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, Larry 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 & 15 others 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

Research output: Contribution to journalArticle

13 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)1143-1150
Number of pages8
JournalGenetics in Medicine
Volume18
Issue number11
DOIs
StatePublished - Nov 1 2016

Fingerprint

Optic Atrophy
Genetic Association Studies
Phenotype
Muscle Hypotonia
Initiator Codon
Corpus Callosum
Gene Deletion
Missense Mutation
Luciferases
Intellectual Disability
Hearing
Medical Records
Seizures
Western Blotting
Mutation
DNA
Proteins

Keywords

  • BBSOAS
  • developmental delay
  • NR2F1
  • optic atrophy

ASJC Scopus subject areas

  • Genetics(clinical)

Cite this

Chen, C. A., Bosch, D. G. M., Cho, M. T., Rosenfeld, J. A., Shinawi, M., Lewis, R. A., ... 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

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

In: Genetics in Medicine, Vol. 18, No. 11, 01.11.2016, p. 1143-1150.

Research output: Contribution to journalArticle

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
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, Larry ; 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. / The expanding clinical phenotype of Bosch-Boonstra-Schaaf optic atrophy syndrome : 20 new cases and possible genotype-phenotype correlations. In: Genetics in Medicine. 2016 ; Vol. 18, No. 11. pp. 1143-1150.
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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.",
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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, Larry

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

PY - 2016/11/1

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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.

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