Please use this identifier to cite or link to this item: https://hdl.handle.net/2440/131134
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Type: Journal article
Title: Integrated in silico and experimental assessment of disease relevance of PCDH19 missense variants
Author: Pham, D.H.
Pitman, M.R.
Sharma, R.
Jolly, L.
Schulz, R.
Gardner, A.
de Nys, R.
Heron, S.E.
Corbett, M.A.
Kothur, K.
Gill, D.
Rajagopalan, S.
Kolc, K.
Halliday, B.J.
Robertson, S.P.
Regan, B.M.
Kirsch, H.E.
Berkovic, S.F.
Scheffer, I.E.
Pitson, S.M.
et al.
Citation: Human Mutation, 2021; 42(8):1030-1041
Publisher: Wiley
Issue Date: 2021
ISSN: 1059-7794
1098-1004
Statement of
Responsibility: 
Duyen H. Pham, Melissa R. Pitman, Raman Kumar, Lachlan A. Jolly, Renee Schulz, Alison E. Gardner ... et al.
Abstract: PCDH19 is a non-clustered protocadherin molecule involved in axon bundling, synapse function and transcriptional co-regulation. Pathogenic variants in PCDH19 cause an infantile onset epilepsy known as PCDH19-clustering epilepsy or PCDH19-CE. Recent advances in DNA sequencing technologies have led to a significant increase in the number of reported PCDH19-CE variants, many of uncertain significance, or VUS. We aimed to determine the best approaches for assessing the disease relevance of missense variants in PCDH19. Application of the American College of Medical Genetics and Association for Molecular Pathology (ACMG-AMP) guidelines was only 50% accurate. Using a training set of 322 known benign or pathogenic missense variants, we identified MutPred2, MutationAssessor and GPP as the best performing in silico tools. We generated a protein structural model of the extracellular domain and assessed 24 missense variants. We also assessed 24 variants using an in vitro reporter assay. A combination of these tools was 93% accurate in assessing known pathogenic and benign PCDH19 variants. We increased the accuracy of the ACMG-AMP classification of 45 PCDH19 variants from 50% to 94%, using these tools. In summary, we have developed a robust toolbox for the assessment of PCDH19 variant pathogenicity to improve the accuracy of PCDH19-CE variant classification. This article is protected by copyright. All rights reserved.
Keywords: PCDH19
VUS
epilepsy
functional test
variant assessment
Description: First published: 03 June 2021
Rights: © 2021 Wiley Periodicals LLC.
DOI: 10.1002/humu.24237
Grant ID: http://purl.org/au-research/grants/nhmrc/1042589
http://purl.org/au-research/grants/nhmrc/1091593
http://purl.org/au-research/grants/nhmrc/1155224
Appears in Collections:Aurora harvest 4
Genetics publications

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