZ SCHAEFER 28 MAX CHRISTOPH LIEBAU 7

1- DEPARTMENT OF PEDIATRICS, UNIVERSITY HOSPITAL COLOGNE AND UNIVERSITY OF COLOGNE, FACULTY OF MEDICINE, COLOGNE, GERMANY
2- INSTITUTE OF HUMAN GENETICS, UNIVERSITY HOSPITAL COLOGNE AND UNIVERSITY OF COLOGNE, FACULTY OF MEDICINE, COLOGNE, GERMANY; CENTER FOR MOLECULAR MEDICINE COLOGNE, UNIVERSITY OF COLOGNE, FACULTY OF MEDICINE, UNIVERSITY HOSPITAL COLOGNE, GERMANY
3- KLINIK FÜR KINDER- UND JUGENDMEDIZIN, KLINIKUM DRITTER ORDEN, MÜNCHEN, GERMANY
4- MEDIZINISCHE GENETIK MAINZ, LIMBACH GENETICS, MAINZ, GERMANY; RENAL DIVISION, DEPARTMENT OF MEDICINE, UNIVERSITY FREIBURG MEDICAL CENTER, FREIBURG, GERMANY
5- DEPARTMENT OF PEDIATRIC NEPHROLOGY AND KIDNEY TRANSPLANTATION, NECKER HOSPITAL, PARIS, FRANCE
6- CENTRE DE RéFéRENCE DE NéPHROLOGIE PéDIATRIQUE SUD, CLINIQUE DE LESPéRANCE, MONTEGNEE, BELGIUM
7- DEPARTMENT OF PEDIATRICS, UNIVERSITY HOSPITAL COLOGNE AND UNIVERSITY OF COLOGNE, FACULTY OF MEDICINE, COLOGNE, GERMANY; CENTER FOR MOLECULAR MEDICINE COLOGNE, UNIVERSITY OF COLOGNE, FACULTY OF MEDICINE, UNIVERSITY HOSPITAL COLOGNE, GERMANY
8- PEDIATRIC NEPHROLOGY UNIT, CHU ARNAUD DE VILLENEUVE-UNIVERSITé DE MONTPELLIER, MONTPELLIER, FRANCE
9- THE CHILDRENS MEMORIAL HEALTH INSTITUTE, WARSAW, POLAND
10- DEPARTMENT OF PEDIATRICS, DR. VON HAUNER CHILDREN’S HOSPITAL, UNIVERSITY HOSPITAL, LMU, MUNICH, GERMANY
11- DIVISION OF NEPHROLOGY, DEPARTMENT OF PEDIATRIC SUBSPECIALTIES, BAMBINO GESù CHILDREN’S HOSPITAL – IRCCS, ROME, ITALY
12- PEDIATRIC NEPHROLOGY, DIALYSIS AND TRANSPLANT UNIT, FONDAZIONE IRCCS Cà GRANDA, OSPEDALE MAGGIORE POLICLINICO, MILAN, ITALY
13- DEPARTMENT OF DEVELOPMENT AND REGENERATION, PKD RESEARCH GROUP, KU LEUVEN, LEUVEN, BELGIUM; DEPARTMENT OF PEDIATRIC NEPHROLOGY, UNIVERSITY HOSPITALS LEUVEN, LEUVEN, BELGIUM
14- DEPARTMENT OF PEDIATRIC NEPHROLOGY AND HYPERTENSION, FACULTY OF MEDICINE, JAGIELLONIAN UNIVERSITY MEDICAL COLLEGE, KRAKOW, POLAND
15- INSTITUTE OF HUMAN GENETICS, RWTH UNIVERSITY HOSPITAL AACHEN, AACHEN, GERMANY
16- CHILDRENS HOSPITAL ST. ELISABETH AND ST. BARBARA, HALLE (SAALE), GERMANY
17- DEPARTMENT OF INHERITED AND ACQUIRED KIDNEY DISEASES, RESEARCH CLINICAL INSTITUTE FOR PEDIATRICS N.A. ACAD. Y. E. VELTISHEV, PIROGOV RUSSIAN NATIONAL RESEARCH MEDICAL UNIVERSITY, MOSCOW, RUSSIA
18- PEDIATRIC NEPHROLOGY UNIT, HôPITAL FEMME MèRE ENFANT, HOSPICES CIVILS DE LYON, CENTRE DE RéFéRENCE MALADIES RéNALES RARES, BRON, FRANCE
19- DEPARTMENT OF PEDIATRICS, UNIVERSITé CATHOLIQUE DE LOUVAIN MEDICAL SCHOOL, SAINT-LUC ACADEMIC HOSPITAL, BRUSSELS, BELGIUM
20- UNIVERSITY CHILDRENS HOSPITAL, UNIVERSITY MEDICAL CENTER HAMBURG EPPENDORF, HAMBURG, GERMANY
21- DEPARTMENT OF PEDIATRICS, DR. VON HAUNER CHILDREN’S HOSPITAL, UNIVERSITY HOSPITAL, LMU, MUNICH, GERMANY; DEPARTMENT OF PEDIATRICS, UNIVERSITY HOSPITAL MOTOL, 2ND FACULTY OF MEDICINE, CHARLES UNIVERSITY PRAGUE, PRAGUE, CZECH REPUBLIC
22- DEPARTMENT OF PEDIATRIC NEPHROLOGY, CERRAHPAŞA SCHOOL OF MEDICINE, ISTANBUL UNIVERSITY CERRAHPASA, ISTANBUL, TURKEY
23- DEPARTMENT OF PEDIATRIC NEPHROLOGY, MEDICAL UNIVERSITY OF LUBLIN, LUBLIN, POLAND
24- DEPARTMENT OF PEDIATRICS, FACULTY OF MEDICAL SCIENCES IN ZABRZE, SUM IN KATOWICE, POLAND
25- CENTRO MATERNO-INFANTIL DO NORTE, CENTRO HOSPITALAR DO PORTO, PORTO, PORTUGAL
26- DEPARTMENT OF PEDIATRIC NEPHROLOGY, CHARITé – UNIVERSITäTSMEDIZIN BERLIN, CORPORATE MEMBER OF FREIE UNIVERSITäT BERLIN, HUMBOLDT-UNIVERSITäT ZU BERLIN, AND BERLIN INSTITUTE OF HEALTH, GERMANY
27- KFH CENTER OF PEDIATRIC NEPHROLOGY, CHILDRENS HOSPITAL MUNICH SCHWABING, MUNICH, GERMANY
28- DIVISION OF PEDIATRIC NEPHROLOGY, CENTER FOR PEDIATRICS AND ADOLESCENT MEDICINE, UNIVERSITY HOSPITAL HEIDELBERG, HEIDELBERG, GERMANY
 
