Intragenic variants in the <i>SMN1</i> gene determine the clinical phenotype in 5q spinal muscular atrophy

Abstract

<h3>Objective</h3> The aim of the study was to report the proportion of homozygous and compound heterozygous variants in the survival motor neuron 1 (<i>SMN1</i>) gene in a large population of patients with spinal muscular atrophy (SMA) and to correlate the severity of the disease with the presence of specific intragenic variants in <i>SMN1</i> and with the <i>SMN2</i> copy number. <h3>Methods</h3> Four hundred fifty Brazilian patients with SMA were included in a retrospective study, and clinical data were analyzed compared with genetic data; the <i>SMN2</i> copy number was obtained by multiplex ligation-dependent probe amplification and pathogenic variants in <i>SMN1</i> by next-generation sequencing. <h3>Results</h3> Four hundred two patients (89.3%) presented homozygous exon 7-<i>SMN1</i> deletion, and 48 (10.7%) were compound heterozygous for the common deletion in one allele and a point mutation in the other allele. Recurrent variants in exons 3 and 6 (c.460C&gt;T, c.770_780dup and c.734_735insC) accounted for almost 80% of compound heterozygous patients. Another recurrent pathogenic variant was c.5C&gt;G at exon 1. Patients with c.770_780dup and c.734_735insC had a clinical phenotype correlated with <i>SMN2</i> copy number, whereas the variants c.460C&gt;T and c.5C&gt;G determined a milder phenotype independently of the <i>SMN2</i> copies. <h3>Conclusions</h3> Patients with specific pathogenic variants (c.460C&gt;T and c.5C&gt;G) presented a milder phenotype, and the <i>SMN2</i> copy number did not correlate with disease severity in this group.