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Familial hemophagocytic lymphohistiocytosis (FHLH; MIM #267700) is an autosomal recessive disorder of immune regulation characterized by fever, hepatosplenomegaly, and cytopenia that is fatal without bone marrow transplantation. Recent studies have suggested the existence of FHLH loci at 9q21.3-22 and t0q21-22 in Asian and European/African/Australian families, respectively. We studied two unrelated Canadian families in which first cousins were affected with FHLH. In an effort to localize the causative gene, we completed a genome-wide screen for homozygosity by descent by using an automated system to genotype 400 highly polymorphic dinucleotide repeat markers covering the genome with an average resolution of 10 centiMorgans (cM). We identified a total of three candidate loci that met the combined criteria for homozygosity by descent in one family and shared maternal alleles in the other family. One of these, D9S1690, had a cytogenetic localization (9q22.33) proximal to a previously reported inversion of chromosome 9 in an FHLH patient. However, additional closely linked flanking markers within 1-2 cM of all three candidates did not conform to the criteria for linkage in either family. Similarly, we excluded the linked 9q21.3-q22 and 10q21-22 regions recently reported in Asian and European/African/Australian families, respectively. The two families were then analyzed independently to encompass the possibility that they were segregating separate genes. Six additional candidate loci were identified on the basis of homozygosity for the same allele in all affected members of one family, but further analysis of closely linked flanking markers did not demonstrate similar homozygosity. Our data provide further evidence of genetic heterogeneity in FHLH and suggest the existence of at least a third locus for this disease.

Further Evidence for Genetic Heterogeneity in Familial Hemophagocytic Lymphohistiocytosis (FHLH)