Expanding the phenotype of the X-linked BCOR microphthalmia syndromes

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 nu...

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Published in:	Human genetics Vol. 138; no. 8-9; pp. 1051 - 1069
Main Authors:	Ragge, Nicola, Isidor, Bertrand, Bitoun, Pierre, Odent, Sylvie, Giurgea, Irina, Cogné, Benjamin, Deb, Wallid, Vincent, Marie, Le Gall, Jessica, Morton, Jenny, Lim, Derek, Le Meur, Guylène, Zazo Seco, Celia, Zafeiropoulou, Dimitra, Bax, Dorine, Zwijnenburg, Petra, Arteche, Anara, Swafiri, Saoud Tahsin, Cleaver, Ruth, McEntagart, Meriel, Kini, Usha, Newman, William, Ayuso, Carmen, Corton, Marta, Herenger, Yvan, Jeanne, Médéric, Calvas, Patrick, Chassaing, Nicolas
Format:	Journal Article
Language:	English
Published:	Berlin/Heidelberg Springer Berlin Heidelberg 01-09-2019 Springer Springer Nature B.V Springer Verlag
Subjects:	Abnormalities, Multiple / genetics Adolescent Adult Atrophy Bcl-6 protein Biomedical and Life Sciences Biomedicine Cataract / congenital Cataract / genetics Cataracts Child, Preschool Children Chromosomes, Human, X / genetics Embryonic development Eye Abnormalities / genetics Eye Genetics Female Females Gene Function Genes, X-Linked / genetics Genetic aspects Genetic Variation / genetics Genetics Heart Septal Defects / genetics Heterozygote Human Genetics Human health and pathology Humans Infant Life Sciences Lipoma Lymphoma Male Males Metabolic Diseases Microphthalmia Microphthalmos / genetics Molecular Medicine Myopia Neuropathy Original Investigation Phenotype Phenotypes Pituitary Proto-Oncogene Proteins / genetics Repressor Proteins / genetics Sensory Organs Syndrome X Chromosome Inactivation / genetics Young Adult
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Summary:	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.
ISSN:	0340-6717 1432-1203
DOI:	10.1007/s00439-018-1896-x