NR2F1 Mutations Cause Optic Atrophy with Intellectual Disability

Bosch, Daniëlle G.M.; Boonstra, F. Nienke; Gonzaga‐Jauregui, Claudia; Xu, Mafei; Ligt, Joep de; Jhangiani, Shalini N.; Wiszniewski, Wojciech; Muzny, Donna M.; Yntema, Helger G.; Pfundt, Rolph; Vissers, Lisenka E.L.M.; Spruijt, Liesbeth; Blokland, Ellen A.W.; Chen, Chun-An; Lewis, Richard A.; Tsai, Sophia Y.; Gibbs, Richard A.; Tsai, Ming Jer; Lupski, James R.; Zoghbi, Huda Y.; Cremers, Frans P.M.; Vries, Bert B.A. de; Schaaf, Christian P.

doi:10.1016/j.ajhg.2014.01.002

Cited by 120 publications

(155 citation statements)

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“…13,[27][28][29] For five genes, HSPG2, PHKB, SRP72, SYNE1, and TENM3, the reported phenotype in literature was not in line with the phenotype of the patient, and those variants were classified as unlikely to be causative for CVI in those patients (#224410, #255800, #261750, #614675, #612998, #610743, #615145). In APOPT1, the phenotype was also not in line with the reported phenotype (#220110).…”

Section: Resultsmentioning

confidence: 99%

“…Three patients (12, 13, and 23) were part of previous reports. 13,26 The variants identified have been submitted to the Leiden Open Variation Databases (LOVDs) (http://databases. lovd.nl/, patient IDs #00025011 and #00039389-#000394012).…”

Section: Methodsmentioning

confidence: 99%

“…12 Moreover, CVI was recently shown to be caused by de novo variants in NR2F1, leading to the Bosch-Boonstra-Schaaf optic atrophy syndrome (#615722, http://www.NR2F1gene.com). 13 In other neurological disorders, such as ID, epileptic encephalopathies, or autism, a high rate of (probably) disease-causing de novo variants were identified by whole-exome sequencing (WES) by using a childparents trio approach. [14][15][16][17][18][19][20] In addition, WES has also shown to be a powerful tool for identifying autosomal-recessive and X-linked variants in persons with ID.…”

Section: Introductionmentioning

confidence: 99%

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Novel genetic causes for cerebral visual impairment

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Novel genetic causes for cerebral visual impairment

et al. 2015

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“…6 WES was performed by the Baylor-Hopkins Center for Mendelian Genomics, using methods reported previously (Supplementary Material and Methods, whole-exome sequencing). 6,30 The results were analyzed for de novo variants, homozygous variants, compound heterozygous variants and hemizygous variants as described in de Ligt et al 31 Truncating variants, splice site variants and missense variants predicted to be pathogenic were validated by Sanger sequencing in the affected subject and his parents. The variants identified have been submitted to the Leiden Open Variation Database LOVD database (http://databases.lovd.nl/, individual #00025011).…”

Section: Whole-exome Sequencing (Wes)mentioning

confidence: 99%

“…5 Moreover, single-gene disorders can be implicated in CVI, and, recently, we identified de novo variants in NR2F1 as a cause of CVI. 6 In addition, in several congenital disorders of glycosylation (CDG type 1a, type 1q and type 1v) CVI has been reported. 4,[7][8][9] Glycosylation disorders are caused by a defect in the glycosylation of glycoproteins and glycolipids, and one subclass is the defect in glycosylphosphatidylinositol (GPI) anchor glycosylation.…”

