Clinical Symptoms and/or Family History of FXS Identify 96% of FXS Cases, Canadian Study Says

Genetic testing for fragile X syndrome (FXS) should be reserved as a second-line strategy for people without clinical features or family history suggestive of FXS, according to a Canadian study.

Researchers argued that 96% of FXS cases were identified through clinical symptoms and/or family history of FXS.

The study “Re-evaluating the first-tier status of fragile X testing in neurodevelopmental disorders” was published in the journal Genetics in Medicine.

Genetic screening for the genetic defect in the FMR1 gene – the cause of FXS – is currently recommended as a first line test for neurodevelopment disorders in children. FXS is caused by a genetic defect, a long repetition of three DNA letters (nucleotides), in the FMR1 gene. Healthy FMR1 gene has less than 40 repeats, while in FXS more than 200 repeats can be detected.

Yet, growing evidence suggests that that FXS testing is likely more suitable as a second line test. Researchers at the Alberta Children’s Hospital’s Molecular Diagnostic Laboratory in Canada tested whether FXS screening should be transitioned as a second-line test in people that  lack  family history but have suggestive clinical features.

In total, they analysed 2,486 pediatric patients with neurodevelopment disorders who were tested for FXS between 2012 and 2017. Of these, only 25 boys and 5 girls tested positive for FXS, meaning their molecular exam found over 200 repeats on the FMR1 gene. These numbers correspond to a diagnostic yield of only 1.2 percent.

From 27 patients with information available, researchers observed that 26 had either clinical features or family history suggestive of FXS, or both, at the time of testing. Only one male patient had neither family history or clinical features suggestive of FXS. These findings suggest that that clinical features or familial history can predict FXS diagnosis in 96% of cases.

“In 96% of FXS-positive cases, there was sufficient clinical suspicion raised on the basis of clinical features and/or family history to perform targeted FXS testing,” researchers wrote.

“Based on our findings, we advocate for a change in current practice guidelines and support the transition of single-gene FXS testing to a second- tier investigation in the identification of genetic etiology of neurodevelopmental disorders without clinical features or family history suggestive of FXS,” they concluded.