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Expanding the phenotype of the X-linked BCOR microphthalmia syndromes

  • Nicola Ragge
  • Bertrand Isidor
  • Pierre Bitoun
  • Sylvie Odent
  • Irina Giurgea
  • Benjamin Cogné
  • Wallid Deb
  • Marie Vincent
  • Jessica Le Gall
  • Jenny Morton
  • Derek Lim
  • DDD Study
  • Guylène Le Meur
  • Celia Zazo Seco
  • Dimitra Zafeiropoulou
  • Dorine Bax
  • Petra Zwijnenburg
  • Anara Arteche
  • Saoud Tahsin Swafiri
  • Ruth Cleaver
  • Meriel McEntagart
  • Usha Kini
  • William Newman
  • Carmen Ayuso
  • Marta Corton
  • Yvan Herenger
  • Médéric Jeanne
  • Patrick Calvas
  • Nicolas Chassaing
Original Investigation
Part of the following topical collections:
  1. Eye Genetics

Abstract

Two distinct syndromes arise from pathogenic variants in the X-linked gene BCOR (BCL-6 corepressor): oculofaciocardiodental (OFCD) syndrome, which affects females, and a severe microphthalmia (‘Lenz’-type) syndrome affecting males. OFCD is an X-linked dominant syndrome caused by a variety of BCOR null mutations. As it manifests only in females, it is presumed to be lethal in males. The severe male X-linked recessive microphthalmia syndrome (‘Lenz’) usually includes developmental delay in addition to the eye findings and is caused by hypomorphic BCOR variants, mainly by a specific missense variant c.254C > T, p.(Pro85Leu). Here, we detail 16 new cases (11 females with 4 additional, genetically confirmed, affected female relatives; 5 male cases each with unaffected carrier mothers). We describe new variants and broaden the phenotypic description for OFCD to include neuropathy, muscle hypotonia, pituitary underdevelopment, brain atrophy, lipoma and the first description of childhood lymphoma in an OFCD case. Our male X-linked recessive cases show significant new phenotypes: developmental delay (without eye anomalies) in two affected half-brothers with a novel BCOR variant, and one male with high myopia, megalophthalmos, posterior embryotoxon, developmental delay, and heart and bony anomalies with a previously undescribed BCOR splice site variant. Our female OFCD cases and their affected female relatives showed variable features, but consistently had early onset cataracts. We show that a mosaic carrier mother manifested early cataract and dental anomalies. All female carriers of the male X-linked recessive cases for whom genetic confirmation was available showed skewed X-inactivation and were unaffected. In view of the extended phenotype, we suggest a new term of X-linked BCOR-related syndrome.

Notes

Acknowledgements

We acknowledge generous support from the families published in this article. This work was supported by Grants from the Clinical Research Hospital Program from the French Ministry of Health (PHRC 09 109 01), the Fondation of France, the Fondation Maladies Rares, Berthe Fouassier, Rétina France, VICTA (Visually Impaired Children Taking Action), MACS (Microphthalmia, Anophthalmia Coloboma Support), Baillie Gifford, Spanish Institute of Health Carlos III (CP12/03256), Spanish Ministry of Economy and Competitiveness (SAF2013-46943-R) and Mutua Madrileña Foundation. The DDD study presents independent research commissioned by the Health Innovation Challenge Fund [Grant Number HICF-1009-003], a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute [Grant Number WT098051]. The views expressed in this publication are those of the authors and not necessarily those of the Wellcome Trust or the Department of Health. The study has UK Research Ethics Committee approval (10/H0305/83, granted by the Cambridge South REC, and GEN/284/12 granted by the Republic of Ireland REC). The research team acknowledges the support of the National Institute for Health Research, through the Comprehensive Clinical Research Network. This study makes use of DECIPHER (http://decipher.sanger.ac.uk), which is funded by the Wellcome Trust.

Compliance with ethical standards

Conflict of interest

On behalf of all authors, the corresponding author states that there is no conflict of interest.

