Identification of autosomal recessive disease loci using out-bred nuclear families

Hum Mutat. 2012 Feb;33(2):338-42. doi: 10.1002/humu.21645. Epub 2011 Nov 28.


Autozygosity mapping has been a powerful method for the identification of autosomal recessive disease genes. However, the approach is limited by the availability of suitable consanguineous pedigrees. While rare autosomal recessive diseases are overrepresented in consanguineous families, a significant proportion of affected patients nonetheless originate in families where the parents are apparently unrelated. However, due to their relative rarity and the heterogeneity of disease alleles, it has proved difficult to use these patients to identify disease loci. Therefore, we developed "Phaser," a computer application that is able to infer the phase of SNP alleles and so haplotype entire chromosomes in small nuclear families ( Once the index case's chromosomes have been haplotyped, it is then possible to deduce those of the parents and subsequently identify the parental origin of all the siblings' DNA. By combining information from a small number of nuclear families, it may then be possible to identify linkage to the recessive disease locus, in both in-bred and out-bred families. We have illustrated the program's utility by using it to correctly identify both the cystic fibrosis locus (using two unrelated compound heterozygous CEPH families) and a new gene mutated in early-onset myopathy with respiratory distress and dysphagia locus in a single consanguineous pedigree.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Computational Biology / methods
  • Cystic Fibrosis / genetics
  • Genes, Recessive*
  • Genetic Diseases, Inborn / genetics*
  • Genetic Loci*
  • Humans
  • Hybridization, Genetic*
  • Nuclear Family*
  • Pedigree
  • Software*