Filtering for compound heterozygous sequence variants in non-consanguineous pedigrees

Area of Science:

• Genomics
• Medical Genetics
• Bioinformatics

Background:

• Identifying disease-causing mutations from next-generation sequencing (NGS) data necessitates efficient filtering.
• Compound heterozygosity is a key inheritance model for rare recessive diseases in non-consanguineous families.

Purpose of the Study:

• To develop and evaluate a web-based tool for filtering compound heterozygous mutations.
• To assess the effectiveness of compound heterozygous filtering in various family structures and ethnicities.

Main Methods:

• Development of a user-friendly, web-based compound heterozygous filter for NGS data.
• Analysis of filtering power using background distributions from diverse ethnic groups.
• Evaluation in trio and complex pedigree structures, including a real-world Mabry syndrome case.

Main Results:

• The compound heterozygous filter effectively reduces the number of candidate genes, especially with increased pedigree data.
• Analysis of healthy individuals provided background distributions for robust filtering.
• Successfully identified the PIGO gene harboring compound heterozygous variants in a Mabry syndrome family.

Conclusions:

• Compound heterozygous filtering is a powerful strategy for identifying recessive disease genes in non-consanguineous families.
• The developed web-server simplifies this filtering process for researchers without extensive bioinformatics expertise.