Supplementary material

439_2018_1896_MOESM1_ESM.xlsx (24 kb)
Supplementary Table 1: Summary of Clinical Features and Variants of Published cases identified with BCOR variants (including current series) (XLSX 24 KB)
439_2018_1896_MOESM2_ESM.xlsx (12 kb)
Supplementary Table 2: Summary of OFCD cases (XLSX 12 KB)
439_2018_1896_MOESM3_ESM.xlsx (11 kb)
Supplementary Table 3: Summary of X-linked BCOR male cases (XLSX 10 KB)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Nicola Ragge
    • 1
    • 2
  • Bertrand Isidor
    • 3
  • Pierre Bitoun
    • 4
  • Sylvie Odent
    • 5
  • Irina Giurgea
    • 6
    • 7
  • Benjamin Cogné
    • 3
  • Wallid Deb
    • 3
  • Marie Vincent
    • 3
  • Jessica Le Gall
    • 3
  • Jenny Morton
    • 2
  • Derek Lim
    • 2
  • DDD Study
    • 8
  • Guylène Le Meur
    • 9
  • Celia Zazo Seco
    • 10
  • Dimitra Zafeiropoulou
    • 11
  • Dorine Bax
    • 1
  • Petra Zwijnenburg
    • 12
  • Anara Arteche
    • 13
  • Saoud Tahsin Swafiri
    • 13
  • Ruth Cleaver
    • 14
  • Meriel McEntagart
    • 14
  • Usha Kini
    • 15
  • William Newman
    • 16
  • Carmen Ayuso
    • 13
    • 17
  • Marta Corton
    • 13
    • 17
  • Yvan Herenger
    • 18
  • Médéric Jeanne
    • 18
  • Patrick Calvas
    • 10
    • 19
  • Nicolas Chassaing
    • 10
    • 19
  1. 1.Department of Biological and Medical Sciences, Faculty of Health and Life SciencesOxford Brookes UniversityOxfordUK
  2. 2.West Midlands Regional Clinical Genetics Service and Birmingham Health PartnersBirmingham Women’s and Children’s Hospital NHS Foundation TrustBirminghamUK
  3. 3.Service de génétique médicale, Hôtel-DieuCHU de NantesNantesFrance
  4. 4.SIDVA 91, Ophthalmic GeneticsJuvisy s/orgeFrance
  5. 5.Service de Génétique Clinique, Centre de référence CLAD-OuestUniversité Rennes 1, UMR 6290 CNRS IGDR, CHU RennesRennesFrance
  6. 6.U.F. de Génétique moléculaire, Hôpital Armand TrousseauAssistance Publique, Hôpitaux de ParisParisFrance
  7. 7.Faculté de médecineINSERM UMR S933, Sorbonne UniversitéParisFrance
  8. 8.DDD StudyWellcome Trust Sanger InstituteCambridgeUK
  9. 9.Service d’ophtalmologieHôtel Dieu, CHU de NantesNantesFrance
  10. 10.UDEAR, UMR 1056 Inserm, Université de ToulouseToulouseFrance
  11. 11.Department of Human GeneticsRadboud University Medical CentreNijmegenThe Netherlands
  12. 12.Department of Clinical GeneticsVU University Medical CenterAmsterdamThe Netherlands
  13. 13.Department of Genetics, Health Research Institute–Jiménez Díaz FoundationUniversity Hospital (IIS-FJD-UAM)MadridSpain
  14. 14.South West Thames Regional Genetics ServiceSt. George’s Healthcare NHS TrustLondonUK
  15. 15.Oxford Centre for Genomic MedicineOxfordUK
  16. 16.Manchester Royal Eye HospitalManchesterUK
  17. 17.Centre for Biomedical Network Research on Rare Diseases (CIBERER), ISCIIIMadridSpain
  18. 18.Service de Génétique MédicaleCHU de ToursToursFrance
  19. 19.Department of Medical GeneticsCHU Toulouse, Purpan HospitalToulouseFrance

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