Clinical characteristics.

NR2F1-related neurodevelopmental disorder (NR2F1-NDD) is characterized by developmental delay / intellectual disability (ranging from profound to mild) and is commonly associated with hypotonia, visual impairment (due to optic nerve abnormalities and/or cerebral visual impairment), epilepsy, and behavioral manifestations (e.g., autism spectrum disorder, attention-deficit/hyperactivity disorder).

Diagnosis/testing.

The diagnosis of NR2F1-NDD is established in a proband with suggestive findings and a heterozygous pathogenic (or likely pathogenic) variant in NR2F1 identified by molecular genetic testing.

Management.

Treatment of manifestations: There is no cure for NR2F1-NDD. Supportive treatment typically relies on multidisciplinary specialists in the fields of neurology, speech-language pathology, ophthalmology (including low-vision services), gastroenterology, nutrition, occupational therapy, physical therapy, audiology, clinical genetics, and genetic counseling.

Surveillance: Regular monitoring of existing manifestations, the individual's response to supportive care, and the emergence of new manifestations.

Genetic counseling.

NR2F1-NDD is an autosomal dominant disorder. Most probands reported to date with an intragenic NR2F1 pathogenic variant whose parents have undergone molecular genetic testing have the disorder as the result of a de novo pathogenic variant. Some recurrences within a family have been reported. Risk to future pregnancies is presumed to be low when the proband has what appears to be a de novo NR2F1 pathogenic variant; however, there is a recurrence risk (~1%) to sibs based on the theoretic possibility of parental germline mosaicism. Given this risk, prenatal and preimplantation genetic testing may be considered.

Suggestive Findings

NR2F1-NDD should be considered in probands with the following clinical and brain MRI findings.

Clinical findings [Rech et al 2020, Bertacchi et al 2022]

• Developmental delay (i.e., delay in milestone acquisition in at least one domain) and/or intellectual disability
• Hypotonia
• Speech difficulties
• Vision impairment, including:
  • Optic atrophy (OA), optic nerve hypoplasia
  • Cerebral visual impairment (CVI), broadly defined here as bilateral visual impairment due to non-ocular causes (i.e., based in the brain) in the presence of normal pupil reactivity. Clinical assessment was corroborated by a parent report survey of behavioral characteristics of CVI including variable visual functioning, visual latency, difficulty with distance viewing, preference for movement, difficulty with visual complexity, color preference, light-gazing, visual field preference, impaired reflex blink to visual threat, preference for familiar objects, and absence of visually guided reach [Rech et al 2020].
  • Other ophthalmologic findings such as nystagmus, strabismus, amblyopia, and refractive errors
• Behavioral findings including:
  • Autism spectrum disorder or autistic features
  • Attention-deficit/hyperactivity disorder
  • Obsessive-compulsive behavior and/or repetitive behaviors
• Feeding difficulties (oromotor dysfunction, mouth stuffing)
• Seizures including infantile spasms
• Hearing impairment
• Other common findings:
  • Alacrima
  • Love of music
  • Good long-term memory
  • High pain tolerance
  • Sleep disturbances
  • Touch sensitivity

Brain imaging. The following brain MRI findings are strongly suggestive of NR2F1-NDD:

• Abnormalities of the corpus callosum (particularly thinning of the corpus callosum)
• Hypoplasia of the optic nerves and optic chiasms
• Other nonspecific findings (See Clinical Description.)

Family history. Because NR2F1-NDD is typically caused by a de novo pathogenic variant, most probands represent a simplex case (i.e., a single occurrence in a family). Rarely, the family history may be consistent with autosomal dominant inheritance (e.g., affected males and females in multiple generations).

Establishing the Diagnosis

The diagnosis of NR2F1-related NDD is established in a proband with suggestive findings and a heterozygous pathogenic (or likely pathogenic) variant in NR2F1 identified by molecular genetic testing (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of a heterozygous NR2F1 variant of uncertain significance does not establish or rule out the diagnosis of the disorder.

