Phenotypic expansion of Bosch–Boonstra–Schaaf optic atrophy syndrome and further evidence for genotype–phenotype correlations |
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| Authors: | Megan E Rech John M McCarthy Chun‐An Chen Jane C Edmond Veeral S Shah Daniëlle G M Bosch Gerard T Berry Linford Williams Suneeta Madan‐Khetarpal Dmitriy Niyazov Charles Shaw‐Smith Erin M Kovar Philip J Lupo Christian P Schaaf |
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| Institution: | 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. https://orcid.org/0000-0002-2148-7490;13. Heidelberg University, Institute of Human Genetics, Heidelberg, Germany;14. Christian P. Schaaf, MD, PhD, FACMG, Institute of Human Genetics, Heidelberg University, INF 366, Heidelberg 69120, Germany. |
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| 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. |
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| Keywords: | BBSOAS developmental delay intellectual disability NR2F1 optic atrophy |
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