Abstract:

 

Objectives

Autosomal recessive polycystic kidney disease (ARPKD) is among the most severe hepatorenal diseases in childhood. It is mainly caused by variants in the PKHD1 gene. PKHD1 encodes the protein fibrocystin, which consists of 4074 amino acids. The basis for the pronounced phenotypic variability in ARPKD is poorly understood. Previous genotype-phenotype correlations are restricted to mainly biallelic truncating variants associating with perinatal demise or severe courses. We aimed to elucidate specific genotype-phenotype correlations with respect to the functionality and localization of variants.

Methods

We analyzed datasets of 304 ARPKD patients surviving the neonatal period with ≥ one PKHD1 variant classified as variant of unknown clinical significance, likely pathogenic or pathogenic. Genotypes were assigned to functional classes. Additionally, missense variants were categorized into four protein regions. The clinical endpoints were start of kidney replacement therapy, signs of portal hypertension and substantial hepatic complications.

Results

Patients with Null/Null variants show severe courses. Additionally, the affected region of missense variants is important: when grouping patients according to the localization of the affected amino acids, we observed better kidney survival in patients with variant combinations affecting AAs 709-1837 and better hepatic outcomes in patients with combinations affecting AAs 1838-2624. Variants affecting AAs 2625-4074 were associated with poorer hepatic outcome.

Conclusions

These results refine our understanding of genotype-phenotype correlations in ARPKD during childhood and adolescence and may serve as a basis for more precise counselling and evaluation of treatment approaches.