Molecular genetic testing in a child with developmental delay or an older individual with intellectual disability may begin with chromosomal microarray analysis (CMA). Other options may include use of a multigene panel or exome sequencing.

• An intellectual disability (ID), optic atrophy (OA), epilepsy, or autism spectrum disorder (ASD) multigene panel that includes NR2F1 and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition in a person with a nondiagnostic CMA while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
• Comprehensive genomic testing does not require the clinician to determine which gene(s) are likely involved. Exome sequencing may be more commonly used and yields results similar to an ID/OA/epilepsy/ASD multigene panel with the additional advantage that exome sequencing includes genes recently identified as causing ID/OA/epilepsy/ASD, whereas some multigene panels may not.
  Genome sequencing is also possible.
  For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Clinical Description

NR2F1-related neurodevelopmental disorder (NR2F1-NDD) is characterized by developmental delay / intellectual disability (ranging from profound to mild) and is commonly associated with hypotonia, visual impairment (due to optic nerve abnormalities and/or cerebral visual impairment), epilepsy, and behavioral issues (such as autism spectrum disorder and attention-deficit/hyperactivity disorder).

To date, 92 individuals have been described with a pathogenic variant in NR2F1 [Jurkute et al 2021, Bertacchi et al 2022]. The following description of the phenotypic features associated with this condition is based on these reports. See Table 2.

Developmental delay (DD) and intellectual disability (ID) are very common among individuals with NR2F1-NDD. DD can affect both motor and speech milestones. The severity of ID can range from profound (IQ <20) to moderate (IQ = 35-49) to mild (IQ = 50-69) [Bertacchi et al 2022].

Based on published reports to date:

• Children are able to sit independently at an average age of 14 months, crawl at 16 months, and walk at 33 months [Rech et al 2020].
• Children are able to speak their first words at an average age of 32 months and combine words by the age of 47 months [Rech et al 2020].
• Some affected individuals have more significant delays, including severe language/speech delays (e.g., they are nonverbal), and others are not able to walk independently [Rech et al 2020].

Vision impairment and other ophthalmologic findings. Vision impairment in individuals with NR2F1-NDD is usually detected in early childhood when they are examined following referrals for evaluation of nystagmus, strabismus, poor fixation, and/or concerns about neurodevelopmental progress. Based on Jurkute et al [2021]:

• Visual acuity is relatively preserved with a mean logMAR of 0.64 (20/90 Snellen equivalent). Fundus examination revealed optic atrophy in 77% of individuals and small and/or tilted hypoplastic optic nerves in 46% of individuals.
• Most individuals have a refractive error (91%) with a predominance of hyperopia (68%).
• Strabismus (77%) and nystagmus (45%) are common features.
• Cerebral visual impairment is present in 55% of children.

Other neurodevelopmental features

• Hypotonia can be present at time of birth and may persist throughout childhood [Rech et al 2020].
• Oromotor dysfunction, including problems with sucking, chewing, or swallowing, is a common feature in neonates and infants and may occasionally necessitate nasogastric tube feeding [Bertacchi et al 2022].

Seizures, reported in 46% of individuals (42/92) [Bertacchi et al 2022], are more prevalent in individuals with variants in the DNA-binding domain [Rech et al 2020] (see Genotype-Phenotype-Correlation). Generalized tonic-clonic, atonic, myoclonic, absence, and focal seizures as well as infantile epileptic spasms syndrome or febrile seizures have been described [Chen et al 2016, Hino-Fukuyo et al 2017, Mio et al 2020, Rech et al 2020, Bertacchi et al 2022].

Electroencephalography may reveal abnormalities, often predominantly in the occipital brain regions [Bertacchi et al 2022].

Behavioral findings include repetitive behavior, obsessive-compulsive behavior, autism spectrum disorder (ASD), and attention-deficit/hyperactivity disorder (ADHD) [Rech et al 2020, Bertacchi et al 2022]. While 38% (32/92) of affected individuals met the diagnostic criteria for ASD, autistic traits were reported in an additional 14% (13/92) of individuals [Bertacchi et al 2022]. ADHD was present in 18% (17/92) [Bertacchi et al 2022].

