A number sign (#) is used with this entry because Bosch-Boonstra-Schaaf optic atrophy syndrome (BBSOAS) is caused by heterozygous mutation in the NR2F1 gene (132890) on chromosome 5q15.

Bosch-Boonstra-Schaaf optic atrophy syndrome (BBSOAS) is an autosomal dominant disorder characterized by delayed development, moderately impaired intellectual development, and optic atrophy. Most patients also have evidence of cerebral visual impairment. Dysmorphic facial features are variable and nonspecific (summary by Bosch et al., 2014).

Bosch et al. (2014) reported 6 unrelated patients with optic nerve atrophy associated with developmental delay and impaired intellectual development (IQ range, 48-74). The patients ranged in age from 2 to 35 years. All had decreased visual acuity, often with visual field defects. Ophthalmologic examination showed variable optic disc abnormalities, including small discs, pale discs, and disc excavation. Five of the patients reportedly had cerebral visual impairment. Other ocular anomalies included strabismus and latent nystagmus. All patients had variable dysmorphic features, but there was no constant pattern. Dysmorphic features included protruding ears, helical anomalies, small nasal ridge, high nasal bridge, upturned nose, epicanthal folds, upslanting palpebral fissures, and tapering fingers. Two patients had hypotonia, and 1 adult patient had severe obsessive-compulsive disorder and autistic features.

Chen et al. (2016) described clinical features in 20 patients, aged 2 to 43 years, with BBSOAS. Nineteen of the 20 patients had impaired intellectual development or developmental delay, 15 had optic nerve atrophy, 15 had hypotonia, 12 had oromotor dysfunction, 8 had repetitive behavior, 7 had autism spectrum disorder, 8 had seizures, 5 had attention deficit-hyperactivity disorder (ADHD), 4 had a hearing defect, and 1 had spasticity. On brain MRI, 8 of 15 patients had a thin corpus callosum. Some individuals had mild dysmorphic features, but they did not appear to be consistent between individuals.

Martin-Hernandez et al. (2018) reported a 17-year-old Spanish patient who presented at 6 months of age with vomiting, hypotonia, impaired consciousness, and strabismus. Laboratory studies showed an elevated creatine kinase. EMG showed myopathic signs. Brain MRI showed a hypoplastic corpus callosum, and EEG was normal. At 7 months of age she presented with right-sided hemiparesis and had a normal EEG. Respiratory chain analysis in a skeletal muscle biopsy showed a deficiency of complex IV. mtDNA sequencing was normal. Ophthalmologic examination at 20 months of age identified partial bilateral optic atrophy and abnormal visual-evoked potentials. MRI/MRS at age 12 years showed a slight lactate peak in the basal ganglia and a hypoplastic corpus callosum. At age 17 she had an IQ of 30-50 on the Stanford-Binet Scale.

Park et al. (2019) reported a 7-year-old Korean boy with delayed motor development (particularly in the fine motor domain), borderline intellectual development, and ADHD. Ophthalmologic exam showed latent nystagmus, reduced visual acuity, optic atrophy and diffuse loss of retinal nerve fiber layers in both eyes. Brain MRI showed thinning of the posterior corpus callosum. Facial features included retrognathia and external ear protrusion.

Bojanek et al. (2020) reported a 30-year-old man with optic nerve hypoplasia, no developmental delay, superior verbal abilities, and reduced nonverbal abilities. After birth, he had hyperbilirubinemia and was treated with phototherapy. At age 3 years, he was diagnosed with pervasive developmental disorder and ADHD. At age 8 he was diagnosed with a nonverbal learning disability, and at age 23 he was diagnosed with autism spectrum disorder. He graduated from college, maintained employment, and lived alone with support. On examination at age 30, he had generalized joint hyperextensibility, bilateral ear cupping, midface hypoplasia, a flat nasal tip, and prominent lips. MRI showed decreased size of the right optic nerve intraocular segment, and OCT testing showed retinal nerve fiber layer thinning.

Walsh et al. (2020) described a boy who was born prematurely to a pregnancy complicated by polyhydramnios. Developmental delay was noted at 8 months of age. At age 2.5 years, he developed myoclonic-astatic seizures. He developed nystagmus and hyperopia, and had severe reduction in vision. At age 6 years, he was found to have unilateral conductive hearing loss. At age 5 years, he developed a cervicothoracic syringomyelia. A brain MRI at age 7 years showed hypoplasia of the optic nerve and optic chiasm and a hypoplastic corpus callosum. He was diagnosed with an autism spectrum disorder. At age 9 years and 10 months, he had macrocephaly, a broad forehead, strabismus and small, low-set ears.

Rech et al. (2020) described clinical features in 18 new patients, provided updated data on 9 previously reported patients, and reviewed an additional 27 patients reported in the literature with BBSOAS. The most common clinical features were developmental delay, speech delay, vision impairment, and hypotonia, all of which were present in at least 89% of patients for whom information was available. Autism spectrum was seen in 80% of patients, cognitive/behavioral features in 78%, oromotor dysfunction in 70%, and mouth stuffing in 84%. General vision impairment was reported in 47 of 52 patients, optic atrophy or optic disc pallor in 41 of 50 patients, and alacrima in 21 of 27 patients; 27 of 40 patients had cortical visual impairment, 19 of 39 had optic nerve hypoplasia or a small optic nerve, and 15 of 29 had latent nystagmus or fusional maldevelopment. Additional behavioral characteristics included love of music (present in 100% of patients surveyed), unusually good long-term memory (76%), high pain tolerance (78%), sleep difficulties (61%), and touch sensitivity (59%).

