• SyncroPatch 384/768i

    全球最高通量的全自动膜片钳系统
  • SyncroPatch 384/768i

    平行记录384个细胞 => 最高可升级到768个
  • SyncroPatch 384/768i

    真正的高通量与GΩ级封接
  • SyncroPatch 384/768i

    Analysis Software even more powerful than before
  • SyncroPatch 384/768i

    高科技保证实验的灵活性

2019 - Predicting Functional Effects of Missense Variants in Voltage-Gated Sodium and Calcium

icon sp96   SyncroPatch 384PE (a predecessor model of the SyncroPatch 384i) Pre-publication in bioRxiv Biology (2019)

Authors:
Heyne H.O., Baez-Nieto D., Iqbal S., Palmer D., Brunklaus A., Johannesen K.M., Lauxmann S., Lemke J.R., Møller R.S., Pérez-Palma E., Scholl U., Syrbe S., Lerche H., May P., Lal D., Campbell A.J., Pan J., Wang H.-R., Daly M.J.

Preprint Source:
bioRxiv (2019) doi: org/10.1101/637041


Abstract:

Malfunctions of voltage-gated sodium and calcium channels (SCN and CACNA1 genes) have been associated with severe neurologic, psychiatric, cardiac and other diseases. Altered channel activity is frequently grouped into gain or loss of ion channel function (GOF or LOF, respectively) which is not only corresponding to clinical disease manifestations, but also to differences in drug response. Experimental studies of channel function are therefore important, but laborious and usually focus only on a few variants at a time. Based on known gene-disease-mechanisms, we here infer LOF (518 variants) and GOF (309 variants) of likely pathogenic variants from disease phenotypes of variant carriers. We show regional clustering of inferred GOF and LOF variants, respectively, across the alignment of the entire gene family, suggesting shared pathomechanisms in the SCN/CACNA1 genes. By training a machine learning model on sequence- and structure-based features we predict LOF- or GOF- associated disease phenotypes (ROC = 0.85) of likely pathogenic missense variants. We then successfully validate the GOF versus LOF prediction on 87 functionally tested variants in SCN1/2/8A and CACNA1I (ROC = 0.73) and in exome-wide data from > 100.000 cases and controls. Ultimately, functional prediction of missense variants in clinically relevant genes will facilitate precision medicine in clinical practice.


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