Hum Mol Genet.: co-auth.: group Reymond

Hum Mol Genet. 2022 Sep 6;ddac225. doi: 10.1093/hmg/ddac225. Online ahead of print.

Germline homozygous missense DEPDC5 variants cause severe refractory early-onset epilepsy, macrocephaly and bilateral polymicrogyria

Athina Ververi 1 2Sara Zagaglia 3 4Lara Menzies 1Julia Baptista 5Richard Caswell 6Stephanie Baulac 7Sian Ellard 5Sally Lynch 8 9Genomics England Research ConsortiumThomas S Jacques 10 11Maninder Singh Chawla 12Martin Heier 13Mari Ann Kulseth 14Inger-Lise Mero 14Anne Katrine Våtevik 15Ichraf Kraoua 16Hanene Ben Rhouma 16Thouraya Ben Younes 16Zouhour Miladi 16Ilhem Ben Youssef Turki 16Wendy D Jones 1Emma Clement 1Christin Eltze 17Kshitij Mankad 18Ashirwad Merve 11Jennifer Parker 19Bethan Hoskins 19Ronit Pressler 20Sniya Sudhakar 18Catherine DeVile 17Tessa Homfray 21Marios Kaliakatsos 17Prab Prabhakar Ponnudas 17Robert Robinson 17Sara Margrete Bøen Keim 14Imen Habibi 22Alexandre Reymond 22Sanjay M Sisodiya 3 4Jane A Hurst 1


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.