The genetics of Aicardi-Goutières syndrome.

In 1984 two French paediatric neurologists, Jean Aicardi and Françoise Goutières, described 8 children with an early onset, progressive encephalopathy characterised by basal ganglia calcification, leukodystrophy, chronic cerebrospinal fluid lymphocytosis and negative serological investigations for common prenatal infections 1. This clinical phenotype had previously only been associated with the sequelae of intrauterine infection. However, the observation of familial cases, affected females and parental consanguinity prompted these authors to propose that the condition they described was inherited as an autosomal recessive trait. Further reports have identified families with affected siblings separated in age by a number of years and in birth order by intervening normal children. These features provide strong evidence against a causative role for an unidentified congenital infective agent. In order to localise the gene/genes involved in Aicardi-Goutières syndrome we recently performed a genome-wide linkage analysis of 23 children from 13 families with a clinical diagnosis of Aicardi-Goutières syndrome 2. The use of linkage analysis in familial disorders represents a method for localising a disease causing gene to a particular chromosomal region. A locus can be defined as the unique chromosomal location of an individual gene or DNA sequence and the basis of linkage analysis is that recombination events occur between 2 genetic loci on the same chromosome at a rate related to the distance between them. The goal of linkage analysis in Mendelian diseases is to determine whether 2 loci (a disease gene and a marker) co-segregate more often than they would if they were not physically close together on the same chromosome. It was not possible to set out to map a disease with a reasonable hope of success until polymorphic markers spaced regularly throughout the genome became available. The development of such genetic maps has revolutionised gene localisation and subsequent gene cloning. Our analysis relied heavily on the statsitical power derived by using consanguineous families in genome-wide linkage analysis. Alleles that are identical because they are 2 copies of the same single allele present in a common ancestor are defined as being autozygous or identical by descent. The increased risk of autosomal recessive disease in the offspring of consanguineous parents arises as a consequence of the associated autozygosity present in an affected individual due to inbreeding. That is, the most