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

• Published in: American journal of medical genetics. Part A Vol. 182; no. 6; pp. 1426 - 1437
• Main Authors: Rech, Megan E., McCarthy, John M., Chen, Chun‐An, Edmond, Jane C., Shah, Veeral S., Bosch, Daniëlle G. M., Berry, Gerard T., Williams, Linford, Madan‐Khetarpal, Suneeta, Niyazov, Dmitriy, Shaw‐Smith, Charles, Kovar, Erin M., Lupo, Philip J., Schaaf, Christian P.
• Format: Journal Article
• Language: English
• Published: Hoboken, USA John Wiley & Sons, Inc 01-06-2020; Wiley Subscription Services, Inc
• Subjects: Atrophy; Autism; BBSOAS; Codon, Nonsense - genetics; Cognitive ability; COUP Transcription Factor I - genetics; developmental delay; DNA-Binding Proteins; Female; Frameshift mutation; Frameshift Mutation - genetics; Genetic Association Studies; Genotype & phenotype; Genotypes; Hereditary diseases; Humans; Hypoplasia; Intellectual disabilities; intellectual disability; Intellectual Disability - complications; Intellectual Disability - genetics; Intellectual Disability - physiopathology; Magnetic resonance imaging; Male; Mutation; Mutation - genetics; Neurodevelopmental disorders; NR2F1; Nystagmus; Optic Atrophies, Hereditary - complications; Optic Atrophies, Hereditary - genetics; Optic Atrophies, Hereditary - physiopathology; Optic atrophy; Optic nerve; Phenotypes; Point Mutation - genetics; Seizures; Seizures - complications; Seizures - genetics; Seizures - physiopathology; Sleep; Tears; Vision; Visual impairment; optic atrophy; NR2F1; developmental delay; BBSOAS; intellectual disability
• ISSN: 1552-4825; 1552-4833
• DOI: 10.1002/ajmg.a.61580

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.