Integrated in silico and experimental assessment of disease relevance of PCDH19 missense variants
| Autor: | Stuart M. Pitson, Mark A. Corbett, Stephen P. Robertson, Rebekah de Nys, Heidi E. Kirsch, Deepak Gill, Melissa R. Pitman, Samuel F. Berkovic, Benjamin J. Halliday, Lachlan A. Jolly, Slavé Petrovski, Jozef Gecz, Kavitha Kothur, Kristy L. Kolc, Brigid M. Regan, Alison Gardner, Duyen H. Pham, Ingrid E. Scheffer, Sulekha Rajagopalan, Raman Kumar, Renèe B. Schulz, Sarah E. Heron |
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| Přispěvatelé: | Pham, Duyen H, Pitman, Melissa R, Kumar, Raman, Jolly, Lachlan A, Pitson, Stuart M, Gecz, Jozef |
| Rok vydání: | 2021 |
| Předmět: |
medicine.medical_specialty
PCDH19 In silico Mutation Missense Protocadherin Disease Computational biology Biology functional test variant assessment 03 medical and health sciences Genetics medicine Humans Missense mutation Relevance (information retrieval) Genetics (clinical) 030304 developmental biology 0303 health sciences Epilepsy Molecular pathology 030305 genetics & heredity Sequence Analysis DNA Cadherins Protocadherins VUS epilepsy Medical genetics Function (biology) |
| Zdroj: | Human Mutation. 42:1030-1041 |
| ISSN: | 1098-1004 1059-7794 |
| Popis: | 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 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. Refereed/Peer-reviewed |
| Databáze: | OpenAIRE |
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