Getting to the point in fragile X syndrome

Create PDF

William Check, PhD

January 2014—Can one equal 600?

Is it possible for a mutation in a single nucleotide base in the FMR1 gene to be as potent as a run of more than 200 triplet repeats in causing fragile X-like symptoms?

That was the question Stephen T. Warren, PhD, FACMG, raised in his keynote lecture at the 2013 meeting of the Association for Molecular Pathology. Two decades ago Dr. Warren and others showed that expansion of CGG triplet runs in the FMR1 gene is responsible for fragile X syndrome, or FXS. At the AMP meeting, Dr. Warren, who received the AMP Award for Excellence in Molecular Diagnostics, presented evidence that a point mutation in an FMR1 gene with a normal CGG repeat number can also cause intellectual disability and developmental delay, just as triplet repeats do, accompanied by other, non-FXS manifestations. In at least one case, a point mutation caused the full fragile X syndrome.

“The spectrum of disease due to mutation in FMR1 is broader than we had known,” Dr. Warren, who is William Patterson Timmie professor of human genetics and Charles Howard Candler chair in human genetics at Emory University School of Medicine, said in an interview. At the AMP meeting, Dr. Warren gave a preview of unpublished research that helps unravel the mechanism by which mutant FMR1 causes symptoms. (See “Synaptic transmission,” page 28.)

In addition, Dr. Warren, chief of the Section of Human Genetics at The Emory Clinic, asked whether laboratories should screen patients with intellectual disability and developmental delay for conventional mutations in the FMR1 gene. “We probably should,” he concluded.

Finally, he talked briefly about ongoing clinical trials with two classes of therapeutic agents in patients with FXS, agents that were selected on the basis of demonstrated biochemical lesions in these patients.

“Dr. Warren gave an outstanding lecture that was highly relevant for laboratory professionals who perform fragile X testing,” Iris Schrijver, MD, director of the molecular pathology laboratory in the Department of Pathology at Stanford University Medical Center, told CAP TODAY. “It is really exciting to see how he has developed that area of testing. I was very interested to hear how he is looking for mutations in those patients for whom the phenotype has not yet been fully explained [by CGG repeats].”

Dr. Schrijver

Dr. Schrijver says it was clear from his talk that additional features are seen in patients with single nucleotide mutations that are somewhat atypical for classic fragile X syndrome and could be explained by the different type of mutations he found. “We would expect to see a broader spectrum of phenotypes in these individuals,” she says.

Elaine Lyon, PhD, medical director of molecular genetics at ARUP Laboratories and associate professor in the Department of Pathology at the University of Utah, also enjoyed Dr. Warren’s talk. “I would be very interested in looking further for mutations in the FMR1 gene,” she told CAP TODAY. “I assume there will be more. We have next-generation sequencing tests including exome sequencing available in our laboratory, so we could examine the gene for point mutations fairly easily.” However, she adds, it would not be easy to interpret the pathogenic significance of any single-nucleotide variants they find because not much work has been published on this type of mutation in FXS.

Dr. Grody

Wayne Grody, MD, PhD, professor of pathology and laboratory medicine, pediatrics, and human genetics at UCLA School of Medicine, says he was surprised by Dr. Warren’s report that point mutations—missense changes in the FMR1 gene—might be as frequent as CGG triplet expansions. “At present, no one does sequencing for routine fragile X testing; we just look for the CGG expansion. If this is true,” Dr. Grody says, “it would certainly have major implications for how we work up mental retardation, developmental delay, autism—anything that includes looking for fragile X. We could go from just measuring CGG repeats to looking at the coding regions of the FMR1 gene and sequencing them.”

Dr. Grody points out that Dr. Warren’s research provides insight into the mechanism by which FXS comes about. Two patients with point mutations described by Dr. Warren had phenotypes different from classical FXS. “That’s explainable if they are still making some dysfunctional FMR protein [FMRP] rather than no protein at all,” Dr. Grody says.

Dr. Hunt

Jennifer L. Hunt, MD, MEd, chair of pathology and laboratory medicine and Aubrey J. Hough Jr., MD, endowed professor of pathology at the University of Arkansas for Medical Sciences, who introduced Dr. Warren, says his talk “illustrated the innovation that has been occurring across genomics.

“What I think will be interesting for all these [genomic] areas will be the cost-benefit analysis of increasing investment into testing for these diseases by adding tests, as compared to the clinical yield,” she says.