Mutation analysis of 419 family and prenatal diagnosis of 339 cases of spinal muscular atrophy in China

Yingjie Sun,Zhenhua Zhao,Xiangdong Kong,Xuechao Zhao

doi:10.1186/s12881-020-01069-z

Yingjie Sun, Zhenhua Zhao + Show 2 more

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https://doi.org/10.1186/s12881-020-01069-z

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Abstract

BackgroundSpinal muscular atrophy (SMA) is a common and lethal autosomal recessive neurodegenerative disease caused by mutations in the survival motor neuron 1 (SMN1) gene. At present, gene therapy medicine for SMA, i.e., Spinraza (Nusinersen), has been approved by the FDA, bringing hope to SMA patients and families. Accurate diagnosis is essential for treatment. Our goal was to detect genetic mutations in SMA patients in China and to show the results of the prenatal diagnosis of SMA.MethodsIn this study, we examined 419 patients in our hospital from January 2010 to September 2019. Multiplex ligation-dependent probe amplification analysis was used to determine the copy numbers of SMN1 and SMN2. Long-range PCR combined with nested PCR was used to detect point mutations in SMN1. In addition to the above detection methods, we also used QF-PCR in prenatal diagnosis to reduce the impact of maternal contamination. We conducted a total of 339 prenatal diagnoses from January 2010 to September 2019.ResultsHomozygous deletion of SMN1 exon 7 was detected in 96.40% (404/419) of patients. Homozygous deletion of SMN1 exon 7 alone was detected in 15 patients (3.60%). In total, 10 point mutations were detected in the 15 pedigrees. Most patients with SMA Type I have 1 ~ 2 copies of the SMN2 gene. Patients with SMA Type II have 2 or 3 copies of the SMN2 gene. The results of prenatal diagnoses showed that 118 fetuses were normal, 149 fetuses were carriers of heterozygous variants, and the remaining 72 fetuses harbored compound heterozygous variants or homozygous variants.ConclusionsOur study found that the most common mutation in SMA was homozygous deletion of SMN1 exon 7 in our study. We suggest that detecting only the deletion of exon 7 of SMN1 can meet most of the screening needs. We also believe that SMN2 copy numbers can help infer the disease classification and provide some reference for future treatment options.

Highlights

Spinal muscular atrophy (SMA) is a common and lethal autosomal recessive neurodegenerative disease caused by mutations in the survival motor neuron 1 (SMN1) gene
Genetic diagnosis of SMA patients SMN1 gene mutation analysis By using multiplex ligation-dependent probe amplification (MLPA) and long-range PCR, we found that approximately 96.4% (404/419) of patients had homozygous deletions for SMN1 (Table 2)
Spinraza is an antisense nucleotide that combines with the splicing site of SMN2 exon 7 to correct the RNA splicing of the defective SMN2 gene to produce a protein product that can better replace the function of the SMN1 gene, thereby achieving the role of disease treatment [13]

Summary

Introduction

Spinal muscular atrophy (SMA) is a common and lethal autosomal recessive neurodegenerative disease caused by mutations in the survival motor neuron 1 (SMN1) gene. Our goal was to detect genetic mutations in SMA patients in China and to show the results of the prenatal diagnosis of SMA. Spinal muscular atrophy (SMA) is the most common autosomal recessive neuromuscular disease that causes death in infants and young children. The pathogenic gene of SMA is the survival motor neuron (SMN) gene located on chromosome 5q13 [3]. This region has a complex structure with repeat sequences and many pseudo gene clusters, which make gene deletion and transformation easy. The SMN1 gene is the causative gene for SMA, and the SMN2 gene functions to modify the SMA phenotype

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