Screening of Neonatal UK Dried Blood Spots Using a Duplex SMN1 Screening Assay

Stuart P Adams,Emma Gravett,Salma Samsuddin,Natalie Kent,Susanne Kricke,Francesco Muntoni,Adeboye Ifederu,Mariacristina Scoto

doi:10.3390/ijns7040069

Abstract

Spinal muscular atrophy (SMA) is an autosomal inherited neuromuscular genetic disease caused, in 95% of cases, by homozygous deletions involving the SMN1 gene exon 7. It remains the leading cause of death in children under 2 years of age. New treatments have been developed and adopted for use in many countries, including the UK. Success of these treatments depends on early diagnosis and intervention in newborn babies, and many countries have implemented a newborn screening (NBS) or pilot NBS program to detect SMN1 exon 7 deletions on dried blood spots. In the UK, there is no current NBS program for SMA, and no pilot studies have commenced. For consideration of adoption of NBS for a new condition, numerous criteria must be satisfied, including critical assessment of a working methodology. This study uses a commercially available real-time PCR assay to simultaneously detect two different DNA segments (SMN1 exon 7 and control gene RPP30) using DNA extracted from a dried blood spot. This study was carried out in a routine clinical laboratory to determine the specificity, sensitivity, and feasibility of SMA screening in a UK NBS lab setting. Just under 5000 normal DBSs were used alongside 43 known SMA positive DBSs. Study results demonstrate that NBS for SMA using real-time PCR is feasible within the current UK NBS Laboratory infrastructure using the proposed algorithm.

Highlights

Spinal muscular atrophy (SMA) is one of the most common lethal recessive genetic conditions, with an incidence of 1:8000 births in Europe dependent on ethnicity [1,2]
Controls and blanks were included in each run with typically one run carried out per day. This permitted reliable analysis of the anonymised, presumed normal dried blood spots (DBSs) and the known SMA-positive DBS, as well as the kit controls provided in the NeoMDx PCR Reagent kit (PerkinElmer Wallac Oy)
This assay is already widely used in numerous newborn screening (NBS) centres, SMA NBS

Summary

Introduction

Spinal muscular atrophy (SMA) is one of the most common lethal recessive genetic conditions, with an incidence of 1:8000 births in Europe dependent on ethnicity [1,2]. In the UK in 2019, there were 712,699 live births [3] (UK Office for National Statistics), suggesting that approximately 71 babies were born that year with a type of SMA. The treatment for SMA was limited to supportive care, but in 2020, Nusinersen (an antisense oligonucleotide administered intrathecally) was approved for use in the UK by the National Institute for Health and Care Excellence (NICE). A second effective therapy (the adeno-associated viral vector onasemnogene abeparvovec) has been sanctioned for use in babies up to 12 months of age by NICE in 2021. Since early diagnosis and intervention is crucial for therapy to be effective, there has been considerable global interest in newborn screening (NBS) for SMA.

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Results

Conclusion