Rapid identification and prioritization of pathogenic variants associated with anomalies of the kidneys and urinary tract
Dr. Helge Martens
Wednesday, December 7, 2016
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Chapters
Introduction
Congenital anomalies of the kidneys and urinary tract
Hannover Medical School CAKUT Research Collaboration
CAKUT facts determining genetic analysis strategies
Workflow used for whole-exome sequencing of CAKUT patients
Our variant prioritization strategy using Ingenuity Variant Analysis (IVA)
Using this strategy on WES data of a sporadic CAKUT patient yielded a known frameshift variant in the known CAKUT gene PAX2
Using the search term “kidney dysplasia” in the Biological Context filter, we identified a novel nonsense variant in the known CAKUT gene SALL1
But what to do with a sporadic CAKUT patient in which an initial analysis did not lead to a rapid elucidation?
Using our trio-based de novo strategy we identified a heterozygous novel frameshift variant in the TBC1D1 gene
Using our trio-based de novo strategy we identified a heterozygous novel frameshift variant in the TBC1D1 gene
Targeted TBC1D1 sequencing identifies variants in 4% of CAKUT patients and provides further evidence for TBC1D1 as a CAKUT candidate gene
Using trio-based de novo analysis in another sporadic patient with severe bilateral CAKUT and no variants in known CAKUT genes
nitial trio-based de novo analysis of externally supplied vcf-files revealed no promising candidates
Reanalyzing the fastq-files with Biomedical Genomics Workbench (BGW)
Using the Biomedical Genomics Workbench and IVA yielded a novel heterozygous de novo frameshift variant in the reanalyzed data
GENE X frameshift variant results in a substantially shortened protein lacking parts of an axin-binding domain
Using a family-of-four-based strategy to identify shared variants in affected family members in familial CAKUT
Initial analysis of externally supplied vcf-files with IVA of this case revealed a long list of uncertain candidates
Family-of-four-based reanalyzing of fastq-files with Biomedical Genomics Workbench (BGW)
Data reanalysis prioritized a heterozygous frameshift variant in GENE Y shared by all affected family members
GENE Y frameshift variant results in a substantially shortened protein lacking parts of an essential interaction site
Solving CAKUT - Conclusion
Acknowledgment
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