A potpourri on NR2F1 mutations

Bosch DG, Boonstra FN, Gonzaga-Jauregui C, Xu M, de Ligt J, Jhangiani S,
Wiszniewski W, Muzny DM, Yntema HG, Pfundt R, Vissers LE, Spruijt L, Blokland EA,
Chen CA; Baylor-Hopkins Center for Mendelian Genomics, Lewis RA, Tsai SY, Gibbs
RA, Tsai MJ, Lupski JR, Zoghbi HY, Cremers FP, de Vries BB, Schaaf CP. NR2F1
mutations cause optic atrophy with intellectual disability. Am J Hum Genet. 2014
Feb 6;94(2):303-9.

Abstract

Optic nerve atrophy and hypoplasia can be primary disorders or can result from trans-synaptic degeneration arising from cerebral visual impairment (CVI). Here we report six individuals with CVI and/or optic nerve abnormalities, born after an uneventful pregnancy and delivery, who have either de novo heterozygous missense mutations in NR2F1, also known as COUP-TFI, or deletions encompassing NR2F1. All affected individuals show mild to moderate intellectual impairment. NR2F1 encodes a nuclear receptor protein that regulates transcription. A reporter assay showed that missense mutations in the zinc-finger DNA-binding domain and the putative ligand-binding domain decrease NR2F1 transcriptional activity. These findings indicate that NR2F1 plays an important role in the neurodevelopment of the visual system and that its disruption can lead to optic atrophy with intellectual disability.

Hino-Fukuyo N, Kikuchi A, Arai-Ichinoi N, Niihori T, Sato R, Suzuki T, Kudo H,
Sato Y, Nakayama T, Kakisaka Y, Kubota Y, Kobayashi T, Funayama R, Nakayama K,
Uematsu M, Aoki Y, Haginoya K, Kure S. Genomic analysis identifies candidate
pathogenic variants in 9 of 18 patients with unexplained West syndrome. Hum
Genet. 2015 Jun;134(6):649-58.

Abstract

West syndrome, which is narrowly defined as infantile spasms that occur in clusters and hypsarrhythmia on EEG, is the most common early-onset epileptic encephalopathy (EOEE). Patients with West syndrome may have clear etiologies, including perinatal events, infections, gross chromosomal abnormalities, or cases followed by other EOEEs. However, the genetic etiology of most cases of West syndrome remains unexplained. DNA from 18 patients with unexplained West syndrome was subjected to microarray-based comparative genomic hybridization (array CGH), followed by trio-based whole-exome sequencing in 14 unsolved families. We identified candidate pathogenic variants in 50% of the patients (n = 9/18). The array CGH revealed candidate pathogenic copy number variations in four cases (22%, 4/18), including an Xq28 duplication, a 16p11.2 deletion, a 16p13.1 deletion and a 19p13.2 deletion disrupting CACNA1A. Whole-exome sequencing identified candidate mutations in known epilepsy genes in five cases (36%, 5/14). Three candidate de novo mutations were identified in three cases, with two mutations occurring in two new candidate genes (NR2F1 and CACNA2D1) (21%, 3/14). Hemizygous candidate mutations in ALG13 and BRWD3 were identified in the other two cases (14%, 2/14). Evaluating a panel of 67 known EOEE genes failed to identify significant mutations. Despite the heterogeneity of unexplained West syndrome, the combination of array CGH and whole-exome sequencing is an effective means of evaluating the genetic background in unexplained West syndrome. We provide additional evidence for NR2F1 as a causative gene and for CACNA2D1 and BRWD3 as candidate genes for West syndrome.

Bosch DG, Boonstra FN, de Leeuw N, Pfundt R, Nillesen WM, de Ligt J, Gilissen
C, Jhangiani S, Lupski JR, Cremers FP, de Vries BB. Novel genetic causes for
cerebral visual impairment. Eur J Hum Genet. 2015 Sep 9. doi:
10.1038/ejhg.2015.186. [Epub ahead of print]

Abstract

Cerebral visual impairment (CVI) is a major cause of low vision in children due to impairment in projection and/or interpretation of the visual input in the brain. Although acquired causes for CVI are well known, genetic causes underlying CVI are largely unidentified. DNAs of 25 patients with CVI and intellectual disability, but without acquired (eg, perinatal) damage, were investigated by whole-exome sequencing. The data were analyzed for de novo, autosomal-recessive, and X-linked variants, and subsequently classified into known, candidate, or unlikely to be associated with CVI. This classification was based on the Online Mendelian Inheritance in Man database, literature reports, variant characteristics, and functional relevance of the gene. After classification, variants in four genes known to be associated with CVI (AHDC1, NGLY1, NR2F1, PGAP1) in 5 patients (20%) were identified, establishing a conclusive genetic diagnosis for CVI. In addition, in 11 patients (44%) with CVI, variants in one or more candidate genes were identified (ACP6, AMOT, ARHGEF10L, ATP6V1A, DCAF6, DLG4, GABRB2, GRIN1, GRIN2B, KCNQ3, KCTD19, RERE, SLC1A1, SLC25A16, SLC35A2, SOX5, UFSP2, UHMK1, ZFP30). Our findings show that diverse genetic causes underlie CVI, some of which will provide insight into the biology underlying this disease process.

Inspired by a colleague having two unrelated patients diagnosed with NR2F1 mutations in a brief interval of time.