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

Focal segmental glomerulosclerosis (FSGS) is the main pathology underlying steroid-resistant nephrotic syndrome (SRNS) and a leading cause of chronic kidney disease. Monogenic forms of pediatric SRNS are predominantly caused by recessive mutations, while the contribution of de novo variants (DNVs) to this trait is poorly understood. Using exome sequencing (ES) in a proband with FSGS/SRNS, developmental delay, and epilepsy, we discovered a nonsense DNV in TRIM8, which encodes the E3 ubiquitin ligase tripartite motif containing 8. To establish whether TRIM8 variants represent a cause of FSGS, we aggregated exome/genome-sequencing data for 2,501 pediatric FSGS/SRNS-affected individuals and 48,556 control subjects, detecting eight heterozygous TRIM8 truncating variants in affected subjects but none in control subjects (p = 3.28 × 10-11). In all six cases with available parental DNA, we demonstrated de novo inheritance (p = 2.21 × 10-15). Reverse phenotyping revealed neurodevelopmental disease in all eight families. We next analyzed ES from 9,067 individuals with epilepsy, yielding three additional families with truncating TRIM8 variants. Clinical review revealed FSGS in all. All TRIM8 variants cause protein truncation clustering within the last exon between residues 390 and 487 of the 551 amino acid protein, indicating a correlation between this syndrome and loss of the TRIM8 C-terminal region. Wild-type TRIM8 overexpressed in immortalized human podocytes and neuronal cells localized to nuclear bodies, while constructs harboring patient-specific variants mislocalized diffusely to the nucleoplasm. Co-localization studies demonstrated that Gemini and Cajal bodies frequently abut a TRIM8 nuclear body. Truncating TRIM8 DNVs cause a neuro-renal syndrome via aberrant TRIM8 localization, implicating nuclear bodies in FSGS and developmental brain disease.

Genetic testing in individuals with cerebral palsy.

AIM To determine which patients with cerebral palsy (CP) should undergo genetic testing, we compared the rate of likely causative genetic variants from whole-exome sequencing in individuals with and without environmental risk factors. METHOD Patients were part of a convenience and physician-referred cohort recruited from a single medical center, and research whole-exome sequencing was completed. Participants were evaluated for the following risk factors: extreme preterm birth, brain bleed or stroke, birth asphyxia, brain malformations, and intrauterine infection. RESULTS A total of 151 unrelated individuals with CP (81 females, 70 males; mean age 25y 7mo [SD 17y 5mo], range 3wks-72y) participated. Causative genetic variants were identified in 14 participants (9.3%). There was no significant difference in diagnostic rate between individuals with risk factors (10 out of 123; 8.1%) and those without (4 out of 28; 14.3%) (Fisher's exact p=0.3). INTERPRETATION While the rate of genetic diagnoses among individuals without risk factors was higher than those with risk factors, the difference was not statistically significant at this sample size. The identification of genetic diagnoses in over 8% of cases with risk factors suggests that these might confer susceptibility to environmental factors, and that further research should include individuals with risk factors. What this paper adds There is no significant difference in diagnostic rate between individuals with and without risk factors. Genetic variants may confer susceptibility to environmental risk factors. Six causative variants were identified in genes not previously associated with cerebral palsy. Global developmental delay/intellectual disability is positively associated with a genetic etiology. Extreme preterm birth, stroke/brain hemorrhage, and older age are negatively associated with a genetic etiology.