Hearing impairment is less common but has been observed (11%) [Bertacchi et al 2022]. Some individuals may need hearing aids.

Neuroimaging may show several abnormalities including abnormalities of the corpus callosum (particularly a thin corpus callosum), malrotated or dysmorphic hippocampus, white matter loss, and cortical dysgyria that may resemble polymicrogyria [Bertacchi et al 2022]. Hypoplasia of the optic nerves and optic chiasm are also commonly seen on brain MRI [Rech et al 2020].

Other associated features

• Autonomic dysfunction, including alacrima (absent or decreased reflex tears) and abnormal temperature regulation, has been described [Rech et al 2020].
• Growth. Short stature is present in some individuals [Kaiwar et al 2017, Rech et al 2020].
• No specific dysmorphic features have been observed. If present, dysmorphic features are nonspecific.

Prognosis. In contrast to other inherited optic neuropathies, vision impairment caused by pathogenic variants in NR2F1 appears to be congenital and non-progressive [Jurkute et al 2021]. Data on possible progression of behavior abnormalities or neurologic findings are currently limited.

Information on life expectancy in individuals with NR2F1-NDD is limited. One individual was alive at age 35 years [Bosch et al 2014], demonstrating that survival into adulthood is possible. Since many adults with disabilities have not undergone advanced genetic testing, it is likely that adults with this condition are underrecognized and underreported.

Genotype-Phenotype Correlations

Preliminary genotype-phenotype correlations based on published reports to date suggest that compared to individuals with pathogenic variants in other domains of NR2F1, individuals with pathogenic variants in the DNA-binding domain have a more severe neurodevelopmental phenotype, including greater prevalence of seizures, more severe language/speech delays (e.g., nonverbal), and more severe motor abnormalities (e.g., inability to walk independently) [Chen et al 2016, Rech et al 2020]. The increased clinical severity could result from a dominant-negative effect [Chen et al 2016, Rech et al 2020].

In addition, individuals with heterozygous whole-gene deletions and other variants causing functional haploinsufficiency have a milder phenotype than those with heterozygous missense variants in the DNA-binding domain [Chen et al 2016, Rech et al 2020].

Nomenclature

The title of this GeneReview, NR2F1-related neurodevelopmental disorder, is based on the dyadic naming approach proposed by Biesecker et al [2021] to delineate mendelian genetic disorders.

Prevalence

NR2F1-NDD appears to be rare, with an estimated prevalence from 1:100,000 to 1:250,000 people worldwide [Bertacchi et al 2022, Gillentine et al 2022]. To date, 92 individuals with pathogenic variants in NR2F1 have been described [Bertacchi et al 2022].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with NR2F1-NDD, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to diagnosis) are recommended.

Treatment of Manifestations

There is no cure for NR2F1-NDD.

Supportive treatment typically relies on multidisciplinary specialists in the fields of neurology, speech-language pathology, ophthalmology (including low-vision services), gastroenterology, nutrition, occupational therapy, physical therapy, audiology, clinical genetics, and genetic counseling (see Table 5).

Surveillance

See Table 6 for recommendations to monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

NR2F1-related neurodevelopmental disorder (NR2F1-NDD) is an autosomal dominant disorder typically caused by a de novo pathogenic variant.

Note: Vertical transmission of a contiguous gene deletion encompassing NR2F1 and some recurrences within a family have been reported [Chen et al 2016, Bertacchi et al 2022].

Risk to Family Members

Parents of a proband

• All probands reported to date with an intragenic NR2F1 pathogenic variant whose parents have undergone molecular genetic testing have the disorder as the result of a de novo pathogenic variant.
• Molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant.
  • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
    * A parent with somatic and germline mosaicism for an NR2F1 pathogenic variant may be mildly/minimally affected.

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband's parents:

• If a parent of the proband is known to have the NR2F1 pathogenic variant identified in the proband, the risk to the sibs of inheriting the variant is 50%.
• If the NR2F1 pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [Rahbari et al 2016].

