Targeted gene mutations test may help ID cause of rare SMA types

Gene sequencing panel found useful in testing of non-5q SMA patients

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

Share this article:

Share article via email
This illustration of a DNA strand highlights its double-helix structure.

A targeted test looking for mutations in known disease-associated genes in spinal muscular atrophy (SMA) was found to be a useful first step in identifying the cause of rare types of SMA, a new study reports.

In fact, according to the researchers, “a total of ten patients with causative variants were identified, nine of whom were index cases” — the first patient identified in a group of related cases of a specific disease — using such testing.

The vast majority of cases of SMA are caused by mutations in the gene SMN1. However, there are a few rare types of SMA that are caused by mutations in other genes. This is referred to as non-5q SMA — with 5q referring to the chromosomal location of the SMN1 gene.

Here, the researchers further proposed that more extensive genetic testing can be done as a second-line strategy if an initial targeted test fails to identify a disease-causing mutation.

A study detailing their findings, titled “Genetic characterization of non-5q proximal spinal muscular atrophy in a French cohort: the place of whole exome sequencing,” was published in the European Journal of Human Genetics.

Recommended Reading
An illustration shows a DNA strand.

New Genetic Analysis Method Aids SMA ‘Silent Carrier’ Detection

Next-generation sequencing urged as first-line test for causes of rare SMA types

There are many different technologies that can be used to identify disease-causing mutations in people with non-5q SMA. Some methods look at just a few genes, while others look at all genes in the genome, or a person’s complete set of genetic instructions. The optimal methods for the diagnosis of non-5q SMA are still being debated.

Now, scientists in France reported data for 24 people with non-5q SMA from 23 families (two of the patients were a mother and son).

All but two of the patients initially underwent a next-generation sequencing or NGS test to look for mutations in more than 100 genes known to cause nerve and/or muscle diseases. This revealed a known disease-causing mutation in eight of the patients from seven families.

Specifically, mutations in the gene DYNC1H1 were found in five patients, while three patients were found to carry mutations in the gene BICD2.

The 14 patients who did not have a disease-causing mutation identified by NGS then underwent whole-exome sequencing, known as WES.

WES is a more extensive genetic test that identifies the sequence of all genes that provide instructions for making a protein. This did not identify any additional disease-causing mutations, though it confirmed that one of the mutations in BICD2 that had been identified by NGS was indeed disease-causing.

In one patient who underwent WES without first undergoing NGS, WES identified disease-causing mutations in the gene ASAH1. The researchers noted that this mutation could not have been identified by NGS, as it was not one of the genes included in the panel.

“We thus recommend updating the gene panels of inherited peripheral neuropathies by including ASAH1,” the scientists wrote.

In the one other patient who also underwent WES without first undergoing NGS, a mutation in the DYNC1H1 gene was found that was deemed likely disease-causing.

”Taken together, these observations suggest that in non-5q-SMA patients, a large NGS panel should be the first choice.

Taking all these data collectively, the researchers concluded that the targeted NGS panel was an effective first-line genetic test to identify, where possible, the cause of non-5q SMA. The scientists suggested that more detailed genetic testing like WES could be employed as a secondary test if targeted NGS fails to identify a disease-causing mutation.

“Taken together, these observations suggest that in non-5q-SMA patients, a large NGS panel should be the first choice, before performing WES” or other more extensive testing, the scientists wrote.