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Hum Genet. 2019 Sep;138(8-9):1051-1069. doi: 10.1007/s00439-018-1896-x. Epub 2018 Jul 4.

Expanding the phenotype of the X-linked BCOR microphthalmia syndromes.

Author information

1
Department of Biological and Medical Sciences, Faculty of Health and Life Sciences, Oxford Brookes University, Oxford, UK. nragge@brookes.ac.uk.
2
West Midlands Regional Clinical Genetics Service and Birmingham Health Partners, Birmingham Women's and Children's Hospital NHS Foundation Trust, Birmingham, UK. nragge@brookes.ac.uk.
3
Service de génétique médicale, Hôtel-Dieu, CHU de Nantes, Nantes, France.
4
SIDVA 91, Ophthalmic Genetics, 1 rue de la Cour de, 91260, Juvisy s/orge, France.
5
Service de Génétique Clinique, Centre de référence CLAD-Ouest, Université Rennes 1, UMR 6290 CNRS IGDR, CHU Rennes, Rennes, France.
6
U.F. de Génétique moléculaire, Hôpital Armand Trousseau, Assistance Publique, Hôpitaux de Paris, 75012, Paris, France.
7
Faculté de médecine, INSERM UMR S933, Sorbonne Université, 75012, Paris, France.
8
West Midlands Regional Clinical Genetics Service and Birmingham Health Partners, Birmingham Women's and Children's Hospital NHS Foundation Trust, Birmingham, UK.
9
Service d'ophtalmologie, Hôtel Dieu, CHU de Nantes, Nantes, France.
10
UDEAR, UMR 1056 Inserm, Université de Toulouse, Toulouse, France.
11
Department of Human Genetics, Radboud University Medical Centre, Geert Grooteplein 10, 6525 GA, Nijmegen, The Netherlands.
12
Department of Biological and Medical Sciences, Faculty of Health and Life Sciences, Oxford Brookes University, Oxford, UK.
13
Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands.
14
Department of Genetics, Health Research Institute-Jiménez Díaz Foundation, University Hospital (IIS-FJD-UAM), Madrid, Spain.
15
South West Thames Regional Genetics Service, St. George's Healthcare NHS Trust, London, UK.
16
Oxford Centre for Genomic Medicine, Oxford, UK.
17
Manchester Royal Eye Hospital, Manchester, UK.
18
Centre for Biomedical Network Research on Rare Diseases (CIBERER), ISCIII, Madrid, Spain.
19
Service de Génétique Médicale, CHU de Tours, Tours, France.
20
Department of Medical Genetics, CHU Toulouse, Purpan Hospital, 31059, Toulouse, France.

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.

PMID:
29974297
DOI:
10.1007/s00439-018-1896-x
[Indexed for MEDLINE]
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