From the Guidelines
Genetic diagnosis of spinal muscular atrophy (SMA) primarily involves testing for homozygous deletions or mutations in the SMN1 gene on chromosome 5q13, with the standard diagnostic approach beginning with quantitative PCR or multiplex ligation-dependent probe amplification (MLPA) to detect SMN1 exon 7 deletions. The importance of genetic testing in the diagnosis of neuromuscular diseases, including SMA, is highlighted in a study by Feingold et al 1, which notes that genetic testing is crucial to the diagnostic workup, allowing for a definitive diagnosis and providing vital information about clinical expectations and genetic counseling.
Key steps in the genetic diagnosis of SMA include:
- Detecting SMN1 exon 7 deletions using quantitative PCR or MLPA, which are present in approximately 95% of SMA patients
- Sequencing of the remaining SMN1 gene to identify point mutations in patients with clinical symptoms of SMA but only one deleted SMN1 allele
- Determining the number of SMN2 gene copies, which serves as an important disease modifier and helps predict disease severity and prognosis
- Offering prenatal diagnosis to families with a known history of SMA through amniocentesis or chorionic villus sampling
- Recommending carrier testing for individuals with a family history of SMA and considering it for reproductive partners of known carriers
As noted in the study by Feingold et al 1, having a precise genetic diagnosis is important because of the heterogeneity in clinical manifestations among neuromuscular diseases, and it is expected that definitive genetic diagnosis will eventually allow not only for disease-specific therapies but also for mutation-specific therapies. The genetic diagnosis is crucial for initiating appropriate treatments like nusinersen, onasemnogene abeparvovec, or risdiplam, which are most effective when started early in the disease course. Newborn screening for SMA is increasingly being implemented in many regions, allowing for early diagnosis and intervention before symptom onset 1.
From the Research
Genetic Diagnosis of Spinal Muscular Atrophy
- Spinal muscular atrophy (SMA) is characterized by degeneration of motor neurons in the spinal cord, causing progressive weakness of the limbs and trunk, followed by muscle atrophy 2.
- The survival motor neuron gene (SMN1) is responsible for SMA, and mutations in this gene can be detected through direct molecular genetic testing 2.
- SMA patients can be classified into different types based on age at onset and clinical course, and the number of SMN2 copies can modulate the SMA phenotype 2.
Molecular Genetic Testing
- Molecular genetic testing for SMA involves determining the SMN1 copy number, and a diagnosis is reached when the copy number is zero 3.
- When the SMN1 copy number is 1, exons and intron/exon boundaries of the allele are examined for single-nucleotide variants (SNVs) 3.
- Genetically undiagnosed cases of SMA can exist when 2 copies of SMN1 exist or when a SNV is in the deep intron 3.
Importance of Full-Length Sequencing
- Full-length sequencing of the SMN1 gene is important for identifying subtle mutations and compound heterozygosity 3, 4.
- Alu-mediated deletions in SMN1 can escape routine diagnostic testing, and parallel analysis of SMN gene dosage, SMN transcripts, and total SMN protein levels can identify genomic rearrangements 4.
Genetic Counseling and Risk Assessment
- Genetic counseling and risk assessment are essential components of SMA genetic testing, and comprehensive testing comprising PCR-RFLP assay, SMN gene dosage analysis, and linkage analysis can provide the most complete evaluation of SMA patients and their families 5, 6.
- New technologies, such as haploid analysis techniques, may be widely available in the future to improve SMA genetic testing and counseling 6.