Abstract
Oculofaciocardiodental (OFCD) and Lenz microphthalmia syndromes form part of a spectrum of X-linked microphthalmia disorders characterized by ocular, dental, cardiac and skeletal anomalies and mental retardation. The two syndromes are allelic, caused by mutations in the BCL-6 corepressor gene (BCOR). To extend the series of phenotypes associated with pathogenic mutations in BCOR, we sequenced the BCOR gene in patients with (1) OFCD syndrome, (2) putative X-linked (‘Lenz’) microphthalmia syndrome, (3) isolated ocular defects and (4) laterality phenotypes. We present a new cohort of females with OFCD syndrome and null mutations in BCOR, supporting the hypothesis that BCOR is the sole molecular cause of this syndrome. We identify for the first time mosaic BCOR mutations in two females with OFCD syndrome and one apparently asymptomatic female. We present a female diagnosed with isolated ocular defects and identify minor features of OFCD syndrome, suggesting that OFCD syndrome may be mild and underdiagnosed. We have sequenced a cohort of males diagnosed with putative X-linked microphthalmia and found a mutation, p.P85L, in a single case, suggesting that BCOR mutations are not a major cause of X-linked microphthalmia in males. The absence of BCOR mutations in a panel of patients with non-specific laterality defects suggests that mutations in BCOR are not a major cause of isolated heart and laterality defects. Phenotypic analysis of OFCD and Lenz microphthalmia syndromes shows that in addition to the standard diagnostic criteria of congenital cataract, microphthalmia and radiculomegaly, patients should be examined for skeletal defects, particularly radioulnar synostosis, and cardiac/laterality defects.
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References
Forrester S, Kovach MJ, Reynolds NM, Urban R, Kimonis V : Manifestations in four males with and an obligate carrier of the Lenz microphthalmia syndrome. Am J Med Genet 2001; 98: 92–100.
Ng D, Hadley DW, Tifft CJ, Biesecker LG : Genetic heterogeneity of syndromic X-linked recessive microphthalmia-anophthalmia: is Lenz microphthalmia a single disorder? Am J Med Genet 2002; 110: 308–314.
Ng D, Thakker N, Corcoran CM et al: Oculofaciocardiodental and Lenz microphthalmia syndromes result from distinct classes of mutations in BCOR. Nat Genet 2004; 36: 411–416.
Lenz W : Recessive, sex-limited microphthalmia with multiple abnormalities. Z Kinderheilkd 1955; 77: 384–390.
Hayward JR : Cuspid gigantism. Oral Surg Oral Med Oral Pathol 1980; 49: 500–501.
Marashi AH, Gorlin RJ : Radiculomegaly of canines and congenital cataracts – a syndrome? Oral Surg Oral Med Oral Pathol 1990; 70: 802–803.
Marashi AH, Gorlin RJ : Radiculomegaly of canine teeth and congenital cataracts: confirmation of a syndrome. Am J Med Genet 1992; 42: 143.
Wilkie AO, Taylor D, Scambler PJ, Baraitser M : Congenital cataract, microphthalmia and septal heart defect in two generations: a new syndrome? Clin Dysmorphol 1993; 2: 114–119.
Aalfs CM, Oosterwijk JC, van Schooneveld MJ, Begeman CJ, Wabeke KB, Hennekam RC : Cataracts, radiculomegaly, septal heart defects and hearing loss in two unrelated adult females with normal intelligence and similar facial appearance: confirmation of a syndrome? Clin Dysmorphol 1996; 5: 93–103.
Gorlin RJ, Marashi AH, Obwegeser HL : Oculo-facio-cardio-dental (OFCD) syndrome. Am J Med Genet 1996; 63: 290–292.
Hilton EN, Manson FD, Urquhart JE et al: Left-sided embryonic expression of the BCL-6 corepressor, BCOR, is required for vertebrate laterality determination. Hum Mol Genet 2007; 16: 1773–1782.
Lin AE, Ticho BS, Houde K, Westgate MN, Holmes LB : Heterotaxy: Associated conditions and hospital-based prevalence in newborns. Genet Med 2000; 2: 157–172.
Niel F, Martin J, Dastot-Le-Moal F et al: Rapid detection of CFTR gene rearrangements impacts on genetic counselling in cystic fibrosis. J Med Genet 2004; 41: e118.
Yau SC, Bobrow M, Mathew CG, Abbs SJ : Accurate diagnosis of carriers of deletions and duplications in Duchenne/Becker muscular dystrophy by fluorescent dosage analysis. J Med Genet 1996; 33: 550–558.
Pinkel D, Straume T, Gray JW : Cytogenetic analysis using quantitative, high-sensitivity fluorescence hybridisation. Proc Natl Acad Sci USA 1986; 83: 2934–2938.
Opitz C, Horn D, Lehmann R, Dimitrova T, Fasmers-Henke K : Oculo-facio-cardio-dental (OFCD) syndrome. J Orofac Orthop 1998; 59: 178–185.
Schulze BR, Horn D, Kobelt A, Tariverdian G, Stellzig A : Rare dental abnormalities seen in oculo-facio-cardio-dental (OFCD) syndrome: three new cases and review of nine patients. Am J Med Genet 1999; 82: 429–435.
Barthelemy I, Samuels L, Kahn DM, Schendel SA : Oculo-facio-cardio-dental syndrome: two new cases. J Oral Maxillofac Surg 2001; 59: 921–925.
