A pipeline combining multiple strategies for prioritizing heterozygous variants for the identification of candidate genes in exome datasets

Human Genomics
Teresa RequenaJose A Lopez-Escamez

Abstract

The identification of disease-causing variants in autosomal dominant diseases using exome-sequencing data remains a difficult task in small pedigrees. We combined several strategies to improve filtering and prioritizing of heterozygous variants using exome-sequencing datasets in familial Meniere disease: an in-house Pathogenic Variant (PAVAR) score, the Variant Annotation Analysis and Search Tool (VAAST-Phevor), Exomiser-v2, CADD, and FATHMM. We also validated the method by a benchmarking procedure including causal mutations in synthetic exome datasets. PAVAR and VAAST were able to select the same sets of candidate variants independently of the studied disease. In contrast, Exomiser V2 and VAAST-Phevor had a variable correlation depending on the phenotypic information available for the disease on each family. Nevertheless, all the selected diseases ranked a limited number of concordant variants in the top 10 ranking, using the three systems or other combined algorithm such as CADD or FATHMM. Benchmarking analyses confirmed that the combination of systems with different approaches improves the prediction of candidate variants compared with the use of a single method. The overall efficiency of combined tools ranges between 68 and...Continue Reading

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Citations

May 6, 2019·European Journal of Human Genetics : EJHG·Swati TomarPoh San Lai
Apr 10, 2018·Frontiers in Genetics·Hena AhmadAdolfo M Bronstein
Oct 22, 2020·The Cerebellum·Eun Hye OhJae-Hwan Choi
Nov 17, 2020·Frontiers in Neurology·Eun Hye OhJae-Hwan Choi
Dec 26, 2019·Hearing Research·Alvaro Gallego-Martinez, Jose A Lopez-Escamez

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Methods Mentioned

BETA
biopsy
exome sequencing

Software Mentioned

VAAST
Exomiser
MendelScan
ANNOVAR
Exomiser Gene
- Phevor
Mutation taster
SAMtools
PhastCons
R

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