Practical guidelines to manage discordant situations of copy number in patients with spinal muscular atrophy.

Objective: Assessment of 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 copy number and establishment of phenotype-genotype correlations.

Methods: We propose a management guide based on a sequence of specified actions once copy number is determined for a given patient. Regardless of the method used to estimate the number of copies, our approach focuses on the manifestations of the patient to recommend how to proceed in each case.

Results: We defined situations according to 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 copy but noncongenital disease forms, 2 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 gene, as the main modifier of SMA phenotype, deserves a more in-depth study to provide more accurate genotype-phenotype correlations.