Kawamoto T, Motohashi N, Ohyama K : A case of oculo-facio-cardio-dental syndrome with integrated orthodontic-prosthodontic treatment. Cleft Palate Craniofac J 2004; 41: 84–94.
Hedera P, Gorski JL : Oculo-facio-cardio-dental syndrome: skewed X chromosome inactivation in mother and daughter suggest X-linked dominant Inheritance. Am J Med Genet 2003; 123: 261–266.
Tsukawaki H, Tsuji M, Kawamoto T, Ohyama K : Three cases of oculo-facio-cardio-dental (OFCD) syndrome. Cleft Palate Craniofac J 2005; 42: 467–476.
Horn D, Chyrek M, Kleier S et al: Novel mutations in BCOR in three patients with oculo-facio-cardio-dental syndrome, but none in Lenz microphthalmia syndrome. Eur J Hum Genet 2005; 13: 563–569.
Oberoi S, Winder AE, Johnston J, Vargervik K, Slavotinek AM : Case reports of oculofaciocardiodental syndrome with unusual dental findings. Am J Med Genet 2005; 136: 275–277.
Turkkahraman H, Sarioglu M : Oculo-facio-cardio-dental syndrome: report of a rare case. Angle Orthod 2006; 76: 184–186.
McGovern E, Al-Mudaffer M, McMahon C, Brosnahan D, Fleming P, Reardon W : Oculo-facio-cardio-dental syndrome in a mother and daughter. Int J Oral Maxillofac Surg 2006; 35: 1060–1062.
Ware SM, Peng JL, Zhu LR et al: Identification and functional analysis of ZIC3 mutations in heterotaxy and related congenital heart defects. Am J Hum Genet 2004; 74: 93–105.
Hoefnagel D, Keenan ME, Allen FH : Heredofamilial bilateral anophthalmia. Arch Ophthalmol 1963; 69: 760–764.
Goldberg MF, McKusick VA : X-linked colobomatous microphthalmos and other congenital anomalies: a disorder resembling Lenz's dysmorphogenetic syndrome. Am J Ophthalmol 1971; 71: 1128–1133.
Ogunye OO, Murray RF, Osgood T : Linkage studies in Lenz microphthalmia. Hum Hered 1975; 25: 493–500.
Baraitser M, Winter RM, Taylor DS : Lenz microphthalmia – a case report. Clin Genet 1982; 22: 99–101.
Glanz A, Forse A, Polomenom RC, Cole DE : Lenz microphthalmia: a malformation syndrome with variable expression of multiple congenital anomalies. Can J Ophthalmol 1983; 18: 41–44.
Pallotta R, Dallapiccola B : A syndrome with true anophthalmia, hand-foot defects and mental retardation. Ophthalmic Paediatr Genet 1983; 4: 19–23.
Brunquell PJ, Papale JH, Horton JC et al: Sex-linked hereditary bilateral anophthalmos: pathologic and radiologic correlation. Arch Ophthalmol 1984; 102: 108–113.
Traboulsi EI, Lenz W, Gonzales-Ramos M, Siegel J, Macrae WG, Maumenee IH : The Lenz microphthalmia syndrome. Am J Ophthalmol 1988; 105: 40–45.
Graham CA, Redmond RM, Nevin NC : X-linked clinical anophthalmos: localization of the gene to Xq27-Xq28. Ophthalmic Paediatr Genet 1991; 12: 43–48.
Antoniades K, Tzouvelekis G, Doudou A, Nanas C : A sporadic case of Lenz microphthalmia syndrome. Ann Ophthalmol 1993; 25: 342–345.
Ozkinay FF, Ozkinay C, Yuksel H, Yenigun A, Sapmaz G, Aksu O : A case of Lenz microphthalmia syndrome. J Med Genet 1997; 34: 604–606.
Temtamy SA, Ismail SI, Meguid NA : Lenz microphthalmia syndrome: three additional cases with rare associated anomalies. Genet Couns 2000; 11: 147–152.
Lehman DM, Sponsel WE, Stratton RF et al: Genetic mapping of a novel X-linked recessive colobomatous microphthalmia. Am J Med Genet 2001; 101: 114–119.
Ersin NK, Tugsel Z, Gokce B, Ozpinar B, Eronat N : Lenz microphthalmia syndrome with dental anomalies: a case report. J Dent Child 2003; 70: 262–265.
Gupta A, Srinivasan R, Panadian DG, Babu KR : Lenz microphthalmia syndrome in an Indian patient. Indian J Ophthalmol 2007; 55: 462–463.
Martinez-Garay I, Tomas M, Oltra S et al: A two base pair deletion in the PQBP1 gene is associated with microphthalmia, microcephaly and mental retardation. Eur J Hum Genet 2006; 15: 29–34.
Acknowledgements
EH is funded by the Wellcome Trust (UK) and BDF Newlife (UK). SW is funded by la Fondation pour la Recherche Médicale (France). This research was supported in part by the Intramural Research program of the National Human Genome Research Institute, NIH (US). We thank Patricia Conteville and Nathalie Collot for technical support.
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Hilton, E., Johnston, J., Whalen, S. et al. BCOR analysis in patients with OFCD and Lenz microphthalmia syndromes, mental retardation with ocular anomalies, and cardiac laterality defects. Eur J Hum Genet 17, 1325–1335 (2009). https://doi.org/10.1038/ejhg.2009.52
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DOI: https://doi.org/10.1038/ejhg.2009.52
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