The clinical utility of a risk-modifying SNP to detect carriers for spinal muscular atrophy with increased sensitivity

Background: Spinal muscular atrophy (SMA) is an autosomal recessive motor neuron disease caused by biallelic inactivation of the survival motor neuron 1 (SMN1) gene. With a prevalence of ~1 in 11,000 live births (carrier frequency of ~1:50), SMA is one of the most common severe childhood-onset diseases; therefore, current guidelines recommend pan-ethnic carrier screening for SMA before or during pregnancy. Routine SMN1 copy number assessment detects ~96% of all SMA carriers, but not the remaining 4% who harbor two copies of SMN1 arrayed in -cis [2 + 0]. The c.*3+80T>G risk-modifying SNP positively correlates with this chromosomal configuration and may be used to modify the residual risk of being a carrier for SMA. Methods: One year after incorporating the detection of the c.*3+80>G risk-modifying SNP into our routine SMA carrier screen, we perform a retrospective chart review to evaluate its frequency and utilization in the prenatal clinic. Results: In comparison with classic carriers for SMA, study data show that individuals with two copies of SMN1 and the risk modifier were counseled less frequently about their increased risk of being a carrier for SMA. Conclusion: Incorporating the c.*3+80T>G risk-modifying SNP is important for detecting carriers for SMA with a higher clinical sensitivity.