Springer Nature is making SARS-CoV-2 and COVID-19 research free. View research | View latest news | Sign up for updates

Expanding the phenotype of the X-linked BCOR microphthalmia syndromes

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.

This is a preview of subscription content, log in to check access.

Fig. 1
Fig. 2
Fig. 3

References

  1. Acampora D, Mazan S, Avantaggiato V, Barone P, Tuorto F, Lallemand Y, Brulet P, Simeone A (1996) Epilepsy and brain abnormalities in mice lacking the Otx1 gene. Nat Genet 14:218–222

  2. Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P et al (2010) A method and server for predicting damaging missense mutations. Nat Methods 7:248–249

  3. Amos-Landgraf JM, Cottle A, Plenge RM, Friez M, Schwartz CE.

  4. Bakrania P, Robinson DO, Bunyan DJ, Salt A, Martin A, Crolla JA, Wyatt A, Fielder A, Ainsworth J, Moore A, Read S, Uddin J, Laws D, Pascuel-Salcedo D, Ayuso C, Allen L, Collin JR, Ragge NK (2007) SOX2 anophthalmia syndrome: 12 new cases demonstrating broader phenotype and high frequency of large gene deletions. Br J Ophthalmol 91(11):1471–1476

  5. Danda S, van Rahden VA, John D, Paul P, Raju R, Koshy S, Kutsche K (2014) Evidence of germline Mosaicism for a novel BCOr mutation in two indian sisters with oculo-facio-cardio dental syndrome. Mol Syndromol 5(5):251–256

  6. Davoody A, Chen IP, Nanda R, Uribe F, Reichenberger EJ (2012) Oculofaciocardiodental syndrome: a rare case and review of the literature. Cleft Palate Craniofac J 49(5):e55-60

  7. Desmet FO, Hamroun D, Lalande M, Collod-Beroud G, Claustres M, Beroud C (2009) Human Splicing Finder: an online bioinformatics tool to predict splicing signals. Nucleic Acids Res 37(9):e67

  8. Di Stefano C, Lombardo B, Fabbricatore C, Munno C, Caliendo I, Gallo F, Pastore L (2015) Oculo-facio-cardio-dental (OFCD) syndrome: the first Italian case of BCOR and co-occurring OTC gene deletion. Gene 559(2):203–206

  9. Dobashi A, Tsuyama N, Asaka R, Togashi Y, Ueda K, Sakata S, Baba S, Sakamoto K, Hatake K, Takeuchi K (2016) Frequent BCOR aberrations in extranodal NK/T-Cell lymphoma, nasal type. Genes Chromosomes Cancer 55(5):460–471

  10. Esmailpour T, Riazifar H, Liu L, Donkervoort S, Huang VH, Madaan S, Shoucri BM, Busch A, Wu J, Towbin A, Chadwick RB, Sequeira A, Vawter MP, Sun G, Johnston JJ, Biesecker LG, Kawaguchi R, Sun H, Kimonis V, Huang T (2014) A splice donor mutation in NAA10 results in the dysregulation of the retinoic acid signalling pathway and causes Lenz microphthalmia syndrome. J Med Genet 51(3):185–196

  11. Fantes J, Ragge NK, Lynch SA, McGill NI, Collin JR, Howard-Peebles PN, Hayward C, Vivian AJ, Williamson K, van Heyningen V, FitzPatrick DR (2003) Mutations in SOX2 cause anophthalmia. Nat Genet 33(4):461–463

  12. Feberwee HE, Feenstra I, Oberoi S, Sama IE, Ockeloen CW, Clum F, Slavotinek A, Kuijpers MA, Dooijes D, Kuijpers-Jagtman AM, Kleefstra T, Carels CE (2014) Novel BCOR mutations in patients with oculofaciocardiodental (OFCD) syndrome. Clin Genet 85(2):194–197

  13. Fujimaki T, Yokoyama T, Kawano H, Fujiki K, Ikeda M, Murakami A (2008) A Case Report of Oculofaciocardiodental Syndrome with novel BCOR gene mutation. Invest Ophthalmol Vis Sci 49(13):465

  14. Hilton E, Johnston J, Whalen S, Okamoto N, Hatsukawa Y, Nishio J, Kohara H, Hirano Y, Mizuno S, Torii C, Kosaki K, Manouvrier S, Boute O, Perveen R, Law C, Moore A, Fitzpatrick D, Lemke J, Fellmann F, Debray FG, Dastot-Le-Moal F, Gerard M, Martin J, Bitoun P, Goossens M, Verloes A, Schinzel A, Bartholdi D, Bardakjian T, Hay B, Jenny K, Johnston K, Lyons M, Belmont JW, Biesecker LG, Giurgea I, Black G (2009) BCOR analysis in patients with OFCD and Lenz microphthalmia syndromes, mental retardation with ocular anomalies, and cardiac laterality defects. Eur J Hum Genet 17(10):1325–1335

