RT Journal Article SR Electronic T1 Practical guidelines to manage discordant situations of SMN2 copy number in patients with spinal muscular atrophy JF Neurology Genetics JO Neurol Genet FD Lippincott Williams & Wilkins SP e530 DO 10.1212/NXG.0000000000000530 VO 6 IS 6 A1 Cuscó, Ivon A1 Bernal, Sara A1 Blasco-Pérez, Laura A1 Calucho, Maite A1 Alias, Laura A1 Fuentes-Prior, Pablo A1 Tizzano, Eduardo F. YR 2020 UL http://ng.neurology.org/content/6/6/e530.abstract AB Objective Assessment of SMN2 copy number in patients with spinal muscular atrophy (SMA) is essential to establish careful genotype-phenotype correlations and predict disease evolution. This issue is becoming crucial in the present scenario of therapeutic advances with the perspective of SMA neonatal screening and early diagnosis to initiate treatment, as this value is critical to stratify patients for clinical trials and to define those eligible to receive medication. Several technical pitfalls and interindividual variations may account for reported discrepancies in the estimation of SMN2 copy number and establishment of phenotype-genotype correlations.Methods We propose a management guide based on a sequence of specified actions once SMN2 copy number is determined for a given patient. Regardless of the method used to estimate the number of SMN2 copies, our approach focuses on the manifestations of the patient to recommend how to proceed in each case.Results We defined situations according to SMN2 copy number in a presymptomatic scenario of screening, in which we predict the possible evolution, and when a symptomatic patient is genetically confirmed. Unexpected discordant cases include patients having a single SMN2 copy but noncongenital disease forms, 2 SMN2 copies compatible with type II or III SMA, and 3 or 4 copies of the gene showing more severe disease than expected.Conclusions Our proposed guideline would help to systematically identify discordant SMA cases that warrant further genetic investigation. The SMN2 gene, as the main modifier of SMA phenotype, deserves a more in-depth study to provide more accurate genotype-phenotype correlations.FL-SMN=full-length SMN; MLPA=multiplex ligation-dependent probe amplification; NGS=next-generation sequencing; SMA=spinal muscular atrophy; SMN=survival motor neuron; SMN-del7=SMN2 transcripts lacking exon 7; SNV=single nucleotide variant