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

Abstract

Mutations in the TRIM8 gene have been described in patients with severe developmental delay, intellectual disability and epilepsy. Only six patients have been described to date. All the previous mutations were truncating variants clustered in the C-terminus of the protein. A previous patient with TRIM8-related epileptic encephalopathy was reported to have nephrotic syndrome. Here we describe the clinical, radiological and histological features of an 8-yearold male patient with a TRIM8 mutation who, in contrast to previous patients, had only mild intellectual disability and well-controlled epilepsy. The patient was found to have proteinuria at 2 years of age. Renal biopsy findings were suggestive of focal segmental glomerulosclerosis. His kidney function declined and peritoneal dialysis was started at 5 years of age. He underwent renal transplant at 7 years of age. Trio-based whole genome sequencing identified a novel de novo heterozygous frameshift mutation in TRIM8 (NM_030912.2) c.1198_1220del, p.(Tyr400ArgfsTer2). This patient is further evidence that TRIM8 mutations cause a syndrome with both neurological and renal features. Our findings suggest the spectrum of TRIM8-related disease may be wider than previously thought with the possibility of milder neurodevelopmental problems and/or a more severe, progressive renal phenotype. We highlight the need for proteinuria screening in patients with TRIM8 mutations.

De novo TRIM8 variants impair its protein localization to nuclear bodies and cause developmental delay, epilepsy, and focal segmental glomerulosclerosis

“…[44][45][46] TRIM8 disease-associated variants are restricted to the last exon (Figures 1C and S2). 23,[41][42][43] Combining our findings with previous reports showed that four individuals from distinct ethnic backgrounds share the identical variant at position c.1375 and two share nonsense variants at position c.1380 (Figure S2). 23,41 This observation suggests that this region is a recurrent germline variant hotspot (Figure S2, Table 1), as has been demonstrated for other rare dominant monogenic causes of syndromic epilepsy 47 and nephrotic syndrome.…”

“…All subjects were diagnosed with renal disease after (10/12) or at the time of (2/12) the development of neurologic disease. Previous case reports have described truncating DNVs in TRIM8 in a total of eight children with developmental delay and epilepsy, but only three of these subjects were described to have nephrotic syndrome (Figure S2), 23,[41][42][43] which left it unsolved whether the renal disease was associated to TRIM8 variants or just coincidental. The early ascertainment of these cases is also consistent with our observation that renal disease presents later in the course of these patients and may not have been apparent yet at the time of these reports.…”

A novel de novo truncating TRIM8 variant associated with childhood-onset focal segmental glomerulosclerosis without epileptic encephalopathy: a case report

“…To date, at least eight reported individuals have been associated with heterozygous truncating variants in TRIM8 , all of whom developed epilepsy or epileptic encephalopathy, including five individuals with proteinuria (Table 1 and Fig. 4 ) [ 3 – 6 ]. The present patient did not present with any neurological manifestations such as developmental delay and epilepsy.…”

“…4 , patient IX). Nevertheless, the variant of patient III, who had mild developmental delay and well-controlled epilepsy [ 6 ], was located more 5’ in the last exon than 5 patients with epileptic encephalopathy reported by Assoum et al and Warren et al [ 4 , 5 ]. Therefore, a difference in the size of the truncated protein may not explain the difference in the severity of the neurological phenotype [ 6 ].…”

“…They also performed immunohistochemical (IHC) staining, using an anti-TRIM8 antibody, and demonstrated a lack of TRIM8 protein expression, with suppressor of cytokine signaling 1 (SOCS1) overexpression, which is regulated by TRIM8, in the podocytes and tubules [ 5 ]. In addition, McClatchey et al presented an individual with FSGS which required renal replacement therapies, but only mild neurodevelopmental problems [ 6 ].…”