The SMN1 gene exhibits a duplication event with sub sequent SNV in exon 7 of SMN2 that affects splicing (Fig. 1). The SMN2 gene retains about 10% wild type transcript and is present in zero to four copies in the general population.
Fig1. (A) A chromosome carrying a normal copy of SMN1 and SMN2. (B) The blank box indicates a deleted gene. A deletion can remove part or all of the SMN1 gene. (C) The curved arrow represents a conversion. With the C>T transition in SMN1, the SMN1 copy now closely resembles SMN2 and is considered SMN2-like. (D) Point mutations occurring in any of the SMN1 exons prior to the last exon can affect the SMN protein. (From Keinath MC, Prior DE, Prior TW: Spinal muscular atrophy: Mutations, testing, and clinical relevance, Appl Clin Genet 14:11–25, 2021. https://doi.org/10.2147/TACG.S239603)
With a carrier frequency of 1 in 40 to 50 and an estimated incidence of 1 in 10,000 live births, SMA is the second most common autosomal recessive disorder. On chromo some 5q13, the survival motor neuron protein SMN1 is reduced in function; however, the modifying SMN2 gene is maintained. The absence of the SMN1 gene accounts for most SMA cases. Ninety-five percent of SMA-affected individuals have a homozygous deletion of SMN1 exon 7 or gene conversion from SMN1 to SMN2, and most of the remaining 5% are compound heterozygotes for an SMN1 exon 7 deletion and an SMN1 SNV (see Fig. 1: normal in A, variants in B and C). A number of intragenic variants can be detected in the compound heterozygous state with an SMN1 deletion and can include missense, nonsense, splice site variants, insertions, deletions, and duplications (see Fig. 1C). Recurrent variants have been discovered in exons 3 and 6, representing hot spots for small and mis sense changes, respectively (see Fig. 1D). Exon 6 codes for a domain in the protein, which plays a role in protein oligomerization, and individuals with exon 6 missense variants have decreased SMN protein self-oligomerization capacity. The exon 6 p.Tyr272Cys missense variant is the most frequently reported SNV in the SMN1 gene.
Because both copies of SMN1 exon 7 are lost in the majority of patients, no phenotype-genotype correlation was initially observed in SMA. The copy number of SMN2 has now been shown to be a significant modifier of SMA severity. All individuals with SMA have at least one copy of SMN2, which generates low amounts of SMN protein but does not fully compensate for the loss of SMN1. The SMN2 gene is unable to create a full transcript because of the presence of the splice variant in exon 7. The copy number varies from zero to three copies in the general population, with around 10% of individuals having no SMN2. A fetus that lacks SMN1 function and has no copies of SMN2 would presumably be nonviable. The majority of individuals who have type 1 SMA have one to two copies of SMN2. The typical number of SMN2 copies in persons with type 2 SMA is three. Patients with milder type 3 and 4 individuals generally exhibit four or more copies of SMN2. These phenotype genotype correlations have paved the way for developing disease-modifying therapies for SMA.
