Researchers Identify Novel Mutations in SMA

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Researchers have identified additional mutations in both SMN1 and other genes, some of which may be associated with the onset of spinal muscular atrophy (SMA).

Using a combination of multiplex ligation probe amplification (MLPA) and complete gene sequencing, researchers have identified additional mutations in both SMN1 and other genes, some of which may be associated with the onset of spinal muscular atrophy (SMA).

The researchers collected blood samples from 28 families of patients with suspected SMA, using MLPA to determine a preliminary diagnosis. They found that 22 had homozygous deletion of SMN1 exon 7 (SMA patients), 3 carried heterozygous deletion of SMN1 exon7 (carriers), and 3 had 2 SMN1 copies (normal patients). The researchers then performed high-throughput sequencing to find more mutations within the SMN1 gene.

From the 83 blood samples, the researchers found 6 single nucleotide variants (SNVs) of SMN1, 3 of which were located in exon, 1 of which was located in UTR5, and 2 of which were located in intron. Novel mutations c.[84C > T], c.[271C > T], c.[−39A > G] and g.[70240639G > C] were also reported.


“Besides, we identified more mutations combined with homozygous absence of SMN1 exons 7,” wrote the researchers. The 3 most commonly observed mutations were insertion mutation c.[−41_- 40insCTCT] in SPTA1 exon1 (rs111674514), the SNV c.[1001A>G] in FUT5 exon2 (rs778984), and the SNV c.[−117A > G] in MCCC2 exon1 (rs11746722).

While these 3 mutations have been reported previously, their clinical significance remains vague, although the researchers suggest they may be involved in the morbidity of SMA as they were commonly seen in the SMA patient sample and were near nonexistent in the patients without SMA.

“At present, MLPA is the gold standard for clinical diagnosis of SMA. However, MLPA can only detect the deletion of SMN1 according to the gene copy number, not detect point mutations of SMN1,” wrote the researchers of the study, noting that the emergence of new therapies has heightened the need for “a more detailed understanding of genetic variation.”

In search of this, the researchers enrolled the 20 children diagnosed with SMA and the 5 diagnosed with non-SMA, who served as controls, to receive whole exome high-throughput sequencing. Compared with the 5 controls, 9102 mutations were selected out in those with SMA. According to the researchers, these were located in the exon region and only occurred in patients with SMA and not in carriers or normal patients.

Of these mutations, 2415 genes and some indefinite genes were included, accounting for 8619 SNVs, 267 deletions, and 216 inserts. The researchers recorded the 30 most frequent mutations seen in these patients, indicating that SPTA1 mutation c.[−41_- 40insCTCT], FUT5 SNV c.[1001A > G], and MCCC2 SNV c.[−117A > G] were the 3 most common, appearing in 95%, 85%, and 75% of patients, respectively.


Zhang R, Gu C, Pu L, Meng Y, Shu J, Cal C. High-throughput screening reveals novel mutations in spinal muscular atrophy patients. Ital I Pediatr. Published online November 4, 2020. doi:10.1186/s13052-020-00925-1.