Starosta et al. (2020) reported a 31-year old female with BBSOAS who had previously been diagnosed with congenital disorder of glycosylation type 1c (603147) based on transferrin isoelectrofocusing and identification of a mutation in the ALG6 gene (604566.0007) by targeted genetic testing. The ALG6 variant was later reclassified as a variant of unknown significance. By whole-exome sequencing, Starosta et al. (2020) identified a previously reported heterozygous mutation in the NR2F1 gene. The patient had typical features of BBSOAS including dysmorphic facies, hypotonia, developmental delay, seizures, and progressive visual impairment with optic atrophy. In addition, the patient had protein-losing enteropathy and ataxia, possibly extending the phenotype of BBSOAS.

The heterozygous mutations in the N2RF1 gene identified in patients with BBSOAS by Bosch et al. (2014) and Chen et al. (2016) occurred de novo.

In 2 patients with BBSOAS, Bosch et al. (2014) identified heterozygous deletions of chromosome 5q (0.83 Mb and 2.85 Mb, respectively) encompassing the NR2F1 gene.

In 5 patients with BBSOAS, including an affected father and son (individuals 17 and 18, respectively), Chen et al. (2016) identified heterozygous deletions on chromosome 5, ranging from 0.2 to 5.0 Mb and encompassing the NR2F1 gene.

In 4 patients with cortical visual impairment and intellectual disability, Bosch et al. (2014) identified 4 different de novo heterozygous missense mutations in the NR2F1 gene (132890.0001-132890.0004). In vitro functional expression assays with a luciferase reporter in HEK293 cells showed that all the missense mutations had significantly decreased transcriptional activity compared to wildtype. The findings suggested haploinsufficiency as the pathogenetic mechanism for the disorder.

In 15 patients with BBSOAS, Chen et al. (2016) identified 15 de novo heterozygous mutations in the NR2F1 gene, including 7 missense mutations, 5 mutations that disrupted translation initiation (see, e.g., 132890.0005), 2 indels resulting in a frameshift, and an in-frame indel. The mutations were identified by whole-exome sequencing and confirmed by Sanger sequencing or by chromosome microarray analysis. Five of the missense mutations were located in the DNA-binding domain (DBD), 1 was located adjacent to the DBD domain, and 1 was located in the ligand-binding domain.

Martin-Hernandez et al. (2018) identified a de novo heterozygous missense mutation in the DBD of the NR2F1 gene (K96E; 132890.0006) in a 17-year-old Spanish patient with BBSOAS. The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing.

In a 7-year-old Korean boy with BBSOAS, Park et al. (2019) identified a heterozygous nonsense mutation in the NR2F1 gene (Y171X; 132890.0007). Parental testing was not performed. The mutation was identified by using a next-generation sequencing panel of 429 genes associated with hereditary optic neuropathy.

By whole-exome sequencing in a 31-year-old woman diagnosed with BBSOAS, Starosta et al. (2020) identified heterozygosity for a de novo Y171X mutation in the NR2F1 gene. The patient had previously been reported with a diagnosis of congenital disorder of glycosylation type Ic (CDG1C; 603147) and had a homozygous Y131H mutation in the ALG6 gene (604566.0007), which was later reclassified as a variant of unknown significance based on its frequency in the gnomAD database.

In a 30-year-old man with BBSOAS, Bojanek et al. (2020) identified a de novo heterozygous nonsense mutation in the NR2F1 gene (Q28X; 132890.0008). The mutation was identified by trio whole-exome sequencing.

In a boy with severe BBSOAS, Walsh et al. (2020) identified a de novo heterozygous frameshift mutation in the LBD of the NR2F1 gene (c.1080del; 132890.0009). Because the mutation occurred in the last exon of N2RF1, Walsh et al. (2020) speculated that the resultant mRNA might not be subject to nonsense-mediated decay, raising the question of whether there may be a dominant-negative effect in this case as has been considered for missense mutations affecting the DBD.

Chen et al. (2016) assessed molecular and clinical features in 20 patients with BBSOAS. The 5 patients with microdeletions encompassing the NR2F1 gene had a lower prevalence of several clinical features when compared to 5 patients with missense mutations that completely abolish transcriptional activity, including hypotonia, oromotor dysfunction, thin corpus callosum, repetitive behaviors, autism spectrum disorder, seizures, and hearing defects. These findings led Chen et al. (2016) to consider whether a dominant-negative effect plays a role in BBSOAS.

Rech et al. (2020) compared the prevalence of clinical features between 22 patients with BBSOAS and point mutations or in-frame deletions in the DNA-binding domain (DBD) of the NR2F gene and 32 patients with BBSOAS and whole-gene deletions, nonsense mutations, frameshift mutations, or point mutations outside of the DBD. Rech et al. (2020) found that mutations in the DBD were associated with a higher prevalence of motor delay, the inability to walk unassisted, the absence of speech, seizures, and sensitivity to touch compared to other types of mutations.