Novel dominant-negative NR2F1 frameshift mutation and a phenotypic expansion of the Bosch-Boonstra-Schaaf optic atrophy syndrome

Abstract

Bosch-Boonstra-Schaaf optic atrophy syndrome (BBSOAS) has been described as an autosomal-dominant disorder caused by mutations in the NR2F1 gene, whose common characteristics include developmental delay, intellectual disability, optic nerve atrophy, hypotonia, attention deficit disorder, autism spectrum disorder, seizures, hearing defects, spasticity and thinning of the corpus callosum. Missense mutations in NR2F1 have been reported to be the major cause of BBSOAS. A possible genotype-phenotype correlation has been considered with missense mutations affecting the ligand-binding domain of NR2F1 as well as whole-gene deletions of NR2F1 showing a milder phenotype of BBSOAS. Here we report on a patient with a novel frameshift mutation in NR2F1 showing the full spectrum of BBOAS indicating an expanded clinical spectrum and a reconsideration of the observed genotype-phenotype correlation.

Introduction

Bosch-Boonstra-Schaaf optic atrophy syndrome (BBSOAS) is an autosomal-dominant disorder characterized by optic atrophy, developmental delay and intellectual disability (OMIM 615722) (Bosch et al., 2014). This disorder is caused by mutations in NR2F1, which encodes a highly conserved nuclear receptor protein consisting of two functional domains, the DNA-binding domain and die ligand-binding domain. However, the ligand of NR2F1 remains still unknown. There are currently 31 cases with BBSOAS described in the literature. Most variants in NR2F1, which have been described so far, are missense mutations. Interestingly, individuals with whole-gene deletions are considered to show a milder phenotype compared to those who carry a deleterious missense mutation (Chen et al., 2016). Here we report on a 9 year-old boy with a novel frameshift mutation in the ligand-binding domain in the last exon of NR2F1, who presented with a severe phenotype of BBSOAS.