title: Genetic Analysis of 'PAX6-Negative' Individuals with Aniridia or Gillespie Syndrome.
abstract: We report molecular genetic analysis of 42 affected individuals referred with a diagnosis of aniridia who previously screened as negative for intragenic PAX6 mutations. Of these 42, the diagnoses were 31 individuals with aniridia and 11 individuals referred with a diagnosis of Gillespie syndrome (iris hypoplasia, ataxia and mild to moderate developmental delay). Array-based comparative genomic hybridization identified six whole gene deletions: four encompassing PAX6 and two encompassing FOXC1. Six deletions with plausible cis-regulatory effects were identified: five that were 3' (telomeric) to PAX6 and one within a gene desert 5' (telomeric) to PITX2. Sequence analysis of the FOXC1 and PITX2 coding regions identified two plausibly pathogenic de novo FOXC1 missense mutations (p.Pro79Thr and p.Leu101Pro). No intragenic mutations were detected in PITX2. FISH mapping in an individual with Gillespie-like syndrome with an apparently balanced X;11 reciprocal translocation revealed disruption of a gene at each breakpoint: ARHGAP6 on the X chromosome and PHF21A on chromosome 11. In the other individuals with Gillespie syndrome no mutations were identified in either of these genes, or in HCCS which lies close to the Xp breakpoint. Disruption of PHF21A has previously been implicated in the causation of intellectual disability (but not aniridia). Plausibly causative mutations were identified in 15 out of 42 individuals (12/32 aniridia; 3/11 Gillespie syndrome). Fourteen of these mutations presented in the known aniridia genes; PAX6, FOXC1 and PITX2. The large number of individuals in the cohort with no mutation identified suggests greater locus heterogeneity may exist in both isolated and syndromic aniridia than was previously appreciated.
authors.affiliation: MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom.
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authors.lastname: Ansari
authors.affiliation: MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom.
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authors.lastname: Rainger
authors.affiliation: MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom.
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authors.affiliation: MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom.
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authors.affiliation: MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom.
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authors.affiliation: MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom.
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authors.affiliation: MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom.
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authors.affiliation: Department of ophthalmopediatrics, Hôpital Universitaire des Enfants Reine Fabiola, Bruxelles, Belgium.
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authors.affiliation: MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom.
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authors.affiliation: Department of Eye and Vision Science, Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, United Kingdom.
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authors.initials: EI
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authors.affiliation: Department Ophthalmology, University Hospital of Coimbra, Coimbra, Portugal.
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authors.initials: ED
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authors.forename: Mukhlis M
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authors.affiliation: Human Genetics Unit, University of Dundee College of Medicine, Dentistry and Nursing, Ninewells Hospital, Dundee, United Kingdom.
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authors.initials: DR
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authors.affiliation: Department of Ophthalmology, Princess Alexandra Eye Pavilion, Chalmers Street, Edinburgh, United Kingdom.
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authors.initials: BW
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authors.affiliation: Institut für Humangenetik, Universitätsklinikum Essen, Universität Duisburg-Essen, Essen, Germany.|Institut für Humangenetik, Universitätsklinikum Düsseldorf, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany.
authors.forename: Dagmar
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authors.lastname: Wieczorek
authors.affiliation: Center for Human Genetics, Freiburg, Germany.
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authors.affiliation: Institute of Child Health, University College London, UK and Great Ormond Street Hospital for Children, London, United Kingdom.
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authors.affiliation: Institute of Child Health, University College London, UK and Great Ormond Street Hospital for Children, London, United Kingdom.
authors.forename: Lily
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authors.affiliation: Department of Clinical Genetics, Odense University Hospital, Odense C, Denmark.
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authors.affiliation: Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.
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authors.initials: TE
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authors.affiliation: Department of Clinical Genetics, Churchill Hospital, Oxford University Hospitals NHS Trust, Oxford, United Kingdom.
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authors.initials: KK
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authors.affiliation: CHU de Saint Etienne, Service de génétique médicale, Saint-Etienne, France.
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authors.affiliation: Academic Unit of Genetic Medicine, Division of Human Genetics, University of Southampton, Southampton, United Kingdom.
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authors.forename: Katherine L
authors.initials: KL
authors.lastname: Lachlan
authors.affiliation: Department of Medical and Biological Sciences, University of Udine, Udine, Italy.
authors.forename: Giuseppe
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authors.affiliation: St. Thomas' Hospital, Westminster Bridge Road, London, United Kingdom.
authors.forename: Danny A
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authors.affiliation: MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom.
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authors.affiliation: MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom.
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mesh_terms: D015783:Aniridia / Q000235:genetics*; D002524:Cerebellar Ataxia / Q000235:genetics*; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics; D041321:Chromosomes, Human, X / Q000235:genetics; D055028:Comparative Genomic Hybridization / Q000379:methods; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics; D020690:GTPase-Activating Proteins / