This variant is classified as a variant of unknown significance because its contribution to a neurodevelopmental disorder has not been confirmed.
In a patient with severe neurologic symptoms, including microcephaly, progressive brain atrophy, and severe muscle hypotonia, Mota et al. (2021) identified a de novo heterozygous mutation in the FOXR1 gene resulting in a met280-to-leu (M280L) substitution at a conserved site. The mutation, which was identified by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the parents or in 3 unaffected sibs. FOXR1 with the M280L mutation was expressed in HEK293 cells and resulted in decreased protein expression, which was shown to be due to instability of the mutant protein. The HEK293 cells with the mutant FOXR1 also formed insoluble nuclear aggregates. A comparison of HEK293 cells expressing wildtype and mutant FOXR1 demonstrated that the mutant FOXR1 resulted in decreased expression of genes associated with the heat shock response. The patient had severe muscle hypotonia from early infancy and acquired microcephaly and progressive brain atrophy. He also had growth delay, optic atrophy, cortical visual impairment, and retinitis pigmentosa. A brain MRI showed progressive hypoplasia of the cerebral cortex, pons and cerebellum from age 1 to 5 years. The patient also had a mutation in the ATP1A3 gene (182350), which was thought to contribute to the phenotype.
