Abstract: SA-PO615
Mutational Burden in Monogenic Glomerular Kidney Disease Genes in Adult CKD Patients
Session Information
- Genetic Epidemiology and Other Genetic Studies of Common Kidney Diseases
November 04, 2017 | Location: Hall H, Morial Convention Center
Abstract Time: 10:00 AM - 10:00 AM
Category: Genetic Diseases of the Kidney
- 803 Genetic Epidemiology and Other Genetic Studies of Common Kidney Diseases
Authors
- Wuttke, Matthias, University of Freiburg, Freiburg, Germany
- Hoppmann, Anselm, University of Freiburg, Freiburg, Germany
- Schultheiss, Ulla T., University of Freiburg, Freiburg, Germany
- Eckardt, Kai-Uwe, Charité University Medicine Berlin, Berlin, Germany
- Lipska-Zietkiewicz, Beata S., University of Gdansk, Gdansk, Poland
- Schaefer, Franz S., University of Heidelberg, Heidelberg, Germany
- Kottgen, Anna, University of Freiburg, Freiburg, Germany
Background
Monogenic kidney diseases often show severe manifestations in childhood (recessive) or mid-age (dominant traits). Conversely, moderate chronic kidney disease (CKD) in adults is often regarded a complex disease with a genetic predisposition. The contribution of mutations in monogenic kidney disease genes in adult CKD patients and the combined effects of rare variants and common susceptibility alleles are understudied.
Methods
341 participants of the German Chronic Kidney Disease study (inclusion criteria CKD stages G1-G3 or A3 with biopsy-proven primary glomerular disease) underwent next-generation gene panel sequencing (Illumina MiSeq) of 37 glomerulopathy-associated monogenic traits. Read alignment and variant calling followed GATK best practices and incorporated consensus calling. Variants were annotated using VEP/SNPeff and filtered using GEMINI based on frequency, predicted impact and presence in clinical mutation databases to obtain putative deleterious mutations.
Results
At present, data are available for 202 patients. Definite pathogenic mutations were identified for 12 patients (median age 44 yr, eGFR 49 ml/min/1.73m2, UACR 357 mg/g, 67% FSGS) in genes with dominant inheritance mode (4 in COL4A5, 2 in PAX2, and 1 each in GLA, INF2 and WT1) and 3 compound heterozygotes in NPHS2. In addition, 21 individuals carried plausible pathogenic variants (in ACTN4, ANLN, ARHGAP24, COL4A5, CRB2, GLA, LMX1B, PAX2, TRPC6, TTC21B and WT1). Within the next weeks, sequencing and evaluation of atypical presentations and extra-renal manifestations as well as integration with common susceptibility alleles from GWAS will be completed.
Conclusion
About 5% of adult patients selected for CKD stages G1-G3 or A3 and with presumed primary glomerular etiology carry pathogenic mutations in monogenic glomerular disease genes. Another 10% carry plausible pathogenic variants. Evaluating rare mutations together with common CKD susceptibility variants may provide further insights into their combined impact and contribution to atypical presentations and a mild disease course.