Contributors: Oxford Brookes University; West Midlands Regional Genetics Service; Birmingham Women's and Children's NHS Foundation Trust; Birmingham Women’s and Children’s Hospitals NHS Foundation Trust; Centre hospitalier universitaire de Nantes (CHU Nantes); SIDVA 91; Institut de Génétique et Développement de Rennes (IGDR); Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1); Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES); Physiopathologie des maladies génétiques d'expression pédiatrique (UMRS_933); Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU); Unité différenciation épidermique et auto-immunité rhumatoïde (UDEAR); Université Toulouse III - Paul Sabatier (UT3); Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM); Radboud University Medical Centre Nijmegen, The Netherlands; VU University Medical Center Amsterdam; Health Research Institute-Jimenez Diaz Foundation; St George's Healthcare NHS Trust; Oxford Centre for Genomic Medicine; Manchester Royal Eye Hospital; CIBER de Enfermedades Raras (CIBERER); Service de Génétique Médicale, Hôpital Bretonneau, Tours; Departement de Génétique Médicale CHU PURPAN; (PHRC 09 109 01), Clinical Research Hospital Program from the French Ministry of Health; CP12/03256, Spanish Institute of Health Carlos III; SAF2013-46943-R, Spanish Ministry of Economy and Competitiveness; HICF-1009-003, Health Innovation Challenge Fund; WT098051, Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute
نبذة مختصرة : International audience ; 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.
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