학술논문
Enhanced Carrier Screening for Spinal Muscular Atrophy: Detection of Silent (SMN1: 2 + 0) Carriers Utilizing a Novel TaqMan Genotyping Method
Science
Science
Document Type
Academic Journal
Author
Source
Laboratory Medicine. July 2020, Vol. 51 Issue 4, p408, 8 p.
Subject
Language
English
ISSN
0007-5027
Abstract
Spinal muscular atrophy (SMA; OMIM #253300) is an autosomal recessive disorder characterized by progressive degeneration of the anterior horn cells of the spinal cord (ie, lower motor neurons). This degeneration [...]
Background: Individuals whose copies of the survival motor neuron 1 (SMN1) gene exist on the same chromosome are considered silent carriers for spinal muscular atrophy (SMA). Conventional screening for SMA only determines SMN1 copy number without any information regarding how those copies are arranged. A single nucleotide variant (SNV) rs143838139 is highly linked with the silent carrier genotype, so testing for this SNV can more accurately assess risk to a patient of having an affected child. Methods: Using a custom-designed SNV-specific Taqman genotyping assay, we determined and validated a model for silent-carrier detection in the laboratory. Results: An initial cohort of 21 pilot specimens demonstrated results that were 100% concordant with a reference laboratory method; this cohort was utilized to define the reportable range. An additional 177 specimens were utilized for a broader evaluation of clinical validity and reproducibility. Allelic-discrimination analysis demonstrated tight clustering of genotype groupings and excellent reproducibility, with a coefficient of variation for all genotypes ranging from 1% to 4%. Conclusion: The custom-developed Taqman SNV genotyping assay we tested provides a rapid, accurate, and cost-effective method for routine SMA silent-carrier screening and considerably improves detection rates of residual risk for SMA carriers. Keywords: spinal muscular atrophy, silent carrier, SNV genotyping, TaqMan genotype assay, population genetics, laboratory-developed testing procedure
Background: Individuals whose copies of the survival motor neuron 1 (SMN1) gene exist on the same chromosome are considered silent carriers for spinal muscular atrophy (SMA). Conventional screening for SMA only determines SMN1 copy number without any information regarding how those copies are arranged. A single nucleotide variant (SNV) rs143838139 is highly linked with the silent carrier genotype, so testing for this SNV can more accurately assess risk to a patient of having an affected child. Methods: Using a custom-designed SNV-specific Taqman genotyping assay, we determined and validated a model for silent-carrier detection in the laboratory. Results: An initial cohort of 21 pilot specimens demonstrated results that were 100% concordant with a reference laboratory method; this cohort was utilized to define the reportable range. An additional 177 specimens were utilized for a broader evaluation of clinical validity and reproducibility. Allelic-discrimination analysis demonstrated tight clustering of genotype groupings and excellent reproducibility, with a coefficient of variation for all genotypes ranging from 1% to 4%. Conclusion: The custom-developed Taqman SNV genotyping assay we tested provides a rapid, accurate, and cost-effective method for routine SMA silent-carrier screening and considerably improves detection rates of residual risk for SMA carriers. Keywords: spinal muscular atrophy, silent carrier, SNV genotyping, TaqMan genotype assay, population genetics, laboratory-developed testing procedure