DEPDC5 Variants Associated Malformations of Cortical Development and Focal Epilepsy With Febrile Seizure Plus/Febrile Seizures: The Role of Molecular Sub-Regional Effect

Liu Liu; Zi-Rong Chen; Hai-Qing Xu; De-Tian Liu; Yong Mao; Han-Kui Liu; Xiao-Rong Liu; Peng Zhou; Si-Mei Lin; Bin Li; Na He; Tao Su; Qiong-Xiang Zhai; Heng Meng; Wei-Ping Liao; Yong-Hong Yi

doi:10.3389/fnins.2020.00821

DEPDC5 Variants Associated Malformations of Cortical Development and Focal Epilepsy With Febrile Seizure Plus/Febrile Seizures: The Role of Molecular Sub-Regional Effect

Front Neurosci. 2020 Aug 11:14:821. doi: 10.3389/fnins.2020.00821. eCollection 2020.

Authors

Liu Liu^{1

2}, Zi-Rong Chen^{1

3}, Hai-Qing Xu⁴, De-Tian Liu¹, Yong Mao⁵, Han-Kui Liu⁵, Xiao-Rong Liu¹, Peng Zhou¹, Si-Mei Lin¹, Bin Li¹, Na He¹, Tao Su¹, Qiong-Xiang Zhai⁶, Heng Meng⁷, Wei-Ping Liao¹, Yong-Hong Yi¹

Affiliations

¹ Institute of Neuroscience, Department of Neurology of the Second Affiliated Hospital of Guangzhou Medical University, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Guangzhou, China.
² Department of Neurology, Xiaoshan First People's Hospital, Hangzhou, China.
³ Department of Neurology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China.
⁴ Department of Neurology, Xuzhou Central Hospital, Affiliated Hospital of Southeast University, Xuzhou, China.
⁵ BGI-Shenzhen, Shenzhen, China.
⁶ Department of Pediatrics, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.
⁷ Department of Neurology of the First Affiliated Hospital of Jinan University and Clinical Neuroscience Institute of Jinan University, Guangzhou, China.

Abstract

To explore the phenotype spectrum of DEPDC5 variants and the possible mechanisms underlying phenotypical variation, we performed targeted next-generation sequencing in 305 patients with focal epilepsies and 91 patients with generalized epilepsies. Protein modeling was performed to predict the effects of missense mutations. All previously reported epilepsy-related DEPDC5 variants were reviewed. The genotype-phenotype correlations with molecular sub-regional implications were analyzed. We identified a homozygous DEPDC5 mutation (p.Pro1031His) in a case with focal cortical dysplasia and eight heterozygous mutations in 11 families with mild focal epilepsies, including 13 patients in eight families with focal epilepsy with febrile seizures plus/febrile seizures (FEFS + /FS). The mutations included one termination codon mutation (p.Ser1601_Ter1604del_ext133), three truncating mutations (p.Val151Serfs^∗27, p.Arg239^∗, and p.Arg838^∗), and four missense mutations (p.Tyr7Cys, p.Tyr836Cys, p.Pro1031His, and p.Gly1545Ser) that were predicted to affect hydrogen bonds and protein stability. Analysis on epilepsy-related DEPDC5 variants revealed that malformations of cortical development (MCDs) had a tendency of higher frequency of null mutations than those without MCD. MCD-associated heterozygous missense mutations were clustered in structural axis for binding arrangement (SABA) domain and close to the binding sites to NPRL2/NPRL3 complex, whereas those associated with FEFS + /FS were a distance away from the binding sites. Evidence from four aspects and one possible evidence from sub-regional implication suggested MCD and FEFS + /FS as phenotypes of DEPDC5 variants. This study suggested that the phenotypes of DEPDC5 variants vary from mild FEFS + /FS to severe MCD. Heterozygous DEPDC5 mutations are generally less pathogenic and commonly associated with mild phenotypes. Bi-allelic mutations and second hit of somatic mutations, together with the genotype-phenotype correlation and sub-regional implication of DEPDC5 variants, explain severe phenotypes.

Keywords: DEPDC5; febrile seizures; focal epilepsy; genotype–phenotype correlation; molecular sub-regional effect.