Relationship between genotype, assessed by HLA typing, and phenotypic expression of iron status markers in families of 29 probands with hereditary haemochromatosis.

The purpose of this pedigree study, comprising 29 families with hereditary haemochromatosis (HH), was to evaluate the relationship between the genotype (G), based on HLA typing, and the phenotype, based on measurement of iron status markers (serum transferrin saturation and serum ferritin). Due to tight linkage between the HH locus and the HLA-A locus, 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 homozygotes (n = 14), according to whether they had no, one or two HLA haplotypes in common with the proband. A high serum transferrin saturation (> 60%) was present in 8/14 = 57.1% of the homozygotes, in 11/105 = 10.5% of the heterozygotes, and in 0/53 = 0% of the normals. Of the 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 status markers. None of the heterozygotes had clinical evidence of iron overload. Analysis of HLA alleles and iron status markers suggested that 11/105 = 10.5% subjects initially classified as heterozygotes (G1) according to HLA typing should be reclassified as homozygotes because of abnormal iron status markers, explained by either: homozygous x heterozygous (n = 7) or heterozygous x heterozygous (n = 2) matings, HLA recombination (n = 1) or strongly abnormal iron status markers (n = 1).(ABSTRACT TRUNCATED AT 250 WORDS)