  15. Horn D, Chyrek M, Kleier S, Luttgen S, Bolz H, Hinkel GK, Korenke GC, Riess A, Schell-Apacik C, Tinschert S, Wieczorek D, Gillessen-Kaesbach G, Kutsche K (2005) Novel mutations in BCOR in three patients with oculo-facio-cardio-dental syndrome, but none in Lenz microphthalmia syndrome. Eur J Hum Genet 13(5):563–569

  16. Jiang YH, Fang P, Adesina AM, Furman P, Johnston JJ, Biesecker LG, Brown CW (2009) Molecular characterization of co-occurring Duchenne muscular dystrophy and X-linked oculo-facio-cardio-dental syndrome in a girl. Am J Med Genet A 149A(6):1249–1252

  17. Kantaputra PN (2014) BCOR mutations and unstoppable root growth: a commentary on oculofaciocardiodental syndrome: novel BCOR mutations and expression in dental cells. J Hum Genet 59(6):297–299

  18. Kondo Y, Saitsu H, Miyamoto T, Nishiyama K, Tsurusaki Y, Doi H, Miyake N, Ryoo NK, Kim JH, Yu YS, Matsumoto N (2012) A family of oculofaciocardiodental syndrome (OFCD) with a novel BCOR mutation and genomic rearrangements involving NHS. J Hum Genet 57(3):197–201

  19. Lee J, Lee BK, Gross JM (2013) Bcl6a function is required during optic cup formation to prevent p53-dependent apoptosis and colobomata. Hum Mol Genet 22(17):3568–3582

  20. Lek M, Karczewski KJ, Minikel EV, Samocha KE, Banks E, Fennell T et al (2016) Analysis of protein-coding genetic variation in 60,706 humans. Nature 536:285–291

  21. Lenz W (1955) Recessive, sex-limited microphthalmia with multiple abnormalities. Z Kinderheilkd 77(4):384–390

  22. Longshore J, Willard HF (2006) X Chromosome–Inactivation Patterns of 1,005 Phenotypically Unaffected Females. Am J Hum Genet 79:493–499

  23. Lozic B, Ljubkovic J, Panduric DG, Saltvig I, Kutsche K, Krzelj V, Zemunik T (2012) Oculo-facio-cardio-dental syndrome in three succeeding generations: genotypic data and phenotypic features. Braz J Med Biol Res 45(12):1315–1319

  24. Ma AS, Grigg JR, Ho G, Prokudin I, Farnsworth E, Holman K, Cheng A, Billson FA, Martin F, Fraser C, Mowat D, Smith J, Christodoulou J, Flaherty M, Bennetts B, Jamieson RV (2016) Sporadic and familial congenital cataracts: mutational spectrum and new diagnoses using next-generation sequencing. Hum Mutat 37(4):371–384

  25. Ng PC, Henikoff S (2003) SIFT: predicting amino acid changes that affect protein function. Nucleic Acids Res 31:3812–3814

  26. Ng D, Thakker N, Corcoran CM, Donnai D, Perveen R, Schneider A, Hadley DW, Tifft C, Zhang L, Wilkie AO, van der Smagt JJ, Gorlin RJ, Burgess SM, Bardwell VJ, Black GC, Biesecker LG (2004) Oculofaciocardiodental and Lenz microphthalmia syndromes result from distinct classes of mutations in BCOR. Nat Genet 36(4):411–416

  27. O’Byrne JJ, Laffan E, Murray DJ, Reardon W (2017) Oculo-facio-cardio-dental syndrome with craniosynostosis temporal hypertrichosis, and deafness. Am J Med Genet A 173(5):1374–1377

  28. Oberoi S, Winder AE, Johnston J, Vargervik K, Slavotinek AM (2005) Case reports of oculofaciocardiodental syndrome with unusual dental findings. Am J Med Genet A 136(3):275–277

  29. Pierron G, Tirode F, Lucchesi C, Reynaud S, Ballet S, Cohen-Gogo S, Perrin V, Coindre JM, Delattre O (2012) A new subtype of bone sarcoma defined by BCOR-CCNB3 gene fusion. Nat Genet 44(4):461–466

  30. Ragge NK, Lorenz B, Schneider A, Bushby K, de Sanctis L, de Sanctis U, Salt A, Collin JR, Vivian AJ, Free SL, Thompson P, Williamson KA, Sisodiya SM, van Heyningen V, Fitzpatrick DR (2005) SOX2 anophthalmia syndrome. Am J Med Genet A 135(1):1–7 discussion 8.