Section: Introductionmentioning

confidence: 99%

Cerebral visual impairment and intellectual disability caused by PGAP1 variants

et al. 2015

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Homozygous variants in PGAP1 (post-GPI attachment to proteins 1) have recently been identified in two families with developmental delay, seizures and/or spasticity. PGAP1 is a member of the glycosylphosphatidylinositol anchor biosynthesis and remodeling pathway and defects in this pathway are a subclass of congenital disorders of glycosylation. Here we performed whole-exome sequencing in an individual with cerebral visual impairment (CVI), intellectual disability (ID), and factor XII deficiency and revealed compound heterozygous variants in PGAP1, c.274_276del (p.(Pro92del)) and c.921_925del (p.(Lys308Asnfs*25)). Subsequently, PGAP1-deficient Chinese hamster ovary (CHO)-cell lines were transfected with either mutant or wild-type constructs and their sensitivity to phosphatidylinositol-specific phospholipase C (PI-PLC) treatment was measured. The mutant constructs could not rescue the PGAP1-deficient CHO cell lines resistance to PI-PLC treatment. In addition, lymphoblastoid cell lines (LCLs) of the affected individual showed no sensitivity to PI-PLC treatment, whereas the LCLs of the heterozygous carrier parents were partially resistant. In conclusion, we report novel PGAP1 variants in a boy with CVI and ID and a proven functional loss of PGAP1 and show, to our knowledge, for the first time this genetic association with CVI. INTRODUCTIONCerebral visual impairment (CVI) accounts for 27% of the visual impairment in children, and is due to a disorder in projection and/or interpretation of the visual input in the brain. 1-3 Acquired damages, for example, due to preterm birth, are well known causes of CVI, whereas genetic factors are largely unidentified. 4 Several chromosomal aberrations have been associated with CVI, such as Phelan-McDermid syndrome (22q13.3 deletion) and 1p36 microdeletion syndrome. 5 Moreover, single-gene disorders can be implicated in CVI, and, recently, we identified de novo variants in NR2F1 as a cause of CVI. 6 In addition, in several congenital disorders of glycosylation (CDG type 1a, type 1q and type 1v) CVI has been reported. 4,[7][8][9] Glycosylation disorders are caused by a defect in the glycosylation of glycoproteins and glycolipids, and one subclass is the defect in glycosylphosphatidylinositol (GPI) anchor glycosylation. 10 GPI anchor many cell-surface proteins with various functions, so called GPI-anchored proteins (GPI-APs), to the membrane of eukaryotic cells. 11-13 GPI is synthesized in the endoplasmic reticulum, transferred to the proteins, and remodeled. During the biosynthesis of GPI anchors, an acyl chain is linked to the inositol. This acyl chain is a transient structure and is necessary for efficient completion of later steps in GPI biosynthesis. After the attachment of GPI to the protein, this acyl chain is removed by PGAP1 (post-GPI attachment to proteins 1), the first step of the remodeling phase. 14 Subsequently, the GPI anchor is transported from the endoplasmic reticulum to the plasma membrane through the Golgi apparatus and further remodeled. When the inositol-linked...

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Clinical and neurocognitive issues associated with Bosch‐Boonstra‐Schaaf optic atrophy syndrome: A case study

Bojanek

Mosconi

Guter

et al. 2019

American J of Med Genetics Pt A

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Nuclear receptor subfamily 2 group F member 1 (NR2F1) is an orphan receptor and transcriptional regulator that is involved in neurogenesis, visual processing and development, and cortical patterning. Alterations in NR2F1 cause Bosch-Boonstra-Schaaf optic atrophy syndrome (BBSOAS), a recently described autosomal dominant disorder characterized by intellectual and developmental disabilities and optic atrophy. This study describes the clinical and neurocognitive features of an individual with a de novo nonsense variant in NR2F1 (NM_005654.5:c.82C > T, p.Gln28*), identified by whole exome sequencing. The patient was diagnosed with autism spectrum disorder (ASD) and unlike most previously reported cases, he had no developmental delay, superior verbal abilities (verbal IQ = 141), and high educational attainment despite reduced nonverbal abilities (nonverbal IQ = 63). He had optic nerve hypoplasia with minimal visual impairment as well as mild dysmorphic features. Compared to both age-matched individuals with ASD and healthy controls, the patient showed reductions in manual motor speed, accuracy of saccadic eye movements, and rates of successful behavioral response inhibition. Although the majority of previously reported cases of BBSOAS have been associated with more global intellectual dysfunction, we report on a patient with selective disruption of nonverbal abilities and superior verbal abilities. K E Y W O R D S autism, Bosch-Boonstra-Schaaf optic atrophy syndrome, cognitive discrepancy, NR2F1

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NR2F1 Mutations Cause Optic Atrophy with Intellectual Disability

Cited by 120 publications

References 47 publications

Novel genetic causes for cerebral visual impairment

Novel genetic causes for cerebral visual impairment

Cerebral visual impairment and intellectual disability caused by PGAP1 variants

Clinical and neurocognitive issues associated with Bosch‐Boonstra‐Schaaf optic atrophy syndrome: A case study

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