Chen, Chun-An; Bosch, Danielle 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; Milian, 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
Abstract
Purpose: Bosch-Boonstra-Schaaf optic atrophy syndrome (BBSOAS) is an autosomal-dominant disorder characterized by optic atrophy and intellectual disability caused by loss-of-function mutations in NR2F1. We report 20 new individuals with BBSOAS, exploring the spectrum of clinical phenotypes and assessing potential genotype-phenotype correlations.; 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.
