SMN1 2 Copies: Genetic Implications for Spinal Muscular Atrophy

Spinal muscular atrophy (SMA) is a genetic condition that affects muscle strength and movement. It results from mutations in the SMN1 gene, which is critical for motor neuron survival. The number of SMN1 copies a person carries influences their risk of developing SMA or being a carrier. Genetic testing can determine an individual’s SMN1 copy number, providing insights into inheritance patterns and health implications.

SMN1 And SMA Relationship

The survival motor neuron 1 (SMN1) gene is the primary genetic determinant of SMA, a neuromuscular disorder marked by progressive muscle weakness and atrophy. It encodes the survival motor neuron (SMN) protein, essential for motor neuron maintenance and function. When both copies of SMN1 are deleted or mutated, the body cannot produce enough functional SMN protein, leading to motor neuron degeneration and loss of voluntary muscle control.

SMA follows an autosomal recessive inheritance pattern, meaning an individual must inherit two defective SMN1 copies—one from each parent—to develop the condition. Carriers, who have one functional copy, typically do not show symptoms but can pass the mutated gene to their children. The estimated carrier rate is about 1 in 40 to 1 in 60 individuals worldwide (Verhaart et al., 2017, Orphanet Journal of Rare Diseases), making SMN1 copy number analysis crucial in reproductive planning and genetic counseling.

While SMN1 loss is the primary cause of SMA, the related SMN2 gene can influence disease severity. Due to a critical nucleotide substitution, SMN2 primarily produces a truncated, less stable SMN protein. However, multiple SMN2 copies can partially compensate for SMN1 loss, leading to a milder disease course. This interplay between SMN1 and SMN2 affects SMA severity.

Effects Of SMN1 Copy Number

SMN1 copy number directly affects an individual’s genetic risk for SMA and carrier status. Most people inherit two copies, ensuring sufficient SMN protein production for normal motor function. Deviations from this can significantly alter genetic risk.

Individuals with no functional SMN1 copies develop SMA due to inadequate full-length SMN protein production. Those with a single copy are asymptomatic carriers but have a 50% chance of passing the altered gene to their children. Carrier frequencies vary by population. For example, a study in Human Genetics (Sugarman et al., 2012) found a carrier rate of about 1 in 54 in individuals of European descent, while African populations have a lower frequency due to a higher prevalence of individuals with more than two SMN1 copies.

Some individuals inherit three or more SMN1 copies due to gene duplication events, reducing their likelihood of being carriers. Those with at least two copies on a single chromosome are considered “silent carriers” because standard genetic tests may not detect their status. Advanced molecular techniques, such as multiplex ligation-dependent probe amplification (MLPA) and quantitative PCR, improve copy number determination, enhancing genetic counseling accuracy.

Relevance Of Having 2 Copies

Having two SMN1 copies is the typical genetic configuration, ensuring adequate SMN protein production for motor neuron function. This prevents SMA, as at least one functional allele supports neuromuscular activity.

Beyond preventing disease, two SMN1 copies reduce the likelihood of being a carrier. Carrier screening typically detects the absence of one SMN1 allele, and individuals with two copies are generally not flagged unless family history suggests otherwise. In reproductive counseling, this genetic profile reassures couples that their risk of passing SMA to offspring is extremely low.

SMN1 copy number distribution varies across ethnic backgrounds, influencing carrier rates. Some populations have higher frequencies of individuals with three or more SMN1 copies, complicating carrier screening. For example, individuals of African ancestry are more likely to have multiple SMN1 copies on a single chromosome, which can obscure carrier status in standard tests. Advances in genetic testing technology have improved SMN1 copy number determination, refining risk assessments across diverse populations.

Distinguishing SMN1 From SMN2

SMN1 and SMN2 share over 99% sequence similarity due to their evolutionary duplication. However, a single nucleotide difference in exon 7 significantly alters function. In SMN1, exon 7 is reliably included in the final messenger RNA transcript, producing a full-length, functional SMN protein. In SMN2, a cytosine-to-thymine substitution at position c.840 disrupts splicing, leading to mostly truncated, unstable SMN protein.

SMN1 is the primary source of functional SMN protein, essential for motor neuron integrity. SMN2 provides limited compensation, as some transcripts include exon 7. The number of SMN2 copies influences its ability to mitigate SMN1 loss. Therapies like nusinersen target this mechanism by promoting exon 7 inclusion in SMN2 transcripts to increase functional protein production.

Genetic Testing For Copy Number

Genetic testing for SMN1 copy number helps assess SMA risk and carrier status, particularly for individuals with a family history of SMA or those from populations with higher carrier frequencies. Testing is crucial for reproductive planning.

Molecular techniques like MLPA and quantitative PCR accurately determine SMN1 copy number. These methods can identify individuals with one, two, or multiple copies, which is essential for detecting silent carriers—those with two copies on one chromosome and none on the other. Standard carrier screening may miss these cases, leading to false negatives. Comprehensive genetic counseling is recommended to interpret results accurately.

Advancements in genomic technologies, such as next-generation sequencing (NGS), are further refining the detection of complex SMN1 variants. These improvements enhance SMA risk assessment and inheritance pattern analysis.