Further delineation of the clinical spectrum of de novo TRIM8 truncating mutations

Abstract

De novo mutations of the TRIM8 gene, which codes for a tripartite motif protein, have been identified using whole exome sequencing (WES) in two patients with epileptic encephalopathy (EE), but these reports were not sufficient to conclude that TRIM8 was a novel gene responsible for EE. Here we report four additional patients presenting with EE and de novo truncating mutations of TRIM8 detected by WES, and give further details of the patient previously reported by the Epi4K consortium. Epilepsy of variable severity was diagnosed in children aged 2 months to 3.5 years of age. All patients had developmental delay of variable severity with no or very limited language, often associated with behavioral anomalies and unspecific facial features or MRI brain abnormalities. The phenotypic variability observed in these patients appeared related to the severity of the epilepsy. One patient presented pharmacoresistant EE with regression, recurrent infections and nephrotic syndrome, compatible with the brain and kidney expression of TRIM8. Interestingly, all mutations were located at the highly conserved C‐terminus section of TRIM8. This collaborative study confirms that TRIM8 is a novel gene responsible for EE, possibly associated with nephrotic syndrome. This report brings new evidence on the pathogenicity of TRIM8 mutations and highlights the value of data‐sharing to delineate the phenotypic characteristics and biological basis of extremely rare disorders.

Focal segmental glomerulosclerosis and mild intellectual disability in a patient with a novel de novo truncating TRIM8 mutation

“…Mutations in TRIM8 have been reported as a rare cause of epilepsy and intellectual disability (Assoum et al, 2018;Sakai et al, 2016). In this report, we describe a seventh individual with a de novo heterozygous truncating mutation in the C-terminal region of TRIM8.…”

“…3b) apart from p.Gln423* which did not fit this pattern. Some variability in the age of onset and treatment response of seizures was noted among previous patients (Assoum et al, 2018). The patient with the earliest-onset seizures (2 months) had profound developmental delay and pharmaco-resistant epilepsy; whilst the patient with the latest-onset seizures (3 years 5 months) had earlier motor milestones, showed no regression and had seizure control on levetiracetam monotherapy.…”

“…These patients had severe developmental delay, normal or mildly distinctive facial features, and mild white matter abnormalities on brain MRI. Three patients were noted to have proteinuria with one being diagnosed with nephrotic syndrome (Assoum et al, 2018). Here, we describe a patient with a C-terminal truncating TRIM8 mutation who presented with severe renal disease but only mild neurodevelopmental problems.…”

“…TRIM8 mutations have recently been described in patients with epilepsy, developmental delay and learning disability (Assoum et al, 2018;Sakai et al, 2016). To date, only six previous patients have been reported.…”

Rise of TRIM8: A Molecule of Duality

“…Pathogenicity of TRIM8 mutations on its C terminus has been established as the causative agent for EE, possibly associated with nephrotic syndrome. 36 , 37 De novo mutation on the C-terminal region of TRIM8 is also associated with focal segmental glomerulosclerosis (FSGS). 38 Liu et al.…”