Positional cloning is a powerful approach to identify genes mutated in human and animal models monogenic diseases, and is the option of choice when there is no functional candidate genes that appear as good candidates based on their known biochemical functions. The genomic DNA region (and the embedded polymorphisms) harbouring the disease-causing mutations segregates with the disease in analyzed pedigrees. However, positional cloning relayed until recently on the availability of large pedigrees to reach a significant linkage.
This protocol describes the use of whole genome genotyping on sporadic consanguineous patients to identify potential disease loci and subsequent positional candidate genes, by homozygosity mapping (Autozygosity). It takes advantage of high density single nucleotide polymorphism (SNP) genotyping arrays, and of the assumption that unrelated patients from several consanguineous families are mutated in the same gene. It was applied to the mapping of a novel gene involved in autosomal recessive centronuclear myopathy, amphiphysin 2/BIN1 (ref. 1).