ESPN 53rd Annual Meeting

ESPN 2021


 
Diagnostic yield and benefits of whole-exome sequencing in patients with congenital anomalies of the kidney and urinary tract (CAKUT) diagnosed in the first thousand days of life
LINA WERFEL 2 HELGE MARTENS 1 IMKE HENNIES 2 ANNE CHRISTIANS 1 ANN CHRISTIN GJERSTAD 3 KERSTIN FRÖDE 2 BARBARA MAGDA LUDWIKOWSKI 4 ROBERT GEFFERS 5 HEIKO BILLING 6 MARTIN KIRSCHSTEIN 7 ALEJANDRO D. HOFMANN 8 ANNA BJERRE 3 DIETER HAFFNER 2 RUTHILD G. WEBER 1

1- DEPARTMENT OF HUMAN GENETICS, HANNOVER MEDICAL SCHOOL, HANNOVER, GERMANY
2- DEPARTMENT OF PEDIATRIC KIDNEY, LIVER AND METABOLIC DISEASES, HANNOVER MEDICAL SCHOOL, HANNOVER, GERMANY
3- DIVISION OF PAEDIATRIC AND ADOLESCENT MEDICINE, OSLO UNIVERSITY HOSPITAL, OSLO, NORWAY
4- DEPARTMENT OF PEDIATRIC SURGERY AND UROLOGY, AUF DER BULT KINDER- UND JUGENDKRANKENHAUS, HANNOVER, GERMANY
5- GENOME ANALYTICS RESEARCH GROUP, HELMHOLTZ CENTRE FOR INFECTION RESEARCH, BRAUNSCHWEIG, GERMANY
6- DEPARTMENT OF PAEDIATRICS I, UNIVERSITY CHILDREN’S HOSPITAL, TÜBINGEN, GERMANY
7- DEPARTMENT OF PEDIATRICS, GENERAL HOSPITAL, CELLE, GERMANY
8- DEPARTMENT OF PEDIATRIC SURGERY, HANNOVER MEDICAL SCHOOL, HANNOVER, GERMANY
 
Introduction:

Congenital anomalies of the kidney and urinary tract (CAKUT) are the predominant cause of chronic kidney disease (CKD) in children and adolescents. CAKUT can occur in an isolated form or with extrarenal comorbidities. Although over 50 genes are known to cause CAKUT if mutated, the diagnostic yield of whole-exome sequencing (WES) studies is typically lower than 15%. Here, we asked for the diagnostic yield in young CAKUT patients and whether an early genetic diagnosis may impact patient management.

Material and methods:

In 100 patients diagnosed with CAKUT in the first 1,000 days of life, WES was performed and variants in 58 established CAKUT-associated genes were extracted and classified according to the ACMG guidelines. The translational value of the genetic findings was assessed.

Results:

In 26% of patients diagnosed with CAKUT early in life, we identified a likely pathogenic (LP) or pathogenic (P) rare variant in one or two of 17 CAKUT-associated genes, including HNF1B, LIFR, SALL1 and UMOD. Of the 24 different variants detected, 12 were loss-of-function and five de novo variants. Thirteen of the affected genes were potentially associated with extrarenal morbidities, e.g. diabetes mellitus or hyperuricemia. Patients with LP/P variants were significantly more likely to have end-stage CKD under three years of age and extrarenal manifestations than those without.

Conclusions:

Our data demonstrate a relatively high diagnostic yield of WES in children diagnosed with CAKUT early in life, particularly with end-stage CKD and extrarenal manifestations, and suggest a benefit for managing comorbidities (Else Kröner-Fresenius-Stiftung, grant no. 2018_Kolleg.12).