Genetic variants in ESRRG are associated with a dominant non-progressive congenital movement disorder with ataxia

The orphan nuclear hormone receptor estrogen-related receptor γ (ESRRG, also known as ERRγ) functions as an inducible transcription factor, regulating the expression of endocrine and metabolic genes. Among its ESRR paralogs, ESRRG exhibits the highest mutational constraint, yet it remains unlinked to a defined disease phenotype. We clinically describe eight individuals from seven unrelated families having heterozygous, mostly de novo variants in ESRRG: c.410G>A (p.Gly137Glu), c.446A>G (p.Lys149Arg), c.539G>A (p.Cys180Tyr), c.550C>T (p.Arg184Cys), c.1346T>G (p.Leu449Arg), and c.1352dup (p.Leu451Phefs^∗38). Cell proliferation and ERR response element (ERRE) reporter gene expression have been examined in transient transfected ESRRG-knockout HEK293T cells for each variant compared to wild-type ESRRG. Immunofluorescence was performed to inspect the protein's subcellular localization. All identified variants are absent in gnomAD (v.4.1), are in silico deleterious, and are located in intolerant segments of the protein. All individuals have motor developmental delay, muscular hypotonia, and eye movement disorders, as well as congenital ataxia or gait imbalance. Other symptoms include joint hyperflexibility, dysarthria, myopia, and growth delay. Molecular modeling of the identified variants suggests a reduction in protein function. ESRRG knockout resulted in a significantly increased proliferation rate in ESRRG-knockout HEK293T cells. Overexpression of wild-type ESRRG restored cell proliferation, while overexpression of the identified variants did not. Despite the correct nuclear localization of all identified variants, the reporter gene assay revealed a significant reduction in transcriptional activity for all identified variants. Given the acquired clinical, molecular, and functional data, we implicate ESRRG in the etiology of a non-progressive congenital movement disorder with ataxia.