A strabismus susceptibility locus on chromosome 7p

Abstract

Strabismus has been known to have a significant genetic component, but the mode of inheritance and the identity of the relevant genes have been enigmatic. This paper reports linkage analysis of nonsyndromic strabismus. The principal results of this study are: (i) the demonstrated feasibility of identifying and recruiting large families in which multiple members have (or had) strabismus; (ii) the linkage in one large family of a presumptive strabismus susceptibility locus to 7p22.1 with a multipoint logarithm of odds score of 4.51 under a model of recessive inheritance; and (iii) the failure to observe significant linkage to 7p in six other multiplex families, consistent with genetic heterogeneity among families. These findings suggest that it will be possible to localize and ultimately identify strabismus susceptibility genes by linkage analysis and mutation screening of candidate genes.

Fig. 1.

Seven pedigrees analyzed by whole genome scanning. The assignment of affected individuals (filled symbols) is described in Materials and Methods. Dots indicate those individuals for whom genotypes were obtained. Haplotypes are shown for family A with the 20 high-resolution chromosome 7p markers (Fig. 2B and Table 3) arranged in order with the most telomere-proximal marker (D7s3056) at the top and the most centromere-proximal marker (D7s1791) at the bottom, as listed to the left of subject 203. For each individual, the paternal haplotype is on the left and maternal haplotype is on the right. Numbers indicate the size of the PCR products in bp. The haplotype for individual 203 was reconstructed from the haplotypes of his children; the phase of the markers for individual 205 cannot be determined with the available data. The four chromosomes in individuals 203 and 204 are color coded.

Fig. 2.

Fine mapping of markers on chromosome 7p. (A) Eight-point LOD scores calculated with the initial set of high-resolution 7p markers. The plot shows recessive LOD scores for all families (LOD), heterogeneous recessive LOD scores for all families (HLOD), and recessive LOD scores for family A alone (LOD, family A). (B) Multipoint recessive LOD scores for family A using the 20 high-resolution 7p markers shown on the horizontal axis. As noted in the legend of Table 1, subjects 333, 430, and 431 were omitted from the LOD score calculation. For all LOD score calculations, parameters were as follows: phenocopy rate = 0.0001; penetrance = 0.9; frequency of disease alleles = 0.001.