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Iterative Sequencing and Variant Screening (ISVS) as a novel pathogenic mutations search strategy - application for
Urszula Lechowicz1, Tomasz Gambin2,3, Agnieszka Pollak1
1Department of Genetics, Institute of Physiology and Pathology of Hearing, Warsaw, Poland.
Scientific Reports
|June 2, 2017
Summary
A new Iterative Sequencing and Variant Screening (ISVS) method efficiently identifies genetic mutations causing rare autosomal recessive diseases (ARD). This approach, along with ISVS Simulator software, aids in assessing variant pathogenicity without needing a control group.
Area of Science:
- Genetics
- Bioinformatics
- Medical Genetics
Background:
- Autosomal recessive diseases (ARD) are genetic disorders caused by mutations in specific genes.
- Identifying causative mutations for ARD is challenging due to their low prevalence and the need for extensive genetic screening.
- Traditional methods often require large control groups for variant pathogenicity assessment.
Purpose of the Study:
- To develop a novel computational approach for efficient identification and pathogenicity evaluation of mutations causing ARD.
- To create a tool that can assess genetic variants without relying on a control group.
- To apply the developed method to identify novel disease-causing mutations in TMPRSS3.
Main Methods:
- Development of the Iterative Sequencing and Variant Screening (ISVS) approach, involving iterative cycles of gene sequencing and mutation screening.
- Creation of ISVS Simulator software for assessing the significance and pathogenicity of detected genetic variants.
- Application of ISVS to a cohort of patients with hearing loss to identify TMPRSS3 variants.
Main Results:
- The ISVS approach successfully identified 4 known and 9 novel TMPRSS3 variants in patients with hearing loss.
- ISVS Simulator provided strong evidence (odds >90:1) for disease association in 3 known and 5 novel variants.
- In-silico predictions supported the pathogenicity of 6 novel mutations, demonstrating the utility of ISVS in detecting disease-causing variants.
Conclusions:
- The Iterative Sequencing and Variant Screening (ISVS) strategy and ISVS Simulator are effective tools for detecting genetic variants responsible for autosomal recessive diseases.
- This novel approach facilitates the identification and pathogenicity assessment of mutations, even with low prevalence, without a control group.
- The study identified several novel TMPRSS3 variants associated with hearing loss, highlighting the potential of ISVS in genetic diagnostics.
