Utility of two SMN1variants to improve spinal muscular atrophy carrier diagnosis and genetic counselling

Spinal muscular atrophy (SMA) is caused by deletions/mutations in SMN1. Most heterozygous SMA carriers have only one SMN1copy in one of the alleles (1/0 carriers). However, a few carriers lack SMN1in one of their chromosomes, but present two gene copies in the other. These “2/0 carriers” are undistinguishable from non-carrier individuals (1/1) with currently available methods. Previous association of SMN1variants c.*3 + 80 T > G and c.*211_*212del with two SMN1copies in cisin Ashkenazi population prompted us to analyze them in 270 Spanish individuals (SMA carriers, patients and general population). Both variants were much more frequently detected in chromosomes with 2 SMN1copies in cisin comparison with chromosomes carrying one copy (17.9 vs. 0.7%; p< 0.001). In particular, one-fifth of 2/0 SMA carriers harboured one or both variants compared to none of 99 non-carriers with two SMN1copies (p< 0.001). The c.*211_*212del variant was also much more frequent in exon 8 of SMN2–SMN1hybrids than in that of intact SMN1genes (20 vs. 0.83%, p< 0.001), suggesting its association with chromosomal rearrangements. Although absence of these variants does not exclude that a particular individual is a 2/0 SMA carrier, their presence is valuable to substantially increase residual risk in putative carriers, thus improving genetic counselling.