NR2F1 – Bosch-Boonstra-Schaaf Optic Atrophy Syndrome

Bosch-Boonstra-Schaaf optic atrophy syndrome (BBSOAS) is a rare autosomal dominant neurodevelopmental disorder caused by haploinsufficiency of the nuclear receptor NR2F1. Clinically, BBSOAS is defined by optic atrophy, global developmental delay, intellectual disability, hypotonia and, in many cases, seizures and cortical visual impairment (PMID:26986877).

Genetic evidence for the NR2F1–BBSOAS association is robust, with over 100 unrelated probands harboring de novo loss-of-function NR2F1 variants reported over the past decade (PMID:39350586). Cohort studies have identified multiple variant types: missense substitutions especially within the zinc-finger DNA-binding domain, nonsense and frameshift mutations, initiation codon alterations, splice-site variants, and whole-gene deletions. Affected individuals consistently present with the BBSOAS phenotype, and no significant conflicting data have been reported.

Inheritance is autosomal dominant, predominantly due to de novo heterozygous NR2F1 mutations. Segregation analysis includes cases of parental gonadal mosaicism leading to two affected siblings (PMID:36775012).

Variants impair NR2F1 transcriptional activity. For example, c.286A>G (p.Lys96Glu) in the DNA-binding domain dramatically reduces luciferase reporter activity, confirming loss of function (PMID:29410510).

Functional studies provide concordant mechanistic insights. Reporter assays demonstrate decreased NR2F1 transcriptional activation for missense and initiation codon variants (PMID:24462372, PMID:26986877). A heterozygous Nr2f1+/- mouse model recapitulates key neurological features, including hypotonia, learning deficits and reduced hippocampal synaptic plasticity, supporting haploinsufficiency as the pathogenic mechanism (PMID:31600777).

Overall, the NR2F1–BBSOAS gene-disease association meets ClinGen Definitive criteria: it is supported by >100 de novo probands, multiple multi-family cohorts, segregation data, and concordant functional and animal model evidence. Genetic testing for NR2F1 variants enables precise diagnosis, informs recurrence risk counseling, and guides surveillance for visual and neurological complications.

Key Take-home: Genetic and functional data conclusively support NR2F1 haploinsufficiency as the cause of BBSOAS, underpinning its diagnostic and clinical management utility.

References

• Genetics in medicine • 2016 • The expanding clinical phenotype of Bosch-Boonstra-Schaaf optic atrophy syndrome: 20 new cases and possible genotype-phenotype correlations. PMID:26986877
• American Journal of Human Genetics • 2014 • NR2F1 mutations cause optic atrophy with intellectual disability. PMID:24462372
• Human Molecular Genetics • 2020 • Nr2f1 heterozygous knockout mice recapitulate neurological phenotypes of Bosch-Boonstra-Schaaf optic atrophy syndrome and show impaired hippocampal synaptic plasticity. PMID:31600777
• Journal of Human Genetics • 2018 • Mitochondrial involvement in a Bosch-Boonstra-Schaaf optic atrophy syndrome patient with a novel de novo NR2F1 gene mutation. PMID:29410510

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