Experience of a 2-year spinal muscular atrophy NBS pilot study in Italy: towards specific guidelines and standard operating procedures for the molecular diagnosis

Abstract

BackgroundSpinal muscular atrophy (SMA) is due to the homozygous absence ofSMN1in around 97% of patients, independent of the severity (classically ranked into types I–III). The high genetic homogeneity, coupled with the excellent results of presymptomatic treatments of patients with each of the three disease-modifying therapies available, makes SMA one of the golden candidates to genetic newborn screening (NBS) (SMA-NBS). The implementation of SMA in NBS national programmes occurring in some countries is an arising new issue that the scientific community has to address. We report here the results of the first Italian SMA-NBS project and provide some proposals for updating the current molecular diagnostic scenario.MethodsThe screening test was performed by an in-house-developed qPCR assay, amplifyingSMN1andSMN2. Molecular prognosis was assessed on fresh blood samples.ResultsWe found 15 patients/90885 newborns (incidence 1:6059) having the followingSMN2genotypes: 1 (one patient), 2 (eight patients), 2+c.859G>C variant (one patient), 3 (three patients), 4 (one patient) or 6 copies (one patient). Six patients (40%) showed signs suggestive of SMA at birth. We also discuss some unusual cases we found.ConclusionThe molecular diagnosis of SMA needs to adapt to the new era of the disease with specific guidelines and standard operating procedures. In detail, SMA diagnosis should be felt as a true medical urgency due to therapeutic implications;SMN2copy assessment needs to be standardised; commercially available tests need to be improved for higherSMN2copies determination; and theSMN2splicing-modifier variants should be routinely tested in SMA-NBS.