Identification of two novel SMN1 point mutations associated with a very severe SMA-I phenotype

Spinal muscular atrophy (SMA) is a common autosomal recessive genetic disorder characterized by degeneration of motor neurons and weakness and muscle atrophy. Approximately 95% of SMA patients are caused by homozygous deletions of the SMN1 gene, whereas the remaining 5% of patients harbor compound heterozygous mutations such as an SMN1 deletion allele and an intragenic mutation (insertions, deletions, or point mutations) in the other SMN1 allele. Although analysis for the SMN1/SMN2 copy number is relatively easy, molecular genetic testing for patients with subtle mutations is still compromised due to the presence of a highly homologous SMN2 gene. Herein, we analyzed the SMN1/SMN2 copy number by multiplex ligation-dependent probe amplification (MLPA) and subtle mutations by long-range PCR (LR-PCR) for two "nondeletion" SMA patients. We identified a missense mutation (c.280G > T, p. (Val94Phe)) and a splicing mutation c.*3+3A > T in SMN1 gene not previously described in the scientific literature. Giving the severe phenotype of the two patients, we speculated that these two point mutations could significantly affect the function of SMN proteins. Our results provide important information for genetic counseling and prenatal diagnosis in these families and enrich the SMN1 mutation database.