Phenotypic expansion of Bosch-Boonstra-Schaaf optic atrophy syndrome and further evidence for genotype-phenotype correlations

doi:10.1002/ajmg.a.61580

. 2020 Jun;182(6):1426-1437.

doi: 10.1002/ajmg.a.61580. Epub 2020 Apr 10.

Phenotypic expansion of Bosch-Boonstra-Schaaf optic atrophy syndrome and further evidence for genotype-phenotype correlations

Megan E Rech^{1

2}, John M McCarthy^{1

2}, Chun-An Chen^{1

2}, Jane C Edmond^{3

4

5}, Veeral S Shah^{4

5}, Daniëlle G M Bosch⁶, Gerard T Berry⁷, Linford Williams⁸, Suneeta Madan-Khetarpal⁸, Dmitriy Niyazov⁹, Charles Shaw-Smith¹⁰, Erin M Kovar¹¹, Philip J Lupo¹¹, Christian P Schaaf^{1

2

12}

Affiliations

¹ Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, Texas, USA.
² Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
³ Department of Ophthalmology, Dell Medical School, University of Texas at Austin, Austin, Texas, USA.
⁴ Division of Ophthalmology, Texas Children's Hospital, Houston, Texas, USA.
⁵ Department of Ophthalmology, Baylor College of Medicine, Houston, Texas, USA.
⁶ Department of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
⁷ Division of Genetics and Genomics, Manton Center for Orphan Disease Research Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
⁸ Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania, USA.
⁹ Department of Pediatrics, Ochsner Health System and University of Queensland, New Orleans, Louisiana, USA.
¹⁰ Department of Clinical Genetics, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK.
¹¹ Section of Hematology and Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA.
¹² Heidelberg University, Institute of Human Genetics, Heidelberg, Germany.

PMID: 32275123
DOI: 10.1002/ajmg.a.61580

Phenotypic expansion of Bosch-Boonstra-Schaaf optic atrophy syndrome and further evidence for genotype-phenotype correlations

Megan E Rech et al. Am J Med Genet A. 2020 Jun.

. 2020 Jun;182(6):1426-1437.

doi: 10.1002/ajmg.a.61580. Epub 2020 Apr 10.

Authors

Affiliations

¹ Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, Texas, USA.
² Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
³ Department of Ophthalmology, Dell Medical School, University of Texas at Austin, Austin, Texas, USA.
⁴ Division of Ophthalmology, Texas Children's Hospital, Houston, Texas, USA.
⁵ Department of Ophthalmology, Baylor College of Medicine, Houston, Texas, USA.
⁶ Department of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
⁷ Division of Genetics and Genomics, Manton Center for Orphan Disease Research Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
⁸ Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania, USA.
⁹ Department of Pediatrics, Ochsner Health System and University of Queensland, New Orleans, Louisiana, USA.
¹⁰ Department of Clinical Genetics, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK.
¹¹ Section of Hematology and Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA.
¹² Heidelberg University, Institute of Human Genetics, Heidelberg, Germany.

PMID: 32275123
DOI: 10.1002/ajmg.a.61580

Abstract

Bosch-Boonstra-Schaaf Optic Atrophy Syndrome (BBSOAS) is an autosomal dominant neurodevelopmental disorder caused by loss-of-function variants in NR2F1 and characterized by visual impairment, developmental delay, and intellectual disability. Here we report 18 new cases, provide additional clinical information for 9 previously reported individuals, and review an additional 27 published cases to present a total of 54 patients. Among these are 22 individuals with point mutations or in-frame deletions in the DNA-binding domain (DBD), and 32 individuals with other types of variants including whole-gene deletions, nonsense and frameshift variants, and point mutations outside the DBD. We corroborate previously described clinical characteristics including developmental delay, intellectual disability, autism spectrum disorder diagnoses/features thereof, cognitive/behavioral anomalies, hypotonia, feeding difficulties, abnormal brain MRI findings, and seizures. We also confirm a vision phenotype that includes optic nerve hypoplasia, optic atrophy, and cortical visual impairment. Additionally, we expand the vision phenotype to include alacrima and manifest latent nystagmus (fusional maldevelopment), and we broaden the behavioral phenotypic spectrum to include a love of music, an unusually good long-term memory, sleep difficulties, a high pain tolerance, and touch sensitivity. Furthermore, we provide additional evidence for genotype-phenotype correlations, specifically supporting a more severe phenotype associated with DBD variants.

