Abstract
BackgroundIn families segregating a monogenic genetic disorder with a single disease gene introduction, patients share a mutation-carrying chromosomal interval with identity-by-descent (IBD). Such a shared chromosomal interval or haplotype, surrounding the actual pathogenic mutation, is typically detected and defined by multipoint linkage and phased haplotype analysis using microsatellite or SNP genotype data. High-density SNP genotype data presents a computational challenge for conventional genetic analyses. A novel non-parametric method termed Homozygosity Haplotype (HH) was recently proposed for the genome-wide search of the autosomal segments shared among patients using high density SNP genotype data.Methodology/Principal FindingsThe applicability and the effectiveness of HH in identifying the potential linkage of disease causative gene with high-density SNP genotype data were studied with a series of monogenic disorders ascertained in eastern Canadian populations. The HH approach was validated using the genotypes of patients from a family affected with a rare autosomal dominant disease Schnyder crystalline corneal dystrophy. HH accurately detected the ∼1 Mb genomic interval encompassing the causative gene UBIAD1 using the genotypes of only four affected subjects. The successful application of HH to identify the potential linkage for a family with pericentral retinal disorder indicates that HH can be applied to perform family-based association analysis by treating affected and unaffected family members as cases and controls respectively. A new strategy for the genome-wide screening of known causative genes or loci with HH was proposed, as shown the applications to a myoclonus dystonia and a renal failure cohort.Conclusions/SignificanceOur study of the HH approach demonstrates that HH is very efficient and effective in identifying potential disease linked region. HH has the potential to be used as an efficient alternative approach to sequencing or microsatellite-based fine mapping for screening the known causative genes in genetic disease study.
Highlights
single nucleotide polymorphisms (SNPs) genotyping technology is developing very rapidly
Phase II of the International HapMap Project has characterized over 3.1 million single nucleotide polymorphisms (SNPs) with the resulting SNP density of approximately one per kilobase [1]
Validation of Homozygosity Haplotype (HH) using a large family with SCCD Schnyder crystalline corneal dystrophy (SCCD, MIM 121800)
Summary
SNP genotyping technology is developing very rapidly. Phase II of the International HapMap Project has characterized over 3.1 million single nucleotide polymorphisms (SNPs) with the resulting SNP density of approximately one per kilobase [1]. High-density SNP genotype data presents a computational challenge for genetic analyses. The determination of haplotype sharing may represent the future direction of linkage analysis due to its better adaptation to high-density SNP genotype data [2]. In families segregating a monogenic genetic disorder with a single disease gene introduction, patients share a mutation-carrying chromosomal interval with identity-by-descent (IBD) Such a shared chromosomal interval or haplotype, surrounding the actual pathogenic mutation, is typically detected and defined by multipoint linkage and phased haplotype analysis using microsatellite or SNP genotype data. High-density SNP genotype data presents a computational challenge for conventional genetic analyses. A novel non-parametric method termed Homozygosity Haplotype (HH) was recently proposed for the genome-wide search of the autosomal segments shared among patients using high density SNP genotype data
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