Minor variants spectrum of the SMN locus

Background. Proximal spinal muscular atrophy 5q is one of the most frequent autosomal recessive disorders worldwide, and is the most common cause of genetically related infant mortality. Globally, approximately 5% of patients are compound heterozygotes with a deletion in one copy of the SMN1 gene and a minor mutation in the other. However, there are only isolated studies on a small number of such cases in Russia. Aim: to study the minor variants spectrum of the SMN locus in proximal spinal muscular atrophy 5q patients. Patients and methods. The research was performed on DNA samples from 2164 unrelated patients referred with the diagnosis of proximal spinal muscular atrophy 5q. A control group consisted of 2973 unrelated individuals. SMN gene copy number was determined by quantitative MLPA. The search for minor mutations in the SMN1 gene was performed by Sanger sequencing. Results and conclusions. SMN1 and SMN2 gene copy number were examined in 2164 patients referred with a presumptive diagnosis of proximal spinal muscular atrophy 5q. The diagnosis of proximal spinal muscular atrophy 5q was confirmed in 1032 patients. Minor mutations in the compound heterozygous state with deletion of 7 and 8 exons were identified in 32 patients (1.5%), and among patients with 1 copy of SMN1 a minor mutation was detected in 43%. Variants (nonsense, missense, frameshift and splice site mutations) were identified in all exons of the SMN1 gene except 2a and 8. Recurrent mutations were detected in exon 6, two of which c.815A>G and c.821C>T occurred 6 and 7 times, respectively. Clinical type of proximal spinal muscular atrophy 5q was found to be associated with both mutation type and copy number of the SMN2 gene. The carrier frequency in the population according to our data is 1/35 people. The estimated carrier frequency of minor mutations in the population is 0.000224. Frequency of minor mutations in a population is 1/4464. The risk of having a child with 5q SMA in a family where the parents are silent carriers is 1/156240.

proximal spinal muscular atrophy, SMN1, SMN2, minor variants, point mutations

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