PalHap, the first Palestinian haplotype exome panel: application in phasing compound heterozygous mutations

Abstract

Next Generation Sequencing (NGS) technology is widely used in clinical diagnosis to identify disease-causing variants. We have utilized NGS data and constructed parental haplotypes surrounding the mutation. Haplotype phasing would facilitate the identification of compound heterozygous mutation in which two distinct haplotypes each harbor a unique sequence variant. The cis- and trans-acting configurations of a compound heterozygous genotype influences gene expression and its potential functional outcome. Classical Mendelian methods are usually used to infer haplotypes phasing which requires genotyping, of all family members. Population-based phasing is currently a promising computational alternative and is shown to produce high phasing accuracy especially when ethnicity-matching haplotype reference panel is used. In this study we built the first Palestinian haplotype reference panel (PalHap) from 600 Palestinians WholeExomes sequenced at the Molecular Genetic Lab, Istishari Arab Hospital using SHAPEIT, a fast population-based phasing algorithm. We showed that PalHap with a sample number less than half of that in the international 1000Genomes reference panel, can outperform 1000Genomes in phasing compound heterozygous mutations in polymorphic CNVs regions. This study stands as the base for future works that may make use of PalHap in other applications such as Preimplantation Genetic Diagnosis (PGD).