Journal article

Integrated in silico and experimental assessment of disease relevance of PCDH19 missense variants

Duyen H Pham, Melissa R Pitman, Raman Kumar, Lachlan A Jolly, Renee Schulz, Alison E Gardner, Rebekah de Nys, Sarah E Heron, Mark A Corbett, Kavitha Kothur, Deepak Gill, Sulekha Rajagopalan, Kristy L Kolc, Benjamin J Halliday, Stephen P Robertson, Brigid M Regan, Heidi E Kirsch, Samuel F Berkovic, Ingrid E Scheffer, Stuart M Pitson Show all

HUMAN MUTATION | WILEY | Published : 2021


PCDH19 is a nonclustered protocadherin molecule involved in axon bundling, synapse function, and transcriptional coregulation. Pathogenic variants in PCDH19 cause 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. We aimed to determine the best approaches for assessing the disease relevance of missense variants in PCDH19. The 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 pat..

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Awarded by National Health and Medical Research Council

Funding Acknowledgements

RAH Research Fund, Grant/Award Number: Florey Fellowship to M.R.P.; WCH Foundation, Grant/Award Number: Research Project Grant to D.H.P.; National Health and Medical Research Council, Grant/Award Numbers: 1042589 to S.M.P., 1091593 to S.F.B., I.E.S., and J.G., 1155224 to J.G., Practitioner Fellowship to I.E.S.