Exome-based mapping and variant prioritization for inherited Mendelian disorders

Area of Science:

• Genetics
• Bioinformatics
• Ophthalmology

Background:

• Exome sequencing aids rare genetic disorder gene discovery.
• Identifying causal mutations among variants is a significant challenge.
• Autosomal-dominant retinitis pigmentosa (adRP) causes vision loss.

Purpose of the Study:

• Develop and validate methods for prioritizing causal variants in family exome data.
• Implement exome-based mapping for autosomal-dominant disorders.
• Identify novel disease genes for rare genetic conditions.

Main Methods:

• Developed a variant prioritization scoring algorithm.
• Created two complementary exome-based mapping approaches for autosomal-dominant disorders.
• Applied methods to exome sequence data from 24 families with probable adRP.

Main Results:

• Eight of 24 (33%) adRP families had high-scoring pathogenic mutations in known RP genes.
• Candidate variants were identified in 17 families, with some confirmed by segregation testing.
• The MendelScan software package was developed to implement these methods.

Conclusions:

• The developed algorithm and mapping tools effectively prioritize causal variants in family-based exome studies.
• These methods facilitate the discovery of Mendelian disease genes.
• MendelScan provides a valuable resource for the research community.