Glucose-6-phosphate dehydrogenase (G6PD; EC 1.1.1.49)-deficient red blood cells from male hemizygotes and female heterozygotes from the island of Sardinia were studied for their ability to support growth in vitro of the malaria-causing organism Plasmodium falciparum. Parasite growth was approximately one-third of normal in both hemi- and heterozygotes for G6PD deficiency. In Sardinians with the beta 0-thalassemia trait, parasite growth was normal except when G6PD deficiency occurred together with the thalassemia trait. The data support the hypothesis that G6PD deficiency may confer a selective advantage in a malarious area; the female heterozygote may be at a particular advantage because resistance to malaria equals that of male hemizygotes, but the risk of fatal hemolysis may be less. However, more female heterozygotes must be studied to confirm this hypothesis. No protective effect of beta 0-thalassemia trait could be demonstrated in vitro.

Autosomal dominant high myopia, a genetic disorder already mapped to region 18p11.31, is common in Carloforte (Sardinia, Italy), an isolated village of 8,000 inhabitants descending from a founder group of 300 in the early 1700s. Fifteen myopic propositi and 36 normal controls were selected for not having ancestors in common at least up to the grandparental generation, although still descendants of the original founders. All subjects were genotyped for 14 markers located on autosome 18 at a resolution of about 10 cM. Allelic distributions were found to be similar at all tested loci in propositi and controls, except for the candidate marker D18S63 known to segregate in close linkage association with high myopia. In particular, the frequency of allele 85 among the propositi was almost double that of the controls (Fisher’s exact test, p = 0.037). The association is more striking when the frequency of the genotype 85/85 in the two groups is compared (Fisher’s exact test, p = 0.005). This conclusion was further evaluated through a bootstrap analysis by computing the overall probability of the observed data under the null hypothesis (i.e. no difference between the two groups in frequency distributions for the chromosome 18 markers). Again, marker D18S63 was found to have a sample probability lower than 0.004, which is significant at the 0.05 level after correcting for simultaneous testing of multiple loci. The study demonstrates the efficiency of our novel strategy to detect identity by descent (IBD) in small numbers of patients and controls when they are both part of well-defined Mendelian breeding units (MBUs). The iterative application of our strategy in separate MBUs is expected to become the method of choice to evaluate the ever-growing number of reported associations between candidate genes and multifactorial traits and diseases.

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Eighteen Sardinian pedigrees segregating for the X-fragile site syndrome were studied with respect to the segregation of the fragile site (FS) at Xq28, mental retardation, and macro-orchidism. No exception was found in the association of this symptomatic triad (MOM-X) in 41 out of 42 patients examined. The exceptional individual had micro- rather than macro-orchidism and was found to have a 47, XXY sex chromosome complement. In six informative sibships, the MOM-X syndrome was found to segregate in close linkage association with G6PD-deficiency or protan colorblindness. The maximum likelihood estimate of recombination if 6% with 90% fiducial limits between 2.5 and 19.5% and an odds ratio in favor of measurable linkage of 428:1. However, no hint of measurable linkage was found in six pedigrees segregating for G6PD and the Renpenning syndrome or other unspecified types of X-linked mental retardation. These data give strong support to the generally held hypothesis that the FS at Zq28, characteristic of the MOM-X syndrome, is a direct expression of a genetic change in the same chromosomal region. They also clearly suggest that X-linked MR without FS may be the result of different allelic mutations at the same locus.

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