Aicardi-Goutieres syndrome: monogenic recessive disease, genetically heterogeneous disease, or multifactorial disease?

Aicardi-Goutieres syndrome (AGS) is a severe progressive familial encephalo pathy, which is usually diagnosed shortly after birth. Using the principle of homozygosity mapping, genome-wide screening of five consanguineous famil ies was performed to search for a homozygous region shared by all affected individuals. A total of 364 markers with an average spacing of 9.9 cM were genotyped, but no homozygous region common to all affected individuals coul d be found. Regions of homozygosity in affected sibs could only be identifi ed within each family individually. This may reflect genetic heterogeneity, possibly related to clinical heterogeneity, since several syndromes are cl inically difficult to distinguish from AGS. Involvement of a small number o f genes and/or of an external factor, such as infection, may also explain t he absence of a homozygous region common to all affected individuals.