TY - JOUR
T1 - The expanding clinical phenotype of Bosch-Boonstra-Schaaf optic atrophy syndrome
T2 - 20 new cases and possible genotype-phenotype correlations
AU - Chen, Chun An
AU - Bosch, Daniëlle G.M.
AU - Cho, Megan T.
AU - Rosenfeld, Jill A.
AU - Shinawi, Marwan
AU - Lewis, Richard Alan
AU - Mann, John
AU - Jayakar, Parul
AU - Payne, Katelyn
AU - Walsh, Laurence
AU - Moss, Timothy
AU - Schreiber, Allison
AU - Schoonveld, Cheri
AU - Monaghan, Kristin G.
AU - Elmslie, Frances
AU - Douglas, Ganka
AU - Boonstra, F. Nienke
AU - Millan, Francisca
AU - Cremers, Frans P.M.
AU - McKnight, Dianalee
AU - Richard, Gabriele
AU - Juusola, Jane
AU - Kendall, Fran
AU - Ramsey, Keri
AU - Anyane-Yeboa, Kwame
AU - Malkin, Elfrida
AU - Chung, Wendy K.
AU - Niyazov, Dmitriy
AU - Pascual, Juan M.
AU - Walkiewicz, Magdalena
AU - Veluchamy, Vivekanand
AU - Li, Chumei
AU - Hisama, Fuki M.
AU - De Vries, Bert B.A.
AU - Schaaf, Christian
N1 - Funding Information:
C.P.S. is generously supported by the Joan and Stanford Alexander family. C.P.S. has received a Clinical Scientist Development Award from the Doris Duke Charitable Foundation. R.A.L. is a senior scientific investigator for Research to Prevent Blindness, whose unrestricted funds to his department support part of these studies. This research is supported by the Intellectual and Developmental Disabilities Research Center (1U54 HD083092), Stichting ODAS (to F.N.B. and F.P.M.C.), Vereniging Bartiméus-Sonneheerdt (5781251 to F.N.B. and F.P.M.C.), Oogfonds (to F.P.M.C., F.N.B., and B.B.A.deV.), and LSBS (to F.P.M.C., F.N.B., and B.B.A.deV.). The authors are grateful to the individuals and their families for their support and for participating in our research study. They thank Ming-Jer Tsai and Mafei Xu for providing technical assistance and Huda Y. Zoghbi for valuable input, guidance, and discussion.
Publisher Copyright:
© American College of Medical Genetics and Genomics.
PY - 2016/11/1
Y1 - 2016/11/1
N2 - 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.
AB - 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.
KW - BBSOAS
KW - NR2F1
KW - developmental delay
KW - optic atrophy
UR - http://www.scopus.com/inward/record.url?scp=84994126494&partnerID=8YFLogxK
U2 - 10.1038/gim.2016.18
DO - 10.1038/gim.2016.18
M3 - Article
C2 - 26986877
AN - SCOPUS:84994126494
VL - 18
SP - 1143
EP - 1150
JO - Genetics in Medicine
JF - Genetics in Medicine
SN - 1098-3600
IS - 11
ER -