Intragenic variants in the <i>SMN1</i> gene determine the clinical phenotype in 5q spinal muscular atrophy
Rodrigo de Holanda Mendonça, Ciro Matsui, Graziela Jorge Polido, André Macedo Serafim da Silva, Leslie Domenici Kulikowski, Alexandre Torchio Dias, Évelin Aline Zanardo, Davi Jorge Fontoura Solla, Juliana Gurgel‐Giannetti, Ana Carolina Monteiro Lessa de Moura, Gabriela Palhares Campolina Sampaio, Acary Souza Bullé Oliveira, Paulo Victor Sgobbi de Souza, Wladimir Bocca Vieira de Rezende Pinto, Eduardo Augusto Gonçalves, Igor Braga Farias, Flávia Nardes, Alexandra Prufer de Queiroz Campos Araújo, Wilson Marques, Pedro José Tomaselli, Mara Dell Ospedale Ribeiro, João Paulo Kitajima, Fabíola Paoli Monteiro, Jonas Alex Morales Saute, Michele Michelin Becker, Maria Luiza Saraiva Pereira, Ana Carolina Brusius‐Facchin, Vanessa van der Linden, Rodrigo Florêncio, André Vinícius Soares Barbosa, Marcela Câmara Machado‐Costa, André Luiz Santos Pessoa, Letícia Silva de Souza, Marcondes C. França, Fernando Kok, Umbertina Conti Reed, Edmar Zanoteli
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>T, c.770_780dup and c.734_735insC) accounted for almost 80% of compound heterozygous patients. Another recurrent pathogenic variant was c.5C>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>T and c.5C>G determined a milder phenotype independently of the <i>SMN2</i> copies. <h3>Conclusions</h3> Patients with specific pathogenic variants (c.460C>T and c.5C>G) presented a milder phenotype, and the <i>SMN2</i> copy number did not correlate with disease severity in this group.