SAMPLE

SAMPLE maps autozygous chromosomal regions compatible with linkage to lethal autosomal recessive disease loci using single nucleotide polymorphism (SNP) genotyping from unaffected members of consanguineous families (Shadow Autozygosity Mapping by Linkage Exclusion).

Key Features:

• Empirical haplotype analysis: Uses SNP genotyping data from parents and unaffected siblings to analyze haplotypes and infer chromosomal regions compatible with linkage to a disease locus.
• Prioritization of regions: Produces ranked candidate regions to focus downstream genetic investigation without requiring affected individuals' DNA.
• Rapid confirmation and fine mapping: Supports limited follow-up genotyping to confirm candidate regions and refine locus boundaries.
• Application in complex pedigrees: Applicable to consanguineous and complex family structures where affected individuals may be unavailable or have poor-quality DNA.
• Utilization of high-density SNP microarrays: Relies on whole-genome genotyping from high-density SNP microarrays rather than microsatellite markers to increase coverage and resolution.

Scientific Applications:

• Locus discovery in lethal recessive disorders: Enables identification of candidate disease loci in lethal autosomal recessive conditions using genotype data exclusively from unaffected family members.
• Example application — MKS3/TMEM67: Has been used to infer the MKS3/TMEM67 locus on chromosome 8q22.1 associated with Meckel-Gruber syndrome from unaffected relatives' genotypes.

Methodology:

Analyzes single nucleotide polymorphism (SNP) genotyping data from parents and unaffected siblings using empirical haplotype analysis to infer chromosomal regions compatible with linkage by exclusion; employs whole-genome high-density SNP microarray genotypes and supports prioritization plus limited follow-up genotyping for confirmation and fine mapping.