Offspring of a proband. Each child of an individual with NR2F1-related NDD has a 50% chance of inheriting the NR2F1 pathogenic variant.

Other family members. Given that most probands with NR2F1-related NDD reported to date have the disorder as a result of a de novo NR2F1 pathogenic variant, the risk to other family members is presumed to be low.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals.

Prenatal Testing and Preimplantation Genetic Testing

Risk to future pregnancies is presumed to be low as the proband most likely has a de novo NR2F1 pathogenic variant. There is, however, a recurrence risk (~1%) to sibs based on the theoretic possibility of parental germline mosaicism [Rahbari et al 2016]. Given this risk, prenatal and preimplantation genetic testing may be considered.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most centers would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

NR2F1 encodes a highly conserved orphan nuclear receptor that is important for the development of the visual and nervous systems [Bosch et al 2014, Jurkute et al 2021]. Acting as a transcriptional regulator, it binds to the DNA as a homodimer and can activate or repress gene expression [Bertacchi et al 2019]. It contains a DNA-binding domain and a ligand-binding domain. Pathogenic variants in the DNA-binding domain appear to cause a more severe phenotype as a result of a dominant-negative effect [Chen et al 2016].

Mechanism of disease causation. Haploinsufficiency due to either gene deletion or loss-of-function variants. Single-nucleotide variants in the DNA-binding domain may cause a dominant-negative effect.

Revision History

• 8 December 2022 (bp) Review posted live
• 17 August 2022 (cs) Original submission

