Complex SMN Hybrids Detected in a Cohort of 31 Patients With Spinal Muscular Atrophy

• Published in: Neurology. Genetics 2024-08, Vol.10 (4), p.e200175
• Main Authors: Costa-Roger, Mar, Blasco-Pérez, Laura, Gerin, Lorene, Codina-Solà, Marta, Leno-Colorado, Jordi, Gómez-García De la Banda, Marta, Garcia-Uzquiano, Rocio, Saugier-Veber, Pascale, Drunat, Séverine, Quijano-Roy, Susana, Tizzano, Eduardo F
• Format: Article
• Language: English
• ISSN: 2376-7839; 2376-7839
• DOI: 10.1212/NXG.0000000000200175

Spinal muscular atrophy (SMA) is a recessive neuromuscular disorder caused by the loss or presence of point pathogenic variants in the gene. The main positive modifier of the SMA phenotype is the number of copies of the gene, a paralog of , which only produces around 10%-15% of functional SMN protein. The copy number is inversely correlated with phenotype severity; however, discrepancies between the SMA type and the copy number have been reported. The presence of hybrids has been proposed as a possible modifier of SMA disease. We studied 31 patients with SMA, followed at a single center and molecularly diagnosed by Multiplex Ligand-Dependent Probe Amplification (MLPA), with a specific next-generation sequencing protocol to investigate their genes in depth. Hybrid characterization also included bioinformatics haplotype phasing and specific PCRs to resolve each hybrid structure. We detected hybrid genes in 45.2% of the patients (14/31), the highest rate reported to date. This represents a total of 25 hybrid alleles, with 9 different structures, of which only 4 are detectable by MLPA. Of particular interest were 2 patients who presented 4 hybrid copies each and no pure copies, an event reported here for the first time. No clear trend between the presence of hybrids and a milder phenotype was observed, although 5 of the patients with hybrid copies showed a better-than-expected phenotype. The higher hybrid detection rate in our cohort may be due to both the methodology applied, which allows an in-depth characterization of the genes and the ethnicity of the patients, mainly of African origin. Although hybrid genes have been proposed to be beneficial for patients with SMA, our work revealed great complexity and variability between hybrid structures; therefore, each hybrid structure should be studied independently to determine its contribution to the SMA phenotype. Large-scale studies are needed to gain a better understanding of the function and implications of hybrid copies, improving genotype-phenotype correlations and prediction of the evolution of patients with SMA.