The expanding clinical phenotype of Bosch-Boonstra-Schaaf optic atrophy syndrome: 20 new cases and possible genotype-phenotype correlations

Chun An Chen; Daniëlle G M Bosch; Megan T. Cho; Jill A. Rosenfeld; Marwan Shinawi; Richard Alan Lewis; John Mann; Parul Jayakar; Katelyn Payne; Laurence Walsh; Timothy Moss; Allison Schreiber; Cheri Schoonveld; Kristin G. Monaghan; Frances Elmslie; Ganka Douglas; F. Nienke Boonstra; Francisca Millan; Frans P M Cremers; Dianalee McKnight; Gabriele Richard; Jane Juusola; Fran Kendall; Keri Ramsey; Kwame Anyane-Yeboa; Elfrida Malkin; Wendy K. Chung; Dmitriy Niyazov; Juan M. Pascual; Magdalena Walkiewicz; Vivekanand Veluchamy; Chumei Li; Fuki M. Hisama; Bert B A De Vries; Christian Schaaf

doi:10.1038/gim.2016.18

The expanding clinical phenotype of Bosch-Boonstra-Schaaf optic atrophy syndrome: 20 new cases and possible genotype-phenotype correlations

Chun An Chen, Daniëlle G M Bosch, Megan T. Cho, Jill A. Rosenfeld, Marwan Shinawi, Richard Alan Lewis, John Mann, Parul Jayakar, Katelyn Payne, Laurence Walsh, Timothy Moss, Allison Schreiber, Cheri Schoonveld, Kristin G. Monaghan, Frances Elmslie, Ganka Douglas, F. Nienke Boonstra, Francisca Millan, Frans P M Cremers, Dianalee McKnightGabriele Richard, Jane Juusola, Fran Kendall, Keri Ramsey, Kwame Anyane-Yeboa, Elfrida Malkin, Wendy K. Chung, Dmitriy Niyazov, Juan M. Pascual, Magdalena Walkiewicz, Vivekanand Veluchamy, Chumei Li, Fuki M. Hisama, Bert B A De Vries, Christian Schaaf

Laboratory Medicine and Pathology

Research output: Contribution to journal › Article › peer-review

55 Scopus citations

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.

Original language	English (US)
Pages (from-to)	1143-1150
Number of pages	8
Journal	Genetics in Medicine
Volume	18
Issue number	11
DOIs	https://doi.org/10.1038/gim.2016.18
State	Published - Nov 1 2016

Bibliographical note

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.

Keywords

BBSOAS
NR2F1
developmental delay
optic atrophy

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Chen, C. A., Bosch, D. G. M., Cho, M. T., Rosenfeld, J. A., Shinawi, M., Lewis, R. A., Mann, J., Jayakar, P., Payne, K., Walsh, L., Moss, T., Schreiber, A., Schoonveld, C., Monaghan, K. G., Elmslie, F., Douglas, G., Boonstra, F. N., Millan, F., Cremers, F. P. M., ... Schaaf, C. (2016). The expanding clinical phenotype of Bosch-Boonstra-Schaaf optic atrophy syndrome: 20 new cases and possible genotype-phenotype correlations. Genetics in Medicine, 18(11), 1143-1150. https://doi.org/10.1038/gim.2016.18

Chen, CA, Bosch, DGM, Cho, MT, Rosenfeld, JA, Shinawi, M, Lewis, RA, Mann, J, Jayakar, P, Payne, K, Walsh, L, Moss, T, Schreiber, A, Schoonveld, C, Monaghan, KG, Elmslie, F, Douglas, G, Boonstra, FN, Millan, F, Cremers, FPM, McKnight, D, Richard, G, Juusola, J, Kendall, F, Ramsey, K, Anyane-Yeboa, K, Malkin, E, Chung, WK, Niyazov, D, Pascual, JM, Walkiewicz, M, Veluchamy, V, Li, C, Hisama, FM, De Vries, BBA & Schaaf, C 2016, 'The expanding clinical phenotype of Bosch-Boonstra-Schaaf optic atrophy syndrome: 20 new cases and possible genotype-phenotype correlations', Genetics in Medicine, vol. 18, no. 11, pp. 1143-1150. https://doi.org/10.1038/gim.2016.18

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title = "The expanding clinical phenotype of Bosch-Boonstra-Schaaf optic atrophy syndrome: 20 new cases and possible genotype-phenotype correlations",

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.",

keywords = "BBSOAS, NR2F1, developmental delay, optic atrophy",

author = "Chen, {Chun An} and Bosch, {Dani{\"e}lle G M} and Cho, {Megan T.} and Rosenfeld, {Jill A.} and Marwan Shinawi and Lewis, {Richard Alan} and John Mann and Parul Jayakar and Katelyn Payne and Laurence Walsh and Timothy Moss and Allison Schreiber and Cheri Schoonveld and Monaghan, {Kristin G.} and Frances Elmslie and Ganka Douglas and Boonstra, {F. Nienke} and Francisca Millan and Cremers, {Frans P M} and Dianalee McKnight and Gabriele Richard and Jane Juusola and Fran Kendall and Keri Ramsey and Kwame Anyane-Yeboa and Elfrida Malkin and Chung, {Wendy K.} and Dmitriy Niyazov and Pascual, {Juan M.} and Magdalena Walkiewicz and Vivekanand Veluchamy and Chumei Li and Hisama, {Fuki M.} and {De Vries}, {Bert B A} and Christian Schaaf",

note = "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 Bartim{\'e}us-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: {\textcopyright} American College of Medical Genetics and Genomics.",

year = "2016",

month = nov,

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doi = "10.1038/gim.2016.18",

language = "English (US)",

volume = "18",

pages = "1143--1150",

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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

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The expanding clinical phenotype of Bosch-Boonstra-Schaaf optic atrophy syndrome: 20 new cases and possible genotype-phenotype correlations

Abstract

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Keywords

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