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

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.

DEPDC5 plays a vital role in epilepsy: Genotypic and phenotypic features in cohort and literature

“…Through an initial search with the search terms, 47 papers were elected. While 28 studies met the inclusion criteria and were included finally 2–7,10–31 . The information extracted from the literature is listed in Table S1.…”

“…It was noteworthy that homozygous missense variants were identified and caused severe phenotype with early onset, DD/ID, FCD, or even SUDEP. 4 Reviewing the literature, several missense variants (c.1010C > G, c.2416C > T) were found to cause diseases only in homozygotes. Dosedependent effect might explained the pathogenicity of the homozygous and functional validations were needed to further the mechanism.…”

“…While 28 studies met the inclusion criteria and were included finally. [2][3][4][5][6][7] The information extracted from the literature is listed in Table S1…”

“…Besides, cases accompanied by developmental delay/intellectual disability (DD/ID) or focal cortical dysplasia (FCD) have been reported. 3,4 Even sudden unexpected death in epilepsy (SUDEP) occurs to patients, and the incidence is reported to be one in every 10 families. 1,5 Given the phenotypic heterogeneity of DEPDC5-related focal epilepsy, many studies explored the genotype-phenotype correlation.…”

“…Epileptiform discharges can originate from any lobe of the cerebral cortex. Besides, cases accompanied by developmental delay/intellectual disability (DD/ID) or focal cortical dysplasia (FCD) have been reported 3,4 . Even sudden unexpected death in epilepsy (SUDEP) occurs to patients, and the incidence is reported to be one in every 10 families 1,5 .…”