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Comment & Response
June 2014

Methylation Analysis in Newborn Screening for Fragile X Syndrome

Author Affiliations
  • 1The Murdoch Childrens Research Institute, Royal Children’s Hospital, Melbourne/Parkville, Victoria, Australia
JAMA Neurol. 2014;71(6):800. doi:10.1001/jamaneurol.2014.142

To the Editor In a recent issue of JAMA Neurology, Tassone1 presented arguments for and against newborn screening (NBS) for fragile X syndrome (FXS), which is caused by large CGG expansion mutations (FM) in the gene FMR1. Tassone described the drawbacks of detecting the smaller gray-zone (GZ) and premutation (PM) alleles, which do not cause FXS but are nonetheless detected by assays based on CGG-expansion sizing. A contentious ethical issue is the detection of the late-onset conditions, fragile X–associated tremor/ataxia syndrome and fragile X–associated primary ovarian insufficiency, in infant carriers of PM alleles and the incomplete understanding of the clinical significance of GZ and PM alleles in child development. The justification for including GZ alleles in the screen is debatable because follow-up cascade testing of relatives of GZ allele carriers would yield very few carriers of PM or FM alleles. Furthermore, because the reported prevalence1 of GZ in the general population is approximately 1 in 26, from a funding and infrastructure perspective, the task of providing pretest counselling and posttest follow-up would be monumental if not impossible.

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