De Novo Truncating Mutation of TRIM8 Causes Early‐Onset Epileptic Encephalopathy

• Published in: Annals of human genetics Vol. 80; no. 4; pp. 235 - 240
• Main Authors: Sakai, Yasunari, Fukai, Ryoko, Matsushita, Yuki, Miyake, Noriko, Saitsu, Hirotomo, Akamine, Satoshi, Torio, Michiko, Sasazuki, Momoko, Ishizaki, Yoshito, Sanefuji, Masafumi, Torisu, Hiroyuki, Shaw, Chad A, Matsumoto, Naomichi, Hara, Toshiro
• Format: Journal Article
• Language: English
• Published: England Wiley Subscription Services, Inc 01.07.2016
• Subjects: Animals; Base Sequence; Brain - metabolism; Carrier Proteins - genetics; Carrier Proteins - metabolism; Child; Codon, Nonsense; developmental delay; Developmental Disabilities - genetics; DNA Mutational Analysis; Epilepsy; Epileptic encephalopathy; Exome; Gene Expression; Humans; Infant; Male; Mice, Inbred C57BL; Mutation; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Spasms, Infantile - diagnosis; Spasms, Infantile - genetics; tripartite motif containing 8 (TRIM8); whole‐exome sequencing (WES); Epileptic encephalopathy; developmental delay; whole-exome sequencing (WES); tripartite motif containing 8 (TRIM8)
• ISSN: 0003-4800; 1469-1809
• DOI: 10.1111/ahg.12157

Summary Background Early‐onset epileptic encephalopathy (EOEE) is a heterogeneous group of neurodevelopmental disorders characterised by infantile‐onset intractable epilepsy and unfavourable developmental outcomes. Hundreds of mutations have been reported to cause EOEE; however, little is known about the clinical features of individuals with rare variants. Case report and methods We present a 10‐year‐old boy with severe developmental delay. He started experiencing recurrent focal seizures at 2 months old. Serial electroencephalograms persistently detected epileptiform discharges from the left hemisphere. Whole‐exome sequencing and array‐comparative genome hybridization were performed to search for de novo variations. Two‐week‐old C57Bl/6 mice were used for immunofluorescence studies. Results This case had a paternally inherited, 0.2‐Mb duplication at chromosome 22q11.22. The whole‐exome sequencing identified a de novo truncating mutation of tripartite motif containing 8 (TRIM8) (NM_030912:c.1099_1100insG:p.C367fs), one of the epileptic encephalopathy‐associated genes. We verified that the murine homologues of these genes are expressed in the postnatal mouse brain. Conclusion This is the second case of EOEE caused by a de novo truncating mutation of TRIM8. Further studies are required to determine the functional roles of TRIM8 in the postnatal development of the human brain and its functional relationships with other EOEE‐associated genes.