‘Sequencing First’ Strategy Aims to Speed Diagnosis
Fabry disease is caused by mutations in the GLA gene located on the X chromosome. This gene provides instructions for making the alpha-galactosidase A enzyme (Gal A), which is needed to break down certain fatty molecules in cells. Consequently, in Fabry disease these fatty molecules build up to toxic levels in the body’s tissues.
Diagnosis of Fabry disease often is a lengthy and complicated process, in part because the disease can manifest very differently in different individuals. According to Mendelics — a Brazilian company that specializes in a type of genetic analysis called next-generation sequencing, which can determine the exact sequence of genes — Fabry disease is under-diagnosed worldwide.
Because the GLA gene is on the sex-determining X chromosome (females have two while males have one), Fabry disease diagnosis often is especially challenging in women, who generally don’t show the same severity of symptoms as males with the disease.
Delays in getting the correct diagnosis lead to delays in initiating appropriate treatments — and delayed treatment is generally associated with poorer clinical outcomes.
Traditional workups for the diagnosis of Fabry disease usually start by doing biochemical analyses on samples of blood or urine, looking for reduced activity of the Gal A enzyme and abnormal increases in the fatty molecules that are associated with the disease. Then, if results indicate potential Fabry disease, the patient’s DNA can be sent for genetic testing to confirm the diagnosis.
According to Mendelics, doing biochemical testing first requires waiting for results from the tests to be available from a laboratory, which often takes a while and tends to extend diagnostic delays.
The company’s novel diagnostic strategy, called Sequencing First, involves reversing the normal diagnostic flow: first doing genetic testing to look for potential disease-causing mutations in the GLA gene, then doing biochemical testing for confirmation of samples that are positive on genetic tests.
“Sequencing First is an innovative approach for the diagnosis of some rare genetic diseases, which consists of DNA sequence analysis as the first diagnostic approach, using biochemical or functional tests as complementary analysis, after an eligible genetic result,” David Schlesinger, geneticist and CEO of Mendelics, said in a press release. “We reversed the order of exams so that the patient benefits from a faster and more accurate diagnosis.”
The test is done on a sample collected by swabbing the inner cheek (buccal swab), and results are available in up to 30 days, which, according to Mendelics, is a much shorter waiting time compared to traditional approaches.
Since Mendelics’ technology determines the exact sequence of the gene, and automatically does computational analyses to determine the probable effect of any mutation, this strategy is expected not only to shorten diagnostic times, but also to reduce the chance of false positives or negatives in biochemical testing that arise due to limitations of techniques used for those assays.
“The test performs the sequencing of all regions of the GLA gene with greater sensitivity, shorter logistics and execution time,” Schlesinger said.