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SMN1 gene copy number analysis for spinal muscular atrophy (SMA) in a Turkish cohort by CODE-SEQ technology, an integrated solution for detection of SMN1 and SMN2 copy numbers and the “2+0” genotype

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Abstract

Introduction

Spinal muscular atrophy (SMA) is one of the common autosomal recessive disorders with global heterozygous carrier frequency of 1:50. Due to high carrier frequency, significant morbidity associated with the infantile onset disease and prohibitive cost of recently approved therapy, American College of Medical Genetics and Genomics (ACMG) recommends population based screening for SMA carrier status in eligible individuals in the reproductive age group. CODE-SEQ is a novel proprietary next generation sequencing (NGS) based assay, which is capable of detecting homozygous as well as heterozygous SMN1 exon 7 deletions. Along with the copy number estimation, this assay is capable of detecting single nucleotide polymorphisms (SNPs) associated with silent SMA carrier status or “2+0” genotype.

Methods

We have validated a proprietary CODE-SEQ technology in a blinded cohort of 80 clinically well characterized samples from Turkish population for the detection of SMA carriers as well as affected cases. The results were correlated with gold standard MLPA assay.

Results

The copy numbers in exon 7 of SMN1 gene matched with MLPA results in all 80 samples giving 100% correlation. The assay accurately detected the presence/ absence of SNPs associated with “2+0” genotype in the reference samples. None of the tested clinical samples had these SNPs.

Conclusion

The results of this study support the notion that CODE-SEQ will be extremely useful in detecting SMA genotypes in large-scale population-based screening studies.

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Acknowledgments

We are thankful to Nikhil Phadke, Karthik Ganesan, Shatakshi Ranade, Kunal Patil, Gülşah Sönmez, Zeynep Demirel, Günce Bayram, and Hilmi Tok for helping in performing the lab experiments and analysis of the data.

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Authors and Affiliations

  1. Department of Medical Genetics, Ankara City Hospital, Ankara, Turkey

    Ahmet Cevdet Ceylan

  2. Department of Medical Genetics, Ankara Diskapi Yildirim Beyazit Training and Research Hospital, Ankara, Turkey

    Haktan Bağış Erdem & İbrahim Şahin

  3. Department of Medical Genetics, GenePath Diagnostics India Private Ltd, Medical Genetics, 1260/B, JM road, Pune, 411004, India

    Meenal Agarwal

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  1. Ahmet Cevdet Ceylan
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  2. Haktan Bağış Erdem
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  3. İbrahim Şahin
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  4. Meenal Agarwal
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Corresponding author

Correspondence to Meenal Agarwal.

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Conflict of interest

MA (MD, DM) is a clinical geneticist and is an employee of GenePath Diagnostics, the organization who has applied patent for this novel CODE-SEQ platform. MA was not involved in the performing the wet lab experiments, analysis of the data, and correlation with gold standards.

Ethical approval

The study was approved by the ethical committee of the Ankara Yıldırım Beyazıt University, School of Medicine.

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Ceylan, A.C., Erdem, H.B., Şahin, İ. et al. SMN1 gene copy number analysis for spinal muscular atrophy (SMA) in a Turkish cohort by CODE-SEQ technology, an integrated solution for detection of SMN1 and SMN2 copy numbers and the “2+0” genotype. Neurol Sci 41, 2575–2584 (2020). https://doi.org/10.1007/s10072-020-04365-x

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