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

Summary and Pricing

Test Method

Exome Sequencing with CNV Detection
Test Code Test Copy GenesTest CPT Code Gene CPT Codes Copy CPT Codes Base Price
8843 NR2F1 81479 81479,81479 $890 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
8843NR2F181479 81479 $890 Order Options and Pricing

Pricing Comments

Our favored testing approach is exome based NextGen sequencing with CNV analysis. This will allow cost effective reflexing to PGxome or other exome based tests. However, if full gene Sanger sequencing is desired for STAT turnaround time, insurance, or other reasons, please see link below for Test Code, pricing, and turnaround time information. If the Sanger option is selected, CNV detection may be ordered through Test #600.

A 25% additional charge will be applied to STAT orders. View STAT turnaround times here.

For Reflex to PGxome pricing click here.

The Sanger Sequencing method for this test is NY State approved.

For Sanger Sequencing click here.

Targeted Testing

For ordering sequencing of targeted known variants, go to our Targeted Variants page.

Turnaround Time

18 days on average

EMAIL CONTACTS

Genetic Counselors

Geneticist

Clinical Features and Genetics

Clinical Features

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).

Genetics

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).

Testing Strategy

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.

Since this test is performed using exome capture probes, a reflex to any of our exome based tests is available (PGxome, PGxome Custom Panels).

Clinical Sensitivity - Sequencing with CNV PGxome

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.

Indications for Test

Patients with symptoms suggestive of inherited optic neuropathy are candidates.

Gene

Official Gene Symbol OMIM ID
NR2F1 132890
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Disease

Name Inheritance OMIM ID
Bosch-Boonstra-Schaaf optic atrophy syndrome AD 615722

Related Test

Name
Optic Atrophy Panel

Citations

  • Al-Kateb H, Shimony JS, Vineyard M, Manwaring L, Kulkarni S, Shinawi M. 2013. NR2F1 haploinsufficiency is associated with optic atrophy, dysmorphism and global developmental delay. Am. J. Med. Genet. A 161A: 377–381. PubMed ID: 23300014
  • Amati-Bonneau P, Milea D, Bonneau D, Chevrollier A, Ferré M, Guillet V, Gueguen N, Loiseau D, Crescenzo M-AP de, Verny C, Procaccio V, Lenaers G, et al. 2009. OPA1-associated disorders: phenotypes and pathophysiology. Int. J. Biochem. Cell Biol. 41: 1855–1865. PubMed ID: 19389487
  • Bosch DGM, Boonstra FN, Gonzaga-Jauregui C, Xu M, Ligt J de, Jhangiani S, Wiszniewski W, Muzny DM, Yntema HG, Pfundt R, Vissers LELM, Spruijt L, et al. 2014. NR2F1 Mutations Cause Optic Atrophy with Intellectual Disability. The American Journal of Human Genetics 94: 303–309. PubMed ID: 24462372
  • Brown KK, Alkuraya FS, Matos M, Robertson RL, Kimonis VE, Morton CC. 2009. NR2F1 deletion in a patient with a de novo paracentric inversion, inv(5)(q15q33.2), and syndromic deafness. American Journal of Medical Genetics Part A 149A: 931–938. PubMed ID: 19353646
  • Carelli V, Morgia C La, Valentino ML, Barboni P, Ross-Cisneros FN, Sadun AA. 2009. Retinal ganglion cell neurodegeneration in mitochondrial inherited disorders. Biochimica et Biophysica Acta (BBA) - Bioenergetics 1787: 518–528. PubMed ID: 19268652
  • Ferré M, Bonneau D, Milea D, Chevrollier A, Verny C, Dollfus H, Ayuso C, Defoort S, Vignal C, Zanlonghi X, Charlin J-F, Kaplan J, et al. 2009. Molecular screening of 980 cases of suspected hereditary optic neuropathy with a report on 77 novel OPA1 mutations. Human Mutation 30: E692–E705. PubMed ID: 19319978
  • Human Gene Mutation Database (Bio-base).
  • Kjer B, Eiberg H, Kjer P, Rosenberg T. 1996. Dominant optic atrophy mapped to chromosome 3q region. II. Clinical and epidemiological aspects. Acta Ophthalmol Scand 74: 3–7. PubMed ID: 8689476
  • Lenaers G, Hamel C, Delettre C, Amati-Bonneau P, Procaccio V, Bonneau D, Reynier P, Milea D. 2012. Dominant optic atrophy. Orphanet J Rare Dis 7: 46–46. PubMed ID: 22776096
  • Qiu Y, Pereira FA, DeMayo FJ, Lydon JP, Tsai SY, Tsai M-J. 1997. Null mutation of mCOUP-TFI results in defects in morphogenesis of the glossopharyngeal ganglion, axonal projection, and arborization. Genes & development 11: 1925–1937. PubMed ID: 9271116
  • Thiselton DL, Alexander C, Morris A, Brooks S, Rosenberg T, Eiberg H, Kjer B, Kjer P, Bhattacharya SS, Votruba M. 2001. A frameshift mutation in exon 28 of the OPA1 gene explains the high prevalence of dominant optic atrophy in the Danish population: evidence for a founder effect. Human genetics 109: 498–502. PubMed ID: 11735024
  • Yu-Wai-Man P, Griffiths PG, Burke A, Sellar PW, Clarke MP, Gnanaraj L, Ah-Kine D, Hudson G, Czermin B, Taylor RW, Horvath R, Chinnery PF. 2010. The Prevalence and Natural History of Dominant Optic Atrophy Due to OPA1 Mutations. Ophthalmology 117: 1538–1546.e1. PubMed ID: 20417570
  • Yu-Wai-Man P, Shankar SP, Biousse V, Miller NR, Bean LJH, Coffee B, Hegde M, Newman NJ. 2011. Genetic Screening for OPA1 and OPA3 Mutations in Patients with Suspected Inherited Optic Neuropathies. Ophthalmology 118: 558–563. PubMed ID: 21036400

Ordering/Specimens

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