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American Journal of Medical Genetics Part A 05/2010; 152A(5):1310-3. · 2.39 Impact Factor
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ABSTRACT: Mutations in the visual system homeobox 2 gene (VSX2, also known as CHX10), which encodes a retinal transcription factor from the paired homeobox family, have been implicated in recessive isolated microphthalmia. In this study, we use genome-wide single nucleotide polymorphism homozygosity mapping in unrelated small consanguineous pedigrees and a candidate gene approach to identify three further causative VSX2 mutations (two novel and one previously reported). All affected individuals with homozygous mutations had bilateral anophthalmia or severe microphthalmia with absent vision. In addition, we identified a novel inner retinal dystrophy in two carrier parents suggesting a semidominant effect for this particular VSX2 mutation. A further study of individuals with retinal degenerative conditions may reveal a causative role for heterozygous mutations in VSX2.
Human Genetics 04/2010; 128(1):51-60. · 5.07 Impact Factor
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Alexander Wyatt,
Preeti Bakrania,
David J Bunyan,
Robert J Osborne,
John A Crolla, Alison Salt,
Carmen Ayuso,
Ruth Newbury-Ecob,
Y Abou-Rayyah,
J Richard O Collin,
David Robinson,
Nicola Ragge
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ABSTRACT: Severe ocular malformations, including anophthalmia-microphthalmia (AM), are responsible for around 25% of severe visual impairment in childhood. Recurrent interstitial deletions of 14q22-23 are associated with AM and a wide range of extra-ocular phenotypes including brain anomalies. The homeobox gene OTX2 is located at 14q22.3 and has recently been identified as mutated in AM patients. Eight human OTX2 mutations have been reported in subjects with severe eye malformations, including AM, and variable developmental delay. We screened a novel AM cohort for mutations and deletions in OTX2, and identified four new mutations in six individuals and two cases of whole gene deletions. Our data suggest that OTX2 mutations and deletions account for 2-3% of AM cases.
Human Mutation 10/2008; 29(11):E278-83. · 5.69 Impact Factor
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Preeti Bakrania,
Maria Efthymiou,
Johannes C Klein, Alison Salt,
David J Bunyan,
Alex Wyatt,
Chris P Ponting,
Angela Martin,
Steven Williams,
Victoria Lindley, [......],
Marie Restori,
Anthony G Robson,
Magella M Neveu,
Graham E Holder,
J Richard O Collin,
David O Robinson,
Peter Farndon,
Heidi Johansen-Berg,
Dianne Gerrelli,
Nicola K Ragge
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ABSTRACT: Developmental ocular malformations, including anophthalmia-microphthalmia (AM), are heterogeneous disorders with frequent sporadic or non-Mendelian inheritance. Recurrent interstitial deletions of 14q22-q23 have been associated with AM, sometimes with poly/syndactyly and hypopituitarism. We identify two further cases of AM (one with associated pituitary anomalies) with a 14q22-q23 deletion. Using a positional candidate gene approach, we analyzed the BMP4 (Bone Morphogenetic Protein-4) gene and identified a frameshift mutation (c.226del2, p.S76fs104X) that segregated with AM, retinal dystrophy, myopia, brain anomalies, and polydactyly in a family and a nonconservative missense mutation (c.278A-->G, p.E93G) in a highly conserved base in another family. MR imaging and tractography in the c.226del2 proband revealed a primary brain developmental disorder affecting thalamostriatal and callosal pathways, also present in the affected grandmother. Using in situ hybridization in human embryos, we demonstrate expression of BMP4 in optic vesicle, developing retina and lens, pituitary region, and digits strongly supporting BMP4 as a causative gene for AM, pituitary, and poly/syndactyly. Because BMP4 interacts with HH signaling genes in animals, we evaluated gene expression in human embryos and demonstrate cotemporal and cospatial expression of BMP4 and HH signaling genes. We also identified four cases, some of whom had retinal dystrophy, with "low-penetrant" mutations in both BMP4 and HH signaling genes: SHH (Sonic Hedgehog) or PTCH1 (Patched). We propose that BMP4 is a major gene for AM and/or retinal dystrophy and brain anomalies and may be a candidate gene for myopia and poly/syndactyly. Our finding of low-penetrant variants in BMP4 and HH signaling partners is suggestive of an interaction between the two pathways in humans.
