Application of robust pedigree analysis in studies of complex genotype-phenotype relationships in fragile X syndrome

Relationships between the fragile X dynamic mutation and palmar and finger epidermal ridge measures were assessed using a robust modification of the maximum likelihood estimators for pedigree data. A total of 34 extended families affected with fragile X syndrome were used. Phenotypic traits included ridge count on the thumb and ridge breadth measured in the second palmar interdigital area bilaterally. Genotypic measures were represented by the number of CGG repeats in the FMR1 gene, the levels of specific FMR1 protein (FMRP), fragile X category defined by the size of the CCG repeat, and methylation status of the gene. The results demonstrated a significant fragile X effect (related to the number of CGG repeats) in the thumb ridge count in males. This effect was more evident in ridge breadth and was found in both sexes. However, the relationship between both phenotypic traits and the level of FMRP was nonsignificant. The study makes a useful contribution to the development of methodologies for the analysis of genotype-phenotype relationships in dynamic mutations, especially in overcoming extensive variability in both the genotype and phenotype, and in approaching the statistical problems related to intergenerational changes in repeat size. The findings support the hypothesis that the fragile X mutation affects limb development during an early fetal period.