A quantitative cSMART assay for noninvasive prenatal screening of autosomal recessive nonsyndromic hearing loss caused by GJB2 and SLC26A4 mutations

Genet Med. 2017 Dec;19(12):1309-1316. doi: 10.1038/gim.2017.54. Epub 2017 May 25.


PurposeThe aim of this study was to assess the performance of a noninvasive prenatal screening (NIPS) assay for accurate fetal genotyping of pregnancies at genetic risk for autosomal recessive nonsyndromic hearing loss (ARNSHL).MethodsA total of 80 pregnant couples carrying known mutations in either the GJB2 or SLC26A4 genes associated with a risk for ARNSHL were recruited to the study. Fetal amniocyte samples were genotyped by invasive prenatal screening (IPS), whereas the cell-free fetal DNA present in maternal plasma samples was genotyped using a novel NIPS method based on circulating single-molecule amplification and resequencing technology (cSMART).ResultsIPS of the 80 at-risk pregnancies identified 20 normal homozygote, 42 heterozygote, 5 affected homozygote, and 13 affected compound heterozygote fetuses. Benchmarking against IPS, 73 of 80 fetuses (91.3%) were correctly genotyped by the cSMART NIPS assay. A low fetal DNA fraction (<6%) was identified as the main contributing factor in five of seven discordant NIPS results. At fetal DNA fractions >6%, the sensitivity and specificity of the cSMART assay for correctly diagnosing ARNSHL were 100 and 96.5%, respectively.ConclusionBased on key performance indicators, the cSMART NIPS assay has clinical potential as an alternative to traditional IPS of ARNSHL.

MeSH terms

  • Connexin 26
  • Connexins / genetics*
  • Deafness / diagnosis*
  • Deafness / genetics*
  • Genes, Recessive*
  • Genetic Testing* / methods
  • Genotype
  • Humans
  • Membrane Transport Proteins / genetics*
  • Mutation*
  • Prenatal Diagnosis* / methods
  • Reproducibility of Results
  • Sensitivity and Specificity
  • Sulfate Transporters


  • Connexins
  • GJB2 protein, human
  • Membrane Transport Proteins
  • SLC26A4 protein, human
  • Sulfate Transporters
  • Connexin 26

Supplementary concepts

  • Nonsyndromic Deafness