SMN1 – Spinal Muscular Atrophy

Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder characterized by degeneration of anterior horn motor neurons, leading to progressive muscle weakness and atrophy. Bi‐allelic mutations in the SMN1 gene result in marked reduction of the survival motor neuron (SMN) protein, the key molecular deficit in SMA. SMN1 is located on chromosome 5q13 and has an almost identical paralog, SMN2, whose copy number modulates disease severity. In >95% of SMA patients, homozygous deletion of SMN1 exon 7 (c.840C>T) is found; in the remaining 5%, compound heterozygous intragenic mutations or frameshifts are observed. The prevalence of SMA is ~1:10 000 live births, with a carrier frequency of ~1:50 worldwide. Early genetic diagnosis is essential for therapeutic intervention with SMN‐enhancing treatments.

1. Clinical Validity

The SMN1–SMA association is classified as Definitive given the overwhelming genetic and experimental data spanning decades. Hundreds of unrelated probands exhibit homozygous SMN1 deletions and rare intragenic mutations, with multi‐family segregation and functional concordance in cellular and animal models. A study of 610 patients confirmed SMN1 exon 7 deletions in 96% of cases and identified recurrent missense variants in nondeletion patients (PMID:11839954). A founder 4-bp deletion (c.399_402del, p.Glu134fs) was reported in four Spanish families, further establishing pathogenicity across diverse populations (PMID:7581461). Functional data demonstrate that loss of SMN protein disrupts snRNP assembly and pre-mRNA splicing, linking molecular defects to motor neuron degeneration.

2. Genetic Evidence

SMA is inherited in an Autosomal recessive manner. Segregation analyses across multiple families document co-segregation of SMN1 null alleles with disease in at least 4 affected relatives (PMID:7581461). Case series describe >400 families with homozygous exon 7 deletions and ~5% of patients with compound heterozygous intragenic variants (PMID:11839954). Variant spectrum includes large deletions of exons 7/8, frameshifts (e.g., c.399_402del (p.Glu134fs)), splice-site mutations, and missense changes, with recurrent and private alleles reported across populations. Recurrent founder mutations (e.g., c.399_402del in Spain) and diverse intragenic variants contribute to genotype–phenotype correlations. Carrier screening and copy-number analysis of SMN1 remain the diagnostic standard.

3. Functional Evidence

Pathogenicity is primarily driven by haploinsufficiency of SMN protein, essential for snRNP assembly and mRNA splicing. Wild-type SMN enhances in vitro splicing and gem formation, whereas patient-derived mutants fail to support snRNP biogenesis (PMID:9845364). Zebrafish knockdown of Smn recapitulates motor axon defects, rescuable by human SMN but not Δ7 or patient mutants, dissociating axonal function from snRNP roles (PMID:17065443). Bifunctional antisense oligonucleotides that restore exon 7 inclusion in SMN2 ameliorate protein levels and gem counts in patient fibroblasts, supporting therapeutic modulation of splicing (PMID:12642665). These concordant findings underscore the critical cellular functions of SMN in motor neurons.

4. Integration & Conclusion

The SMN1–SMA relationship demonstrates robust genetic and mechanistic evidence, fulfilling criteria for a Definitive ClinGen classification. Strong genetic evidence (homozygous deletions, compound heterozygosity, segregation) is reinforced by moderate functional data (cellular and animal models). No significant conflicting evidence has been reported. Additional modifiers, such as SMN2 copy number and rare intragenic variants, refine clinical heterogeneity but do not undermine the core SMN1–SMA link.

Key Take-Home: Bi-allelic loss‐of‐function variants in SMN1 cause autosomal recessive SMA; early molecular diagnosis and SMN-enhancing therapies are critical for patient management.

References

• Nature Genetics • 1995 • A frame-shift deletion in the survival motor neuron gene in Spanish spinal muscular atrophy patients. PMID:7581461
• Genetics in Medicine • 2002 • Molecular analysis of spinal muscular atrophy and modification of the phenotype by SMN2. PMID:11839954
• The Journal of Neuroscience • 2006 • Survival motor neuron function in motor axons is independent of functions required for small nuclear ribonucleoprotein biogenesis. PMID:17065443
• Proceedings of the National Academy of Sciences of the USA • 2003 • Bifunctional antisense oligonucleotides provide a trans-acting splicing enhancer that stimulates SMN2 gene expression in patient fibroblasts. PMID:12642665
• Cell • 1998 • A novel function for SMN, the spinal muscular atrophy disease gene product, in pre-mRNA splicing. PMID:9845364

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