Accurate genetic testing ‘crucial’ for early diagnosis of SMA: Report
The use of advanced genetic testing techniques helped clinicians in China to identify novel mutations in the SMN1 gene in two unrelated children — and thus correctly diagnose them with spinal muscular atrophy (SMA), according to a new case series.
The two children had exhibited limb weakness and developmental delays prior to their first birthdays, but routine genetic testing did not detect their novel mutations in the SMN1 gene.
SMN1 mutations are the most common cause of SMA, and inconsistencies in the children’s test results led their doctors to then additionally try RNA sequencing — a more advanced approach.
That testing led the team to uncover the new mutations, though the clinicians noted that the children’s diagnosis was delayed.
“This underscores the crucial role of accurate genetic testing methods in achieving early diagnosis of SMA,” the researchers wrote.
The study, “Delayed Diagnosis of Spinal Muscular Atrophy in Two Chinese Families due to Novel SMN1 Deletions,” was published in the American Journal of Medical Genetics.
Researchers use RNA sequencing, a more advanced genetic testing technique
Most types of SMA are caused by mutations in both copies of the SMN1 gene — one inherited from each biological parent. In more than 95% of cases, the disease-causing mutation is the complete loss of exon 7 in both copies of the SMN1 gene. Exons are the sections of a gene that contain instructions for the production of needed proteins.
The gold standard for an SMA diagnosis is genetic testing to identify disease-causing mutations. However, “routine genetic testing methods may overlook structural variants outside of exon 7, potentially leading to misdiagnosis of SMA patients,” the researchers wrote.
In this study, the clinicians detailed the cases of two children in the Tianjin area of northern China who had delayed SMA diagnoses. The families of both patients sought medical care at an early age — one at 6 month and the other at 9 months — for limb weakness and developmental delays. Physical examinations of both infants confirmed low muscle strength and tone in the limbs.
Electromyography tests, essentially electrical recordings of muscle activity, were done to assess the health of muscles and nerve cells in both children. These tests revealed widespread damage to motor neurons in the spinal cord, a classic symptom of SMA. The progressive loss of motor neurons in SMA leads to symptoms like muscle weakness and wasting.
When the children were examined at either 11 or 18 months of age, they had not reached the expected motor milestones. Both infants were unable to stand or walk independently.
Based on the age of SMA onset and the motor milestones achieved, the children were diagnosed with SMA type 2.
We demonstrated the significant value of RNA sequencing in cases where children are highly suspected of having SMA but present negative results in routine genetic testing.
Routine genetic testing revealed that both youngsters had inherited one copy of the SMN1 gene with deletions affecting exons 7-8, but had seemingly normal copies of SMN1 from the other parent.
According to the researchers, these results were “inconsistent with the typical genetic pattern of SMA.” That led the team to turn to RNA sequencing. This more advanced testing can help find changes in messenger RNA, a template made from DNA with instructions to make proteins.
Looking at the patients’ complete set of genes, RNA sequencing revealed that both children had novel mutations in other SMN1 exons, specifically a deletion of exons 2a-5.
“We demonstrated the significant value of RNA sequencing in cases where children are highly suspected of having SMA but present negative results in routine genetic testing,” the researchers wrote.
The team championed RNA sequencing as “an important complement to traditional SMA gene testing”.
To learn more, the scientists also performed ultra-long read sequencing, a technique used to analyze large segments of DNA. Those results showed that the deletions were within Alu-repetitive elements, or types of transposable elements in genes that readily change position within DNA, causing deletions. The SMN gene has a notably high prevalence of Alu elements, the scientists noted.
“To our knowledge, this is the first case where a combination of RNA sequencing and ultra-long read sequencing has been used to diagnose SMA,” the researchers wrote.
The researchers concluded that “the combination of [RNA sequencing] and [ultra-long read sequencing] can uncover cryptic variants in genetic disorders, thereby enhancing the detection rate of SMA.”
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