Newborn Screening for Spinal Muscular Atrophy in China Using DNA Mass Spectrometry.

Lin Zhu,Chiju Yang,Chenggang Huang,Jianbin Yang,Haili Hu,Chien-Hsing Lin,Yiming Lin,Xinwen Huang,Qingqing Ma,Xigui Chen,Xueqin Shi,Yuyan Shen,Zhenzhen Hu,Yaping Shen,Xiaoshan Yin

doi:10.3389/fgene.2019.01255

Abstract

Background: Spinal muscular atrophy (SMA) is the most common neurodegenerative disorder and the leading genetic cause of infant mortality. Early detection of SMA through newborn screening (NBS) is essential to selecting pre-symptomatic treatment and ensuring optimal outcome, as well as, prompting the urgent need for effective screening methods. This study aimed to determine the feasibility of applying an Agena iPLEX SMA assay in NBS for SMA in China. Methods: We developed an Agena iPLEX SMA assay based on the matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, and evaluated the performance of this assay through assessment of 167 previously-genotyped samples. Then we conducted a pilot study to apply this assay for SMA NBS. The SMN1 and SMN2 copy number of screen-positive patients were determined by multiplex ligation-dependent probe amplification analysis. Results: The sensitivity and specificity of the Agena iPLEX SMA assay were both 100%. Three patients with homozygous SMN1 deletion were successfully identified and conformed by multiplex ligation-dependent probe amplification analysis. Two patients had two SMN2 copies, which was correlated with severe SMA type I phenotype; both of them exhibited neurogenic lesion and with decreased muscle power. Another patient with four SMN2 copies, whose genotype correlated with milder SMA type III or IV phenotype, had normal growth and development without clinical symptoms. Conclusions: The Agena iPLEX SMA assay is an effective and reliable approach for population-based SMA NBS. The first large-scale pilot study using this assay in the Mainland of China showed that large-scale implementation of population-based NBS for SMA is feasible.

Highlights

Spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disorder and the leading genetic cause of infant mortality, with an incidence around 1 in 10,000 live births (Verhaart et al, 2017a; Verhaart et al, 2017b)
We described the development of an Agena iPLEX SMA assay to detect the homozygous survival of motor neuron 1 (SMN1) deletion, which is applicable to SMA newborn screening (NBS)
The Agena iPLEX SMA assay was validated in a double-blind testing of 167 previously-genotyped dried blood spot (DBS) samples with known SMN1 and SMN2 copy numbers

Summary

Introduction

Spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disorder and the leading genetic cause of infant mortality, with an incidence around 1 in 10,000 live births (Verhaart et al, 2017a; Verhaart et al, 2017b). About 95% of the SMA-affected patients are caused by the homozygous deletion of the survival of motor neuron 1 (SMN1) gene, resulting in deficiency of SMN protein (Lefebvre et al, 1995; Lefebvre et al, 1997). Larger number of SMN2 copies are associated with milder phenotypes (Mailman et al, 2002; Calucho et al, 2018). Spinal muscular atrophy (SMA) is the most common neurodegenerative disorder and the leading genetic cause of infant mortality.

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