Transmission of an FMR1 premutation allele in a large family identified through newborn screening: the role of AGG interruptions

J Hum Genet. 2013 Aug;58(8):553-9. doi: 10.1038/jhg.2013.50. Epub 2013 Jun 6.

Abstract

The CGG repeat within the premutation range in the fragile X mental retardation 1 (FMR1) gene can lead to neurodegenerative disorders and intellectual disabilities. An increase in size upon the transmission from parent to child is more likely to occur for larger alleles and without AGG interruptions. We describe the molecular structure and the transmission of an FMR1 premutation allele in a multigenerational family, identified through newborn screening for fragile X syndrome. Transmission of the premutation allele was traced through five generations in 14 of the 23 individuals who were genotyped through cascade testing. Allele size instability during transmission was observed, but no expansions to a full mutation were detected. Clinical and molecular characterizations of the participants lead to the diagnosis of fragile X-associated tremor ataxia syndrome in one subject identified as a premutation carrier. A gradual small increase in the size of the premutation allele was observed during transmission through five generations. The relative stability is likely due to the presence of two AGGs within the allele. The detection of AGG interruptions within the premutation alleles is important in genetic counseling, to better predict the risk of expansion during transmission from a premutation to a full-mutation allele.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Alleles*
  • Electrophoresis, Capillary
  • Family
  • Female
  • Fragile X Mental Retardation Protein / genetics*
  • Fragile X Mental Retardation Protein / metabolism
  • Gene Expression Regulation
  • Haplotypes / genetics
  • Humans
  • Infant, Newborn
  • Male
  • Mutation / genetics*
  • Neonatal Screening*
  • Pedigree
  • Trinucleotide Repeat Expansion / genetics*

Substances

  • FMR1 protein, human
  • Fragile X Mental Retardation Protein