Bosch-Boonstra-Schaaf Optic Atrophy Syndrome via the NR2F1 Gene

Optic Atrophy (OA) is the most prevalent inherited optic neuropathy besides Leber’s hereditary optic neuropathy (LHON). Both share a common pathological hallmark, the preferential loss of retinal ganglion cells (RGCs) (Carelli et al. 2009; Yu-Wai-Man et al. 2010). OA is clinically characterized by bilateral reduction in visual acuity that progresses insidiously from early childhood (Yu-Wai-Man et al. 2011). Other symptoms include central or near central scotomas, tritanopia, variable degree of ptosis, central visual field defects and/or ophthalmalgia and optic nerve pallor. The most common OA is inherited in an autosomal dominant (AD) mode (DOA). Phenotype-genotype studies found that 20% of DOA patients develop a more severe phenotype called “DOA plus” (DOA+), which is characterized by extraocular multi-systemic features, including neurosensory hearing loss, or less commonly chronic progressive external ophthalmoplegia, myopathy, peripheral neuropathy, multiple sclerosis-like illness, spastic paraplegia or cataracts (Yu-Wai-Man et al. 2010; Amati-Bonneau et al. 2009). Disease prevalence is estimated at ~1/30,000 in most populations in the world, but in Denmark it can reach to 1/10,000 due to a founder effect (Kjer et al. 1996; Thiselton et al. 2001; Lenaers et al. 2012).

Bosch-Boonstra-Schaaf optic atrophy syndrome (BBSOAS) is an AD disorder, which is characterized by OA with mild to moderate intellectual disability. Developmental delay, cerebral visual impairment, variable and nonspecific dysmorphic facial features have been reported in most patients (Bosch et al. 2014; Al-Kateb et al. 2013).

Mutations in NR2F1 (nuclear receptor subfamily 2, group F, member 1 gene) are associated with BBSOAS, which exhibits AD inheritance. NR2F1, also known as COUP-TFI, (one of the two chicken ovalbumin upstream promoter transcription factors) is an orphan member of the steroid/thyroid hormone receptor superfamily. Mouse mutant studies have shown that COUP-TFs are highly expressed in developing nervous systems and have a role in neurogenesis and neural crest cell differentiation (Qiu et al. 1997).

Bosch et al. (2014) reported that the NR2F1 encoded nuclear receptor protein regulates transcription. In vitro reporter (luciferase) assays have shown that missense mutations (which were identified in their patient cohort) in the zinc-finger DNA-binding domain and the putative ligand-binding domain lead to reduced NR2F1 transcriptional activity. Notably, patients with point mutations and deletions had similar phenotypes, which suggested that optic atrophy with intellectual impairment is due to NR2F1 haploinsuffiency (Bosch et al. 2014). NR2F1 haploinsufficiency has been shown to be associated with optic atrophy, dysmorphism and global developmental delay and also syndromic deafness (Al-Kateb et al. 2013; Bosch et al. 2014; Brown et al. 2009). About ten causative mutations have been reported in NR2F1 that are associated with BBSOAS (Human Gene Mutation Database).

Although heterogeneous, the majority of suspected hereditary optic neuropathy patients (>60%) harbor pathogenic mutations within OPA1, and ~3% have OPA3 mutations (Ferre et al. 2009). Optic nerve degeneration or optic atrophy is present in many disorders where mitochondrial impairment is the underlying cause for the RGC pathophysiology (Yu-Wai-Man et al. 2011). Examples are Wolfram’s syndrome, Mohr-Tranebjaerg syndrome or other neuropathies associated with neurological diseases such as spinocerebellar ataxias, Friedreich’s syndrome, Charcot Marie-Tooth type 2 and 6, and Deafness-Dystonia-Optic Neuropathy syndromes (Lenaers et al. 2012).

Predicting clinical sensitivity for the NR2F1 gene is challenging due to genetic heterogeneity of optic atrophy. However, approximately 50% of the reported mutations are detectable by this method (Human Gene Mutation Database). Large deletions in this gene appear to comprise a significant portion of pathogenic mutations.

This test provides full coverage of all coding exons of the NR2F1 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).