Expanding the phenotype of the X-linked BCOR microphthalmia syndromes

Nicola Ragge (1, 2, 3) , Bertrand Isidor (4) , Pierre Bitoun (5) , Sylvie Odent (6) , Irina Giurgea (7, 8) , Benjamin Cogné (4) , Wallid Deb (4) , Marie Vincent (4) , Jessica Le Gall (4) , Jenny Morton (3) , Derek Lim (3) , Guylène Le Meur (4) , Celia Zazo Seco (9) , Dimitra Zafeiropoulou (10) , Dorine Bax (1) , Petra Zwijnenburg (11) , Anara Arteche (12) , Saoud Tahsin Swafiri (12) , Ruth Cleaver (13) , Meriel Mcentagart (13) , Usha Kini (14) , William Newman (15) , Carmen Ayuso (12, 16) , Marta Corton (12, 16) , Yvan Herenger (17) , Médéric Jeanne (17) , Patrick Calvas (9, 18) , Nicolas Chassaing (9, 18)

1 Oxford Brookes University
2 West Midlands Regional Genetics Service
3 Birmingham Women’s and Children’s Hospitals NHS Foundation Trust
4 CHU Nantes - Centre Hospitalier Universitaire de Nantes
5 SIDVA 91
6 IGDR - Institut de Génétique et Développement de Rennes
7 U933 - Maladies génétiques d'expression pédiatrique
8 CHU Trousseau [APHP]
9 UDEAR - Unité différenciation épidermique et auto-immunité rhumatoïde
10 Radboud University Medical Center [Nijmegen]
11 VU University Medical Center [Amsterdam]
12 Health Research Institute-Jimenez Diaz Foundation
13 St George's Healthcare NHS Trust
14 Oxford Centre for Genomic Medicine
15 Manchester Royal Eye Hospital
16 CIBER de Enfermedades Raras (CIBERER)
17 Service de Génétique Médicale, Hôpital Bretonneau, Tours
18 Service Génétique Médicale [CHU Toulouse]

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.

Domaines: Génétique humaine; Organes des sens

Nicola Ragge, Bertrand Isidor, Pierre Bitoun, Sylvie Odent, Irina Giurgea, et al.. Expanding the phenotype of the X-linked BCOR microphthalmia syndromes. Human Genetics, 2019, 138 (8-9), pp.1051-1069. ⟨10.1007/s00439-018-1896-x⟩. ⟨hal-01863370⟩