Prenatal diagnosis of sickle cell anemia by restriction endonuclease analysis: HindIII polymorphisms in γ-globulin genes extend test applicability

J. A. Phillips, S. R. Panny, H. H. Kazazian, C. D. Boehm, A. F. Scott, K. D. Smith

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Polymorphism for a Hpa I restriction endonuclease site associated with about 60% of β(s) genes in American Blacks allows exact prenatal diagnosis of sickle cell anemia by amniocentesis in 36% of couples at risk. In three families in whom exact diagnosis by Hpa I sites was impossible, we found analysis for the presence of polymorphic HindIII sites in the (G)γ and (A)γ intervening sequences would allow an exact prenatal diagnosis of sickle cell status in all three. In one of these families, the presence of an (A)γ HindIII site in amniocyte DNA confirmed the diagnosis (sickle cell trait) made by synthetic studies using fetal erythrocytes obtained at fetoscopy. Studies of other Black families and individuals provide evidence for linkage disequilibrium in the (G)γ-(A)γ-δ-β gene complex involving the four sites, (G)γ HindIII, (A)γ HindIII, β(s), and Hpa I, which span 33 kilobases (kb). Ten of 14 chromosomes bearing a β(s) gene in a 7.6-kb Hpa I fragment contained a (G)γ but not an (A)γ HindIII site, whereas 16 of 16 chromosomes bearing a β(s) gene in a 13-kb Hpa I fragment lacked both the (G)γ and (A)γ HindIII sites. Two-thirds of β(A)-bearing chromosomes lacked both (G)γ and (A)γ sites, whereas one-third contained either the (G)γ or both (G)γ and (A)γ sites. These data demonstrate that combined analysis of both Hpa I and HindIII polymorphism and verification of their linkage phase should increase the fraction of couples for whom amniocentesis can provide an exact diagnosis of sickle cell status from 36% to greater than 80%.

Original languageEnglish (US)
Pages (from-to)2853-2856
Number of pages4
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number5 I
StatePublished - Dec 1 1980


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