دورية أكاديمية
Germline homozygous missense DEPDC5 variants cause severe refractory early-onset epilepsy, macrocephaly and bilateral polymicrogyria
| العنوان: | Germline homozygous missense DEPDC5 variants cause severe refractory early-onset epilepsy, macrocephaly and bilateral polymicrogyria |
|---|---|
| المؤلفون: | Ververi, A., Zagaglia, S., Menzies, L., Baptista, J., Caswell, R., Baulac, S., Ellard, S., Lynch, S., Consortium, G. E. R., Jacques, T. S., Chawla, M. S., Heier, M., Kulseth, M. A., Mero, I. L., Våtevik, A. K., Kraoua, I., Rhouma, H. B., Younes, T. B., Miladi, Z., Turki, I. B. Y., Jones, W. D., Clement, E., Eltze, C., Mankad, K., Merve, A., Parker, J., Hoskins, B., Pressler, R., Sudhakar, S., DeVile, C., Homfray, T., Kaliakatsos, M., Ponnudas, P. P., Robinson, R., Keim, S. M. B., Habibi, I., Reymond, A., Sisodiya, S. M., Hurst, J. A. |
| بيانات النشر: | Oxford University Press |
| سنة النشر: | 2022 |
| المجموعة: | RD&E Research Repository (Royal Devon and Exeter NHS Foundation Trust) |
| الوصف: | PURPOSE: DEPDC5 (DEP Domain-Containing Protein 5) encodes an inhibitory component of the mTOR pathway and is commonly implicated in sporadic and familial focal epilepsies, both non-lesional and in association with focal cortical dysplasia. Germline pathogenic variants are typically heterozygous and inactivating. We describe a novel phenotype caused by germline biallelic missense variants in DEPDC5. METHODS: Cases were identified clinically. Available records, including MRI and EEG, were reviewed. Genetic testing was performed by whole exome and whole genome sequencing and cascade screening. In addition, immunohistochemistry was performed on skin biopsy. RESULTS: The phenotype was identified in nine children, eight of which are described in detail herein. Six of the children were of Irish Traveller, two of Tunisian and one of Lebanese origin. The Irish Traveller children shared the same DEPDC5 germline homozygous missense variant (p.Thr337Arg), whereas the Lebanese and Tunisian children shared a different germline homozygous variant (p.Arg806Cys). Consistent phenotypic features included extensive bilateral polymicrogyria, congenital macrocephaly and early-onset refractory epilepsy, in keeping with other mTOR-opathies. Eye and cardiac involvement, and severe neutropenia, were also observed in one or more patients. Five of the children died in infancy or childhood, the other four are currently aged between five months and six years. Skin biopsy immunohistochemistry was supportive of hyperactivation of the mTOR pathway. DISCUSSION: The clinical, histopathological and genetic evidence supports a causal role for the homozygous DEPDC5 variants, expanding our understanding of the biology of this gene. ; This article is freely available online. Click on the 'Additional Link' above to access the full-text via the publisher's site. ; Published version, accepted version (12 month embargo), submitted version |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| العلاقة: | Hum Mol Genet. 2022 Sep 6:ddac225. doi:10.1093/hmg/ddac225.; https://rde.dspace-express.com/handle/11287/622578Test; Human molecular genetics |
| DOI: | 10.1093/hmg/ddac225 |
| الإتاحة: | https://doi.org/10.1093/hmg/ddac225Test https://rde.dspace-express.com/handle/11287/622578Test |
| حقوق: | © The Author(s) 2022. Published by Oxford University Press. |
| رقم الانضمام: | edsbas.EE2908D5 |
| قاعدة البيانات: | BASE |
| DOI: | 10.1093/hmg/ddac225 |
|---|