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

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

Abstract

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.