The expanding clinical phenotype of Bosch-Boonstra-Schaaf optic atrophy syndrome: 20 new cases and possible genotype-phenotype correlations.
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Chen Chun-An, Bosch Daniëlle G M, Cho Megan T, Rosenfeld Jill A, Shinawi Marwan, Lewis Richard Alan, Mann John, Jayakar Parul, Payne Katelyn, Walsh Laurence, Moss Timothy, Schreiber Allison, Schoonveld Cheri, Monaghan Kristin G, Elmslie Frances, Douglas Ganka, Boonstra F Nienke, Millan Francisca, Cremers Frans P M, McKnight Dianalee, Richard Gabriele, Juusola Jane, Kendall Fran, Ramsey Keri, Anyane-Yeboa Kwame, Malkin Elfrida, Chung Wendy K, Niyazov Dmitriy, Pascual Juan M, Walkiewicz Magdalena, Veluchamy Vivekanand, Li Chumei, Hisama Fuki M, de Vries Bert B A, Schaaf Christian
Аннотация
METHODS: Clinical features of individuals with pathogenic NR2F1 variants were evaluated by review of medical records. The functional relevance of coding nonsynonymous NR2F1 variants was assessed with a luciferase assay measuring the impact on transcriptional activity. The effects of two start codon variants on protein expression were evaluated by western blot analysis.
RESULTS: We recruited 20 individuals with novel pathogenic NR2F1 variants (seven missense variants, five translation initiation variants, two frameshifting insertions/deletions, one nonframeshifting insertion/deletion, and five whole-gene deletions). All the missense variants were found to impair transcriptional activity. In addition to visual and cognitive deficits, individuals with BBSOAS manifested hypotonia (75%), seizures (40%), autism spectrum disorder (35%), oromotor dysfunction (60%), thinning of the corpus callosum (53%), and hearing defects (20%).
CONCLUSION: BBSOAS encompasses a broad range of clinical phenotypes. Functional studies help determine the severity of novel NR2F1 variants. Some genotype-phenotype correlations seem to exist, with missense mutations in the DNA-binding domain causing the most severe phenotypes.Genet Med 18 11, 1143-1150.