GENOTYPE-PHENOTYPE RELATIONSHIPS IN FRAGILE-X SYNDROME - A FAMILY STUDY

Relationships between the measures of intellectual and physical status in the fragile X syndrome and the size of amplification of the fragil e X-specific fragment, equivalent to the number of CCG repeats within the FMR1 locus, were studied by a maximum-likelihood scoring technique for analysis of pedigree data. This allows for estimation of random e ffects (genetic and environmental variance) concurrently with other (f ixed) effects in a quantitative trait. FMR1 expression is usually shut down in males penetrant for the fragile X syndrome who have hypermeth ylated CCG amplifications of greater-than-or-equal-to 0.6 kb. The assu mption of the step versus curvilinear function representing this relat ionship was tested by the likelihood-ratio criterion. The maximum-like lihood parameters were based on the most appropriate model for each me asure. The results were indicative of the presence of a curvilinear re lationship between the amplification size and the two intellectual sco res, the Peabody Picture Vocabulary Test and Block Design Test, measur ing verbal and spatial abilities, respectively. Reasons for the unexpe cted curvilinear regression between the amplification size and intelle ctual scores were explained further by methylation analysis of fragile X males with amplifications of 0.6 < DELTA less-than-or-equal-to 1.2 kb who appeared to be responsible for the curvilinearity of the relati onship. Four of these showed unmethylated status of the amplified band s in lymphocytes, which were presumably transcriptionally active. Remo val of the aberrant individuals led to the anticipated step function b etween amplification and intellectual scores. For the combined anthrop ometric score, as well as for several single physical measures, the st ep function was the most appropriate model regardless of the inclusion or omission of the aberrant individuals in the pedigree sample.