RELATIONSHIP BETWEEN GENOTYPE, ASSESSED BY HLA TYPING, AND PHENOTYPIC-EXPRESSION OF IRON STATUS MARKERS IN FAMILIES OF 29 PROBANDS WITH HEREDITARY HEMOCHROMATOSIS

The purpose of this pedigree study, comprising 29 families with heredi tary haemochromatosis (HH), was to evaluate the relationship between t he genotype (G), based on HLA typing, and the phenotype, based on meas urement of iron status markers (serum transferrin saturation and serum ferritin). Due to tight linkage between the HH locus and the HLA-A lo cus, 172 relatives of the 29 unrelated probands could be assigned into three groups: G0 who were considered to be normal (n=53), G1 who were considered to be heterozygotes (n=105), and G2 who were considered to be humozygotes (n=14), according to whether they had no, one or two H LA haplotypes in common with the proband. A high serum transferrin sat uration (>60%) was present in 8/14 = 57.1% of the homozygotes, in 11/1 05 = 10.5% of the heterozygotes, and in 0/53 = 0% of the normals. Of t he homozygotes, 8/14 = 57.1% had preclinical disease, 4/14 = 28.6% had clinically overt iron overload, while 2/14 = 14.3% had normal iron st atus markers. None of the heterozygotes had clinical evidence of iron overload. Analysis of HLA alleles and iron status markers suggested th at 11/105 = 10.5% subjects initially classified as heterozygotes (G1) according to HLA typing should he reclassified as homozygotes because of abnormal iron status markers, explained by either: homozygous x het erozygous (n=7) or heterozygous x heterozygous (n=2) matings, HLA reco mbination (n=1) or strongly abnormal iron status markers (n=1). Furthe rmore, 12/53 = 22.6% subjects initially classified as normal (G0) acco rding to HLA typing or because they were spouses should be reclassifie d as heterozygotes because of abnormal iron status markers. The study emphasizes the importance of a meticulous screening of all individuals in families where HH has been diagnosed.