Genetic Mapping of the 21-Hydroxylase-Deficiency Gene within the HLA Linkage Group

To document further the proposed genetic linkage between congenital adrenal hyperplasia due to 21-hydroxylase deficiency and HLA, 34 unrelated families from New York and Zurich, with a total of 48 patients, 48 siblings and their parents, were studied. All patients were HLA genotypically different from the healthy sibs; when two or more children were affected in the same sibship they were always HLA-B identical. The gene for 21-hydroxylase deficiency was separated by genetic recombination from the HLA-A locus and from the locus for glyoxalase I-polymorphism. No HLA-A, HLA-B or HLA-C antigen was selectively increased among the 34 unrelated patients. Lod-score analysis for HLA-B:21-hydroxylase deficiency gave a peak for θ≈0.00 at 5.20 for females and 4.30 for males, giving a total peak lod score of 9.5 at θ≈0.00 when male and female lod scores were combined. Close genetic linkage between HLA-B and 21-hydroxylase deficiency was thus established. (N Engl J Med 299:911–915, 1978) CONGENITAL adrenal hyperplasia due to 21-hydroxylase deficiency is an inborn error of metabolism in which the hormonal pathophysiology is well defined.¹ Early studies provided evidence that the disorder is transmitted by an autosomal recessive gene.^{2 3 4} We have recently presented preliminary evidence that congenital adrenal hyperplasia of the 21-hydroxylase-deficiency type is closely linked to HLA (the major histocompatibility complex of man).⁵ In this paper we report on studies of 34 unrelated families with a total of 48 patients. The studies demonstrate that the gene for congenital adrenal hyperplasia of the 21-hydroxylase-deficiency type is located very close to the HLA-B locus and.