The American Journal of Human Genetics 02/2008; 82(2):304-19. · 10.60 Impact Factor
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Nicola K Ragge,
Alison G Brown,
Charlotte M Poloschek,
Birgit Lorenz,
R Alex Henderson,
Michael P Clarke,
Isabelle Russell-Eggitt,
Alistair Fielder,
Dianne Gerrelli,
Juan Pedro Martinez-Barbera, [......],
Jane Hurst,
J Richard O Collin, Alison Salt,
Simon T Cooper,
Pamela J Thompson,
Sanjay M Sisodiya,
Kathleen A Williamson,
David R Fitzpatrick,
Veronica van Heyningen,
Isabel M Hanson
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ABSTRACT: Major malformations of the human eye, including microphthalmia and anophthalmia, are examples of phenotypes that recur in families yet often show no clear Mendelian inheritance pattern. Defining loci by mapping is therefore rarely feasible. Using a candidate-gene approach, we have identified heterozygous coding-region changes in the homeobox gene OTX2 in eight families with ocular malformations. The expression pattern of OTX2 in human embryos is consistent with the eye phenotypes observed in the patients, which range from bilateral anophthalmia to retinal defects resembling Leber congenital amaurosis and pigmentary retinopathy. Magnetic resonance imaging scans revealed defects of the optic nerve, optic chiasm, and, in some cases, brain. In two families, the mutations appear to have occurred de novo in severely affected offspring, and, in two other families, the mutations have been inherited from a gonosomal mosaic parent. Data from these four families support a simple model in which OTX2 heterozygous loss-of-function mutations cause ocular malformations. Four additional families display complex inheritance patterns, suggesting that OTX2 mutations alone may not lead to consistent phenotypes. The high incidence of mosaicism and the reduced penetrance have implications for genetic counseling.
The American Journal of Human Genetics 07/2005; 76(6):1008-22. · 10.60 Impact Factor
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Nicola K Ragge,
Birgit Lorenz,
Adele Schneider,
Kate Bushby,
Luisa de Sanctis,
Ugo de Sanctis, Alison Salt,
J Richard O Collin,
Anthony J Vivian,
Samantha L Free,
Pamela Thompson,
Kathleen A Williamson,
Sanjay M Sisodiya,
Veronica van Heyningen,
David R Fitzpatrick
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ABSTRACT: Heterozygous, de novo, loss-of-function mutations in SOX2 have been shown to cause bilateral anophthalmia. Here we provide a detailed description of the clinical features associated with SOX2 mutations in the five individuals with reported mutations and four newly identified cases (including the first reported SOX2 missense mutation). The SOX2-associated ocular malformations are variable in type, but most often bilateral and severe. Of the nine patients, six had bilateral anophthalmia and two had anophthalmia with contralateral microphthalmia with sclerocornea. The remaining case had anophthalmia with contralateral microphthalmia, posterior cortical cataract and a dysplastic optic disc, and was the only patient to have measurable visual acuity. The relatively consistent extraocular phenotype observed includes: learning disability, seizures, brain malformation, specific motor abnormalities, male genital tract malformations, mild facial dysmorphism, and postnatal growth failure. Identifying SOX2 mutations from large cohorts of patients with structural eye defects has delineated a new, clinically-recognizable, multisystem disorder and has provided important insight into the developmental pathways critical for morphogenesis of the eye, brain, and male genital tract.
American Journal of Medical Genetics Part A 06/2005; 135(1):1-7; discussion 8. · 2.39 Impact Factor
