Tissue-specific methylation differences and cognitive function in fragile X premutation females

Abstract

Tissue-specific variation in (CGG)n repeat size and methylation status of the FMR1 gene was investigated in 17 female premutation carriers. Minor variation in premutation repeat size among leukocyte, lymphoblast, and fibroblast tissues was noted in some subjects. One subject exhibited a premutation size allele of (CGG)64 in leukocyte and fibroblast tissues by polymerase chain reaction analysis but a normal-size allele of (CGG)46 in lymphoblast cells, suggesting low-level mosaicism in blood and clonality of the lymphoblast cell line. Six subjects exhibited differences in methylation pattern between leukocytes and lymphoblasts but not between leukocytes and fibroblasts, whereas 2 subjects showed large differences in methylation pattern between leukocytes and fibroblasts. Cognitive function was studied in 14 subjects using the Wechsler Adult Intelligence Scale-Revised. Mean Verbal and Performance IQs were well within the average range as was the mean Full Scale IQ; nevertheless, a trend toward lower Performance IQ compared with Verbal IQ was observed. No significant correlation was apparent between Full Scale IQ and (CGG)n repeat size; however, a significant positive correlation was observed between Full Scale IQ and the proportion of the active X carrying the normal FMR1 allele in fibroblasts but not in leukocytes or lymphoblasts.