  31. Schwarz JM, Cooper DN, Schuelke M, Seelow D (2014) MutationTaster2: mutation prediction for the deep sequencing age. Nat Methods 11(4):361–362. https://doi.org/10.1038/nmeth.2890

  32. Scott AF, Mohr DW, Kasch LM, Barton JA, Pittiglio R, Ingersoll R, Craig B, Marosy BA, Doheny KF, Bromley WC, Roderick TH, Chassaing N, Calvas P, Prabhu SS, Jabs EW (2014) Identification of an HMGB3 frameshift mutation in a family with an X-linked colobomatous microphthalmia syndrome using whole-genome and X-exome sequencing. JAMA Ophthalmol 132(10):1215–1220

  33. Surapornsawasd T, Ogawa T, Moriyama K (2015) Identification of nuclear localization signals within the human BCOR protein. FEBS Lett 589(21):3313–3320

  34. Suzumori N, Kaname T, Muramatsu Y, Yanagi K, Kumagai K, Mizuno S, Naritomi K, Saitoh S, Sugiura-Ogasawara M (2013) Prenatal diagnosis of X-linked recessive Lenz microphthalmia syndrome. J Obstet Gynaecol Res 39(11):1545–1547

  35. Tanaka T, Nakajima-Takagi Y, Aoyama K, Tara S, Oshima M, Saraya A, Koide S, Si S, Manabe I, Sanada M, Nakayama M, Masuko M, Sone H, Koseki H, Iwama A (2017) Internal deletion of BCOR reveals a tumor suppressor function for BCOR in T lymphocyte malignancies. J Exp Med 214(10):2901–2913

  36. Tiberi L, Bonnefont J, van den Ameele J, Le Bon SD, Herpoel A, Bilheu A, Baron BW, Vanderhaeghen P (2014) A BCL6/BCOR/SIRT1 complex triggers neurogenesis and suppresses medulloblastoma by repressing Sonic Hedgehog signaling. Cancer Cell 26(6):797–812

  37. Traboulsi EI, Lenz W, Gonzales-Ramos M, Siegel J, Macrae WG, Maumenee IH (1988) The Lenz microphthalmia syndrome. Am J Ophthalmol 105(1):40–45

  38. Ueno-Yokohata H, Okita H, Nakasato K, Akimoto S, Hata J, Koshinaga T, Fukuzawa M, Kiyokawa N (2015) Consistent in-frame internal tandem duplications of BCOR characterize clear cell sarcoma of the kidney. Nat Genet 47(8):861–863

  39. Wildeman M, van Ophuizen E, den Dunnen JT, Taschner PE (2008) Improving sequence variant descriptions in mutation databases and literature using the Mutalyzer sequence variation nomenclature checker. Hum Mutat 29(1):6–13

  40. Wright CF, Fitzgerald TW, Jones WD, Clayton S, McRae JF, van Kogelenberg M, King DA, Ambridge K, Barrett DM, Bayzetinova T, Bevan AP, Bragin E, Chatzimichali EA, Gribble S, Jones P, Krishnappa N, Mason LE, Miller R, Morley KI, Parthiban V, Prigmore E, Rajan D, Sifrim A, Swaminathan GJ, Tivey AR, Middleton A, Parker M, Carter NP, Barrett JC, Hurles ME, FitzPatrick DR, HV Firth, DDD Study (2015). “Genetic diagnosis of developmental disorders in the DDD study: a scalable analysis of genome-wide research data.” Lancet 385(9975):1305–1314

  41. Zhou Y, Wojcik A, Sanders VR, Rahmani B, Kurup SP (2017). Ocular findings in a patient with oculofaciocardiodental (OFCD) syndrome and a novel BCOR pathogenic variant. Int Ophthalmol. https://doi.org/10.1007/s10792-017-0754-5

  42. Zhu X, Dai FR, Wang J, Zhang Y, Tan ZP, Zhang Y (2015) “Novel BCOR mutation in a boy with Lenz microphthalmia/oculo-facio-cardio-dental (OFCD) syndrome. Gene 571(1):142–144

Download references

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.

Author information

Correspondence to Nicola Ragge.

Ethics declarations

Conflict of interest

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

Additional information

See Nature 2017; 542;7642;433-438 for full list of collaborators.

Electronic supplementary material

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Ragge, N., Isidor, B., Bitoun, P. et al. Expanding the phenotype of the X-linked BCOR microphthalmia syndromes. Hum Genet 138, 1051–1069 (2019). https://doi.org/10.1007/s00439-018-1896-x

Download citation