Refining genotype-phenotype correlations in 304 patients with autosomal recessive polycystic kidney disease and PKHD1 gene variants
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Refining genotype-phenotype correlations in 304 patients with autosomal recessive polycystic kidney disease and PKHD1 gene variants. / Burgmaier, Kathrin; Brinker, Leonie; Erger, Florian; Beck, Bodo; Benz, Marcus; Bergmann, Carsten; Boyer, Olivia; Collard, Laure; Dafinger, Claudia; Fila, Marc; Kowalewska, Claudia; Lange-Sperandio, Bärbel; Massella, Laura; Mastrangelo, Antonio; Mekahli, Djalila; Miklaszewska, Monika; Ortiz-Bruechle, Nadina; Patzer, Ludwig; Prikhodina, Larisa; Ranchin, Bruno; Ranguelov, Nadejda; Schild, Raphael; Seeman, Tomas; Sever, Lale; Sikora, Przemyslaw; Szczepanska, Maria; Teixeira, Ana; Thumfart, Julia; Uetz, Barbara; Weber, Lutz Thorsten; Wühl, Elke; Zerres, Klaus; ESCAPE Study Group; Dötsch, Jörg; Schaefer, Franz; Liebau, Max Christoph.
In: KIDNEY INT, Vol. 100, No. 3, 09.2021, p. 650-659.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Refining genotype-phenotype correlations in 304 patients with autosomal recessive polycystic kidney disease and PKHD1 gene variants
AU - Burgmaier, Kathrin
AU - Brinker, Leonie
AU - Erger, Florian
AU - Beck, Bodo
AU - Benz, Marcus
AU - Bergmann, Carsten
AU - Boyer, Olivia
AU - Collard, Laure
AU - Dafinger, Claudia
AU - Fila, Marc
AU - Kowalewska, Claudia
AU - Lange-Sperandio, Bärbel
AU - Massella, Laura
AU - Mastrangelo, Antonio
AU - Mekahli, Djalila
AU - Miklaszewska, Monika
AU - Ortiz-Bruechle, Nadina
AU - Patzer, Ludwig
AU - Prikhodina, Larisa
AU - Ranchin, Bruno
AU - Ranguelov, Nadejda
AU - Schild, Raphael
AU - Seeman, Tomas
AU - Sever, Lale
AU - Sikora, Przemyslaw
AU - Szczepanska, Maria
AU - Teixeira, Ana
AU - Thumfart, Julia
AU - Uetz, Barbara
AU - Weber, Lutz Thorsten
AU - Wühl, Elke
AU - Zerres, Klaus
AU - ESCAPE Study Group
AU - Dötsch, Jörg
AU - Schaefer, Franz
AU - Liebau, Max Christoph
N1 - Copyright © 2021 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.
PY - 2021/9
Y1 - 2021/9
N2 - Autosomal recessive polycystic kidney disease (ARPKD) is a severe disease of early childhood that is clinically characterized by fibrocystic changes of the kidneys and the liver. The main cause of ARPKD are variants in the PKHD1 gene encoding the large transmembrane protein fibrocystin. The mechanisms underlying the observed clinical heterogeneity in ARPKD remain incompletely understood, partly due to the fact that genotype-phenotype correlations have been limited to the association of biallelic null variants in PKHD1 with the most severe phenotypes. In this observational study we analyzed a deep clinical dataset of 304 patients with ARPKD from two independent cohorts and identified novel genotype-phenotype correlations during childhood and adolescence. Biallelic null variants frequently show severe courses. Additionally, our data suggest that the affected region in PKHD1 is important in determining the phenotype. Patients with two missense variants affecting amino acids 709-1837 of fibrocystin or a missense variant in this region and a null variant less frequently developed chronic kidney failure, and patients with missense variants affecting amino acids 1838-2624 showed better hepatic outcome. Variants affecting amino acids 2625-4074 of fibrocystin were associated with poorer hepatic outcome. Thus, our data expand the understanding of genotype-phenotype correlations in pediatric ARPKD patients and can lay the foundation for more precise and personalized counselling and treatment approaches.
AB - Autosomal recessive polycystic kidney disease (ARPKD) is a severe disease of early childhood that is clinically characterized by fibrocystic changes of the kidneys and the liver. The main cause of ARPKD are variants in the PKHD1 gene encoding the large transmembrane protein fibrocystin. The mechanisms underlying the observed clinical heterogeneity in ARPKD remain incompletely understood, partly due to the fact that genotype-phenotype correlations have been limited to the association of biallelic null variants in PKHD1 with the most severe phenotypes. In this observational study we analyzed a deep clinical dataset of 304 patients with ARPKD from two independent cohorts and identified novel genotype-phenotype correlations during childhood and adolescence. Biallelic null variants frequently show severe courses. Additionally, our data suggest that the affected region in PKHD1 is important in determining the phenotype. Patients with two missense variants affecting amino acids 709-1837 of fibrocystin or a missense variant in this region and a null variant less frequently developed chronic kidney failure, and patients with missense variants affecting amino acids 1838-2624 showed better hepatic outcome. Variants affecting amino acids 2625-4074 of fibrocystin were associated with poorer hepatic outcome. Thus, our data expand the understanding of genotype-phenotype correlations in pediatric ARPKD patients and can lay the foundation for more precise and personalized counselling and treatment approaches.
U2 - 10.1016/j.kint.2021.04.019
DO - 10.1016/j.kint.2021.04.019
M3 - SCORING: Journal article
C2 - 33940108
VL - 100
SP - 650
EP - 659
JO - KIDNEY INT
JF - KIDNEY INT
SN - 0085-2538
IS - 3
ER -