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We have identified five unrelated patients, all of north European origin, who have hemoglobin H (Hb H) disease and profound mental handicap. Surprisingly, detailed molecular analysis of the alpha globin complex is normal in these subjects. Clinically, they present with a rather uniform constellation of abnormalities, notably severe mental handicap, microcephaly, relative hypertelorism, unusual facies and genital anomalies. Hematologically, their Hb H disease has subtly but distinctly milder properties than the recognized Mendelian forms of the disease. These common features suggest that these five "nondeletion" patients have a similar underlying mutation, quite distinct from the 16p13.3 deletion associated with alpha thalassemia and mild to moderate mental retardation described in the accompanying paper. We speculate that the locus of this underlying mutation is not closely linked to the alpha globin complex and may encode a trans-acting factor involved in the normal regulation of alpha globin expression.


Journal article


Am J Hum Genet

Publication Date





1127 - 1140


Adolescent, Animals, Child, Child, Preschool, Chromosome Mapping, Female, Gene Expression Regulation, Genes, Genetic Linkage, Globins, Humans, Hybrid Cells, Infant, Intellectual Disability, Male, Mutation, Syndrome, Thalassemia