Linkage analysis using heterozygote detection in phenylketonuria

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Abstract
This linkage investigation was undertaken utilizing an improved method for phenylketonuria (PKU) heterozygote detection. This method is based on studies of semi‐fasting, noon‐time, blood specimens obtained from 85 obligate heterozygotes and 45 controls who were neither pregnant nor on birth control medication. The best separation between heterozygotes and normals was achieved with a discriminant function involving the logarithms of the serum concentrations of phenylalanine, tyrosine and tryptophan. The theoretical overlap area between the distributions of heterozygotes and controls, based on the above function, was 3.75 %. In 19 obligate heterozygotes and 13 controls who were either pregnant or on birth control medication, the best separation was achieved with a discriminant function involving the logarithms of the serum concentrations of phenylalanine and tyrosine. The theoretical overlap area was 8.23 %. These equations identified heterozygotes with sufficient accuracy to permit efficient genetic linkage analysis. We were unable to demonstrate genetic linkage between the PKU locus and 15 common blood, serum, and urinary markers. All but loose linkage (θ > 0.3) was excluded for Rh, ABO, Gc, Kidd, and AP. Moderate linkage exclusion (θ < 0.2) was shown for PGM, Duffy, Hp, MNS, HL‐A, and Kell. Close linkage (θ < 0.1) was excluded for Amy2, 6PGD, P, and ADA. We were unable to find linkage heterogeneity between the Amish and non‐Amish populations.