New SMN1 deletions found in 2 women with mild adult-onset SMA
Long-read sequencing helped map hard-to-detect genetic changes
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- Long-read sequencing identified two novel large deletions involving SMN1 in two women with mild adult-onset SMA.
- Both women had four SMN2 gene copies, which may have helped preserve motor function into adulthood.
- LR-WGS may improve SMA diagnosis and genetic counseling by helping detect complex genetic changes.
Two previously unknown large deletions involving the SMN1 gene, whose loss is the primary cause of spinal muscular atrophy (SMA), were identified in two women with a mild form of the disease using long-read whole-genome sequencing (LR-WGS), a technology that can help identify difficult-to-detect genetic changes.
“Integrating LR-WGS with orthogonal validation enhances diagnostic precision, informing genetic counseling and advancing molecular diagnostics for SMA,” the researchers wrote.
The study, “Detection and characterization of SMN1 deletions in type IV spinal muscular atrophy using long-read whole-genome sequencing,” was published in Clinica Chimica Acta.
How SMN1 and SMN2 shape SMA severity
The most common cause of SMA, accounting for about 94% of cases, is the complete loss of both copies of the SMN1 gene, one inherited from each biological parent. This loss prevents the production of enough SMN protein, which is essential for the health of nerve cells that control movement. As a result, these nerve cells gradually become damaged and die, causing symptoms such as muscle weakness, fatigue, and breathing problems.
In addition to SMN1, another gene called SMN2 also provides instructions for making the SMN protein. However, SMN2 produces only limited amounts of fully functional SMN protein and therefore can only partially compensate when SMN1 is missing or not working properly. Most people carry two copies of SMN2, though some have extra copies. Because extra SMN2 copies can help the body make more SMN protein, people with more SMN2 copies often have milder forms of SMA.
Still, researchers have suggested that mild SMA may not always be explained by SMN2 copy number alone. In some people, the SMN1 and SMN2 genes can form hybrid or rearranged versions that may also affect disease severity. Yet these more complex genetic changes can be difficult to fully identify using standard genetic tests.
However, “accurate detection of SMN1 deletions and mutations is crucial for the diagnosis and genetic counseling” of people with SMA, the researchers wrote.
With this in mind, the team sought to better characterize the genetic changes underlying SMA type 4, a milder adult-onset form of the disease, in two women with the condition.
Long-read sequencing maps SMN1 deletions
The women were identified through routine prenatal screening at a hospital in China. One was 32 years old and the other 31. Standard genetic testing showed that both had a homozygous deletion of the SMN1 gene, meaning it was missing from both copies, and had four copies of the SMN2 gene.
The researchers then used LR-WGS, a type of genetic testing that can examine longer stretches of DNA and provide a more complete picture of large or complex genetic changes.
The analysis uncovered two previously unknown deletions that removed the entire SMN1 gene. One woman carried a deletion covering about 81,000 DNA building blocks and the other about 70,000 — both far larger than the SMN1 gene itself. Additional genetic testing confirmed the findings and pinpointed the exact locations of the deletions.
The team also looked for SMN1–SMN2 hybrid haplotypes or chimeric sequences — in other words, mixed or rearranged gene patterns that earlier studies suggested might help explain milder disease. But none were found, supporting that both women had complete deletions involving SMN1.
Despite losing both copies of SMN1, the two women maintained motor function into adulthood. Because no SMN1–SMN2 hybrid haplotypes or chimeric sequences were found, the researchers said the women’s four copies of the SMN2 gene may have helped preserve motor function, underscoring “the critical protective role played by SMN2 copy number in modulating disease severity,” the researchers wrote.
Further testing showed both women had significantly lower levels of full-length SMN messenger RNA, which is used to make functional SMN protein, than one healthy control. However, family members of one woman, none of whom had SMA, had significantly higher full-length SMN messenger RNA levels than the same healthy control, even though their SMN1 and SMN2 copy numbers varied. This suggests that additional genetic factors may influence how efficiently the SMN genes work. The researchers noted that SMN levels were measured in blood, which may not fully reflect SMN levels in motor neurons.
“Our findings not only expand the clinical and genetic spectrum of SMA but also highlight the importance of integrating multiple genomic technologies for accurate diagnosis and carrier screening,” the researchers concluded.