Keywords: BBSOAS; NR2F1; developmental delay; intellectual disability; optic atrophy.

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References

REFERENCES

1. Adams, J., & Schaaf, C. P. (2018). Diagnosis and genetics of alacrima. Clinical Genetics, 94(1), 54-60. https://doi.org/10.1111/cge.13173
1. Alfano, C., Magrinelli, E., Harb, K., & Studer, M. (2014). The nuclear receptors COUP-TF: A long-lasting experience in forebrain assembly. Cellular and Molecular Life Sciences, 71(1), 43-62. https://doi.org/10.1007/s00018-013-1320-6
1. Al-Kateb, H., Shimony, J. S., Vineyard, M., Manwaring, L., Kulkarni, S., & Shinawi, M. (2013). NR2F1 haploinsufficiency is associated with optic atrophy, dysmorphism and global developmental delay. American Journal of Medical Genetics Part A, 161(2), 377-381. https://doi.org/10.1002/ajmg.a.35650
1. Allely, C. S. (2013). Pain sensitivity and observer perception of pain in individuals with autistic spectrum disorder. The Scientific World Journal, 2013. https://doi.org/10.1155/2013/916178
1. Allen, R., Hill, E., & Heaton, P. (2009). The subjective experience of music in autism Spectrum disorder. Annals of the New York Academy of Sciences, 1169(1), 326-331. https://doi.org/10.1111/j.1749-6632.2009.04772.x

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[1] Adams, J., & Schaaf, C. P. (2018). Diagnosis and genetics of alacrima. Clinical Genetics, 94(1), 54-60. https://doi.org/10.1111/cge.13173

[2] Adams, J., & Schaaf, C. P. (2018). Diagnosis and genetics of alacrima. Clinical Genetics, 94(1), 54-60. https://doi.org/10.1111/cge.13173

[3] Alfano, C., Magrinelli, E., Harb, K., & Studer, M. (2014). The nuclear receptors COUP-TF: A long-lasting experience in forebrain assembly. Cellular and Molecular Life Sciences, 71(1), 43-62. https://doi.org/10.1007/s00018-013-1320-6

[4] Alfano, C., Magrinelli, E., Harb, K., & Studer, M. (2014). The nuclear receptors COUP-TF: A long-lasting experience in forebrain assembly. Cellular and Molecular Life Sciences, 71(1), 43-62. https://doi.org/10.1007/s00018-013-1320-6

[5] Al-Kateb, H., Shimony, J. S., Vineyard, M., Manwaring, L., Kulkarni, S., & Shinawi, M. (2013). NR2F1 haploinsufficiency is associated with optic atrophy, dysmorphism and global developmental delay. American Journal of Medical Genetics Part A, 161(2), 377-381. https://doi.org/10.1002/ajmg.a.35650

[6] Al-Kateb, H., Shimony, J. S., Vineyard, M., Manwaring, L., Kulkarni, S., & Shinawi, M. (2013). NR2F1 haploinsufficiency is associated with optic atrophy, dysmorphism and global developmental delay. American Journal of Medical Genetics Part A, 161(2), 377-381. https://doi.org/10.1002/ajmg.a.35650

[7] Allely, C. S. (2013). Pain sensitivity and observer perception of pain in individuals with autistic spectrum disorder. The Scientific World Journal, 2013. https://doi.org/10.1155/2013/916178

[8] Allely, C. S. (2013). Pain sensitivity and observer perception of pain in individuals with autistic spectrum disorder. The Scientific World Journal, 2013. https://doi.org/10.1155/2013/916178

[9] Allen, R., Hill, E., & Heaton, P. (2009). The subjective experience of music in autism Spectrum disorder. Annals of the New York Academy of Sciences, 1169(1), 326-331. https://doi.org/10.1111/j.1749-6632.2009.04772.x

[10] Allen, R., Hill, E., & Heaton, P. (2009). The subjective experience of music in autism Spectrum disorder. Annals of the New York Academy of Sciences, 1169(1), 326-331. https://doi.org/10.1111/j.1749-6632.2009.04772.x

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Phenotypic expansion of Bosch-Boonstra-Schaaf optic atrophy syndrome and further evidence for genotype-phenotype correlations

Affiliations

Phenotypic expansion of Bosch-Boonstra-Schaaf optic atrophy syndrome and further evidence for genotype-phenotype correlations

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