Low-cost method may quickly spot carriers of SMA-causing mutations

Potential seen to better identify people at risk of passing disease to their children

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by Andrea Lobo |

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Researchers in China report having developed a way to quickly and more easily screen for people who carry SMN1 gene mutations associated with spinal muscular atrophy (SMA).

This method showed high accuracy for correctly identifying both those who are and are not carriers of SMA-causing mutations, compared with standard techniques. Mutation carriers do not develop SMA, but they can pass the disease to their children.

The researchers are confident their low-cost technique is simpler, faster, “and has full potential for application in population spinal muscular atrophy carriers screening,” particularly in the healthcare systems of developing countries.

The study, “Development of a low-cost and accurate carrier screening method for spinal muscular atrophy in developing countries,” was published in the European Journal of Medical Genetics.

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1 in 59 women in region of China found to be SMA carrier: Study

Current carrier screening methods can be costly and time consuming

SMA is mainly caused by inherited mutations in the SMN1 gene that lead to the progressive loss of motor neurons, the nerve cells that control voluntary movements, resulting in disease  symptoms marked by muscle weakness and atrophy.

The disease requires disease-causing mutations be present in both copies of the SMN1 gene; everyone inherits two gene copies, one from each biological parent. In about 95% of cases, this mutation involves the deletion of a protein-coding region of the SMN1 gene called exon 7.

Those who inherit only one mutated gene copy, along with one healthy copy, are called carriers, meaning they will not develop SMA but can pass the mutation to their children. Previous studies estimate a carrier frequency of 1 in every 40 to 70 people in the general population.

Considering the disease severity and high carrier frequency, professional organizations recommend population-based screening for SMA carriers in people planning to conceive.

Researchers noted that the prevalence of SMA screening in China is not at optimal levels, mainly due to the limitations of the existing carrier screening methods in terms of their cost, feasibility, and time consumption.

As such, a team at Xiamen University developed an easier and more accessible method to detect the deletion of exon 7. In a test, remnant DNA samples from previous SMA diagnostic tests were analyzed using a technique called droplet digital polymerase chain reaction (ddPCR) to detect the number of SMN1 gene copies.

The method is based on a commercially available digital PCR, in which each PCR reaction is separated into thousands of individual droplets, each containing a small amount of the target DNA region, which can be measured independently. The technique allows the absolute quantification of the target region gene, by considering the amount of droplets that have or do not have the mutated gene.

Then, by establishing cutoff values that compare with an established quantification method, it is possible to identify people with none, one, or two SMN1 mutated gene copies.

Test show ddPCR-based screening to be highly accurate

Diagnostic accuracy of the new method was evaluated in samples from 482 participants, 219 of whom previously were identified as carriers and 76 of whom had SMA, with a deletion in both copies of the SMN1 gene.

Overall, the new method accurately identified all SMA carriers and those who were not carriers, compared with a currently used method for SMA carrier screening called multiplex ligation-dependent probe amplification (MLPA) assay. There was an almost complete agreement between the two methods, with a 100% correct classification of the samples, the researchers reported.

The ddPCR-based assay also demonstrated high sensitivity and accuracy in detecting those with an SMA diagnosis, although this was not the study’s purpose.

“Compared to conventional methods, our ddPCR assay has the advantages of being highly accurate, rapid, and inexpensive (USD 10 per test), indicating a good potential for clinical application in the healthcare systems of developing countries,” the researchers concluded.