Genotype/phenotype correlations in the fragile X syndrome: Comparison of FMR1 DNA patterns in lymphocytes, lymphoblasts and fibroblasts
- Carolinas Medical Center, Charlotte, NC (United States)
- Hospital for Sick Children, Toronto (Canada); and others
The predominant mutation in the fragile X syndrome is an amplification of a CGG repeat in the 5{prime} untranslated region of the FMR 1 gene. An amplification of > 200 repeats (full mutation) usually results in the methylation of an adjacent CpG island resulting in the loss of FMR1 gene expression. The highly variable phenotype of fragile X individuals has been proposed to be a result of DNA mosaicism resulting in only partial absence of FMR1 expression. We have utilized Southern blot analysis and PCR to analyze the CGG repeat expansion and degree of methylation of the FMR1 gene in genomic DNA isolated from lymphocytes, lymphoblasts and fibroblasts from fragile X individuals to determine the best available tissue to evaluate genotype/phenotype correlations. While in many kindreds the degree of expansion and methylation observed were similar, two exceptions are described. Individual 1A was initially identified as a non-penetrant male but demonstrated 3% fragile X expression on chromosome studies. Molecular studies on lymphocyte, lymphoblast, fibroblast and sperm samples revealed that the FMR1 region was unmethylated in all tissues with significant size (from pre- to full mutation) variation observed between tissues. In family 2, individual 2A is more severely affected than his brother 2B. Analysis of lymphocyte DNA revealed that while both individuals carried full mutations in the FMR1 gene and were methylation mosaics, 2B had a much greater extent of methylation. These DNA findings do not appear to correlate with the degree of cognitive functioning. Analysis of fibroblast DNA revealed no methylation mosaicism for either brother and a larger expansion in the more severely affected brother 2A, more closely correlating with phenotype. Our results show that there is variability between tissues with respect to FMR1 size and methylation status and suggest that fibroblast DNA patterns may more accurately reflect the level of cognitive functioning in fragile X individuals.
- OSTI ID:
- 134174
- Report Number(s):
- CONF-941009-; ISSN 0002-9297; TRN: 95:005313-0910
- Journal Information:
- American Journal of Human Genetics, Vol. 55, Issue Suppl.3; Conference: 44. annual meeting of the American Society of Human Genetics, Montreal (Canada), 18-22 Oct 1994; Other Information: PBD: Sep 1994
- Country of Publication:
- United States
- Language:
- English
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