ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000005.9) (NC_000005.10)

Haploinsufficiency phenotype comments:

Variants in NR2F1 have been reported in individuals with cerebral visual impairment (CVI), optic nerve abnormalities, and developmental delay, also known as Bosch-Boonstra optic atrophy syndrome. Bosch et al. 2014 (PMID: 24462372) report six individuals with variants involving NR2F1 and similar phenotypes, including 4 with missense variants and 2 with microdeletions encompassing NR2F1 (as well as other genes). The authors proposed that haploinsufficiency was the mechanism by which NR2F1 was contributing to this phenotype: Using a luciferase reporter assay, they showed that the 4 missense variants lost their ability to fully activate the NR2F1-COUP-TFI reporter, suggesting that these variants resulted in loss of function of the NR2F1-COUP-TFI product. Additionally, the group reported that the probability of identifying even 3 de novo variants in NR2F1 in a cohort of 56 individuals with CVI is p=1.40 x 10E-10, indicating that these observations were highly unlikely to occur by chance. Al-Kateb et al. (2013) (PMID:23300014) also report an individual with developmental delay, dysmorphic features, and bilateral optic atrophy associated with visual motor integration deficit and visual perceptual disorder. This individual was found to have a 582kb de novo deletion involving NR2F1 and 4 other genes, including one microRNA gene. While there have been several other reports of deletions involving NR2F1 in the literature, not all of these individuals have been noted to have cerebral visual impairment or optic atrophy; however, one cannot be certain in all cases whether it truly did not exist in the patient, or was simply not assessed. Brown et al. (2009) (PMID:19353646) "report a 4-year-old girl with profound deafness, a history of feeding difficulties, dysmorphism, strabismus, developmental delay, and an apparently balanced de novo paracentric chromosome 5 inversion, inv(5)(q15q33.2)...[with] microdeletions of approximately 400-500 kb at or near both breakpoints," including a total deletion of NR2F1. The child was noted to have strabismus, but no other ocular phenotype was mentioned. Additionally, Cardoso et al. (2009) (PMID: 19073947) report three individuals with "epilepsy, mental retardation, and bilateral [periventricular heterotopia] in the walls of the temporal horns of the lateral ventricles" and large, de novo deletions of the 5q14.3-15 region, ranging from 6-17Mb in size. None of these patients were described as having CVI, though one was noted to have iris coloboma. More information is neccessary to determine the role of NR2F1 haploinsufficiency in Bosch-Boonstra syndrome.

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity