Report of the first patient with a homozygous OTUD7A variant responsible for epileptic encephalopathy and related proteasome dysfunction

Abstract

Heterozygous microdeletions of chromosome 15q13.3 (MIM: 612001) show incomplete penetrance and are associated with a highly variable phenotype that may include intellectual disability, epilepsy, facial dysmorphism and digit anomalies. Rare patients carrying homozygous deletions show more severe phenotypes including epileptic encephalopathy, hypotonia and poor growth. For years, CHRNA7 (MIM: 118511), was considered the candidate gene that could account for this syndrome. However, recent studies in mouse models have shown that OTUD7A/CEZANNE2 (MIM: 612024), which encodes for an ovarian tumor (OTU) deubiquitinase, should be considered the critical gene responsible for brain dysfunction. In this study, a patient presenting with severe global developmental delay, language impairment and epileptic encephalopathy was referred to our genetics center. Trio exome sequencing (tES) analysis identified a homozygous OTUD7A missense variant (NM_130901.2:c.697C>T), predicted to alter an ultraconserved amino acid, p.(Leu233Phe), lying within the OTU catalytic domain. Its subsequent segregation analysis revealed that the parents, presenting with learning disability, and brother were heterozygous carriers. Biochemical assays demonstrated that proteasome complex formation and function were significantly reduced in patient‐derived fibroblasts and in OTUD7A knockout HAP1 cell line. We provide evidence that biallelic pathogenic OTUD7A variation is linked to early‐onset epileptic encephalopathy and proteasome dysfunction.

Biallelic loss of OTUD7A causes severe muscular hypotonia, intellectual disability, and seizures

“…Recently, one patient with a homozygous nonsynonymous variant (derived from consanguineous parents) in OTUD7A was reported to have muscular hypotonia, intellectual disability, and early‐onset epileptic encephalopathy [Garret and others 2020]. However, a lack of patients with unequivocal truncating variants in OTUD7A has obscured our understanding of the pathogenic contribution of OTUD7A .…”

Chromosomal Microarray Analysis as First-Tier Genetic Test for Schizophrenia

“…Garret and colleagues reported a homozygous missense mutation of OTUD7A in a male patient with severe global developmental delay, language impairment, and epileptic encephalopathy. His parents and a younger brother who manifested learning disability were heterozygous carriers of the missense mutation (Garret et al, 2020). Suzuki and colleagues also reported the biallelic loss of function of OTUD7A in a male patient with hypotonia, intellectual disability, and seizures (Suzuki et al, 2021).…”

SPOP and OTUD7A Control EWS–FLI1 Protein Stability to Govern Ewing Sarcoma Growth

“…[ 51 ] Recently, a homozygous OTUD7A–L233F mutation was found in a patient with the 15q13.3 microdeletion syndrome with characterized proteasome dysfunction presumably caused by the loss of function of the OTUD7A deubiquitinase activity. [ 52 ] Although it remains unclear if these neurological disorders caused by OTUD7A dysfunction are limited to changes in dendritic spines, these results offer additional considerations if 7Ai or other OTUD7A inhibitors begin preclinical evaluation for Ewing sarcoma.…”