Literature Cited

• Al-Kateb H, Shimony JS, Vineyard M, Manwaring L, Kulkarni S, Shinawi M. NR2F1 haploinsufficiency is associated with optic atrophy, dysmorphism and global developmental delay. Am J Med Genet A. 2013;161A:377-81. [PubMed: 23300014]
• Bertacchi M, Parisot J, Studer M. The pleiotropic transcriptional regulator COUP-TFI plays multiple roles in neural development and disease. Brain Res. 2019;1705:75-94. [PubMed: 29709504]
• Bertacchi M, Tocco C, Schaaf CP, Studer M. Pathophysiological heterogeneity of the BBSOA neurodevelopmental syndrome. Cells. 2022;11:1260. [PMC free article: PMC9024734] [PubMed: 35455940]
• Biesecker LG, Adam MP, Alkuraya FS, Amemiya AR, Bamshad MJ, Beck AE, Bennett JT, Bird LM, Carey JC, Chung B, Clark RD, Cox TC, Curry C, Dinulos MBP, Dobyns WB, Giampietro PF, Girisha KM, Glass IA, Graham JM Jr, Gripp KW, Haldeman-Englert CR, Hall BD, Innes AM, Kalish JM, Keppler-Noreuil KM, Kosaki K, Kozel BA, Mirzaa GM, Mulvihill JJ, Nowaczyk MJM, Pagon RA, Retterer K, Rope AF, Sanchez-Lara PA, Seaver LH, Shieh JT, Slavotinek AM, Sobering AK, Stevens CA, Stevenson DA, Tan TY, Tan WH, Tsai AC, Weaver DD, Williams MS, Zackai E, Zarate YA. A dyadic approach to the delineation of diagnostic entities in clinical genomics. Am J Hum Genet. 2021;108:8-15. [PMC free article: PMC7820621] [PubMed: 33417889]
• 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, Lewis RA, Tsai SY, Gibbs RA, Tsai MJ, Lupski JR, Zoghbi HY, Cremers FP, de Vries BB, Schaaf CP, et al. NR2F1 mutations cause optic atrophy with intellectual disability. Am J Hum Genet. 2014;94:303-9. [PMC free article: PMC3928641] [PubMed: 24462372]
• Chen CA, Bosch DG, Cho MT, Rosenfeld JA, Shinawi M, Lewis RA, Mann J, Jayakar P, Payne K, Walsh L, Moss T, Schreiber A, Schoonveld C, Monaghan KG, Elmslie F, Douglas G, Boonstra FN, Millan F, Cremers FP, McKnight D, Richard G, Juusola J, Kendall F, Ramsey K, Anyane-Yeboa K, Malkin E, Chung WK, Niyazov D, Pascual JM, Walkiewicz M, Veluchamy V, Li C, Hisama FM, de Vries BB, Schaaf C. The expanding clinical phenotype of Bosch-Boonstra-Schaaf optic atrophy syndrome: 20 new cases and possible genotype-phenotype correlations. Genet Med. 2016;18:1143-1150. [PubMed: 26986877]
• Gillentine MA, Wang T, Eichler EE. Estimating the prevalence of de novo monogenic neurodevelopmental disorders from large cohort studies. Biomedicines. 2022;10:2865. [PMC free article: PMC9687899] [PubMed: 36359385]
• Hino-Fukuyo N, Kikuchi A, Yokoyama H, Iinuma K, Hirose M, Haginoya K, Niihori T, Nakayama K, Aoki Y, Kure S. Long-term outcome of a 26-year-old woman with West syndrome and an nuclear receptor subfamily 2 group F member 1 gene (NR2F1) mutation. Seizure. 2017;50:144-6. [PubMed: 28654857]
• Jurkute N, Bertacchi M, Arno G, Tocco C, Kim US, Kruszewski AM, Avery RA, Bedoukian EC, Han J, Ahn SJ, Pontikos N, Acheson J, Davagnanam I, Bowman R, Kaliakatsos M, Gardham A, Wakeling E, Oluonye N, Reddy MA, Clark E, Rosser E, Amati-Bonneau P, Charif M, Lenaers G, Meunier I, Defoort S, Vincent-Delorme C, Robson AG, Holder GE, Jeanjean L, Martinez-Monseny A, Vidal-Santacana M, Dominici C, Gaggioli C, Giordano N, Caleo M, Liu GT, Webster AR, Studer M, Yu-Wai-Man P, et al. Pathogenic NR2F1 variants cause a developmental ocular phenotype recapitulated in a mutant mouse model. Brain Commun. 2021;3:fcab162. [PMC free article: PMC8397830] [PubMed: 34466801]
• Kaiwar C, Zimmermann MT, Ferber MJ, Niu Z, Urrutia RA, Klee EW, Babovic-Vuksanovic D. Novel NR2F1 variants likely disrupt DNA binding: molecular modeling in two cases, review of published cases, genotype-phenotype correlation, and phenotypic expansion of the Bosch-Boonstra-Schaaf optic atrophy syndrome. Cold Spring Harb Mol Case Stud. 2017;3:a002162. [PMC free article: PMC5701304] [PubMed: 28963436]
• Mio C, Fogolari F, Pezzoli L, D’Elia AV, Iascone M, Damante G. Missense NR2F1 variant in monozygotic twins affected with the Bosch-Boonstra-Schaaf Optic Atrophy syndrome. Mol Genet Genomic Med. 2020;8:e1278. [PMC free article: PMC7336747] [PubMed: 32412696]
• Rahbari R, Wuster A, Lindsay SJ, Hardwick RJ, Alexandrov LB, Turki SA, Dominiczak A, Morris A, Porteous D, Smith B, Stratton MR, Hurles ME, et al. Timing, rates and spectra of human germline mutation. Nat Genet. 2016;48:126-33. [PMC free article: PMC4731925] [PubMed: 26656846]
• Rech ME, McCarthy JM, Chen CA, Edmond JC, Shah VS, Bosch DG, Berry GT, Williams L, Madan-Khetarpal S, Niyazov D, Shaw-Smith C, Kovar EM, Lupo PJ, Schaaf CP. Phenotypic expansion of Bosch-Boonstra-Schaaf optic atrophy syndrome and further evidence for genotype-phenotype correlations. Am J Med Genet A. 2020;182:1426-37. [PubMed: 32275123]
• Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405-24. [PMC free article: PMC4544753] [PubMed: 25741868]