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Evidence that methylation of the FMR-I locus is responsible for variable phenotypic expression of the fragile X syndrome.

Publication ,  Journal Article
McConkie-Rosell, A; Lachiewicz, AM; Spiridigliozzi, GA; Tarleton, J; Schoenwald, S; Phelan, MC; Goonewardena, P; Ding, X; Brown, WT
Published in: Am J Hum Genet
October 1993

DNA at the FMR-1 locus was analyzed by Southern blot using probe StB12.3 in an unusual fragile X family with six brothers, three of whom are affected with fragile X to varying degrees, two of whom are nonpenetrant carriers, and one of whom is unaffected. Fragile X chromosome studies, detailed physical examinations, and psychological testing were completed on all six. Two of the affected brothers and the two nonpenetrant brothers were found to be methylation mosaics. The three affected males spanned the phenotypic and cognitive spectrum of the fragile X syndrome. A correlation was seen between the degree of methylation and the phenotypic expression identified in the three affected males. The two males initially classified as nonpenetrant were found to have mild phenotypic expression which consisted of minor cognitive deficits and a partial physical phenotype. These two, who were negative on fragile X chromosome studies, were found on DNA analysis to have large broad smears, with approximately 97% of the DNA unmethylated. The results described here indicate that some "nonpenetrant" carrier males may have varying amounts of methylation of the FMR-1 region, which can result in mild expression of the fragile X syndrome. The apparently mild phenotypic and cognitive expression of the fragile X syndrome in the two males, initially classified as nonpenetrant, who are mosaic for hypermethylation of an expansion of the CGG repeat in the premutation range, indicates that expression of the syndrome is not confined to males with large, hypermethylated expansions (full mutation) but has instead a gradient effect with a threshold for the full expression of the phenotype.

Duke Scholars

Published In

Am J Hum Genet

ISSN

0002-9297

Publication Date

October 1993

Volume

53

Issue

4

Start / End Page

800 / 809

Location

United States

Related Subject Headings

  • RNA-Binding Proteins
  • Psychological Tests
  • Phenotype
  • Pedigree
  • Nerve Tissue Proteins
  • Middle Aged
  • Methylation
  • Male
  • Humans
  • Genetics & Heredity
 

Citation

APA
Chicago
ICMJE
MLA
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McConkie-Rosell, A., Lachiewicz, A. M., Spiridigliozzi, G. A., Tarleton, J., Schoenwald, S., Phelan, M. C., … Brown, W. T. (1993). Evidence that methylation of the FMR-I locus is responsible for variable phenotypic expression of the fragile X syndrome. Am J Hum Genet, 53(4), 800–809.
McConkie-Rosell, A., A. M. Lachiewicz, G. A. Spiridigliozzi, J. Tarleton, S. Schoenwald, M. C. Phelan, P. Goonewardena, X. Ding, and W. T. Brown. “Evidence that methylation of the FMR-I locus is responsible for variable phenotypic expression of the fragile X syndrome.Am J Hum Genet 53, no. 4 (October 1993): 800–809.
McConkie-Rosell A, Lachiewicz AM, Spiridigliozzi GA, Tarleton J, Schoenwald S, Phelan MC, et al. Evidence that methylation of the FMR-I locus is responsible for variable phenotypic expression of the fragile X syndrome. Am J Hum Genet. 1993 Oct;53(4):800–9.
McConkie-Rosell, A., et al. “Evidence that methylation of the FMR-I locus is responsible for variable phenotypic expression of the fragile X syndrome.Am J Hum Genet, vol. 53, no. 4, Oct. 1993, pp. 800–09.
McConkie-Rosell A, Lachiewicz AM, Spiridigliozzi GA, Tarleton J, Schoenwald S, Phelan MC, Goonewardena P, Ding X, Brown WT. Evidence that methylation of the FMR-I locus is responsible for variable phenotypic expression of the fragile X syndrome. Am J Hum Genet. 1993 Oct;53(4):800–809.
Journal cover image

Published In

Am J Hum Genet

ISSN

0002-9297

Publication Date

October 1993

Volume

53

Issue

4

Start / End Page

800 / 809

Location

United States

Related Subject Headings

  • RNA-Binding Proteins
  • Psychological Tests
  • Phenotype
  • Pedigree
  • Nerve Tissue Proteins
  • Middle Aged
  • Methylation
  • Male
  • Humans
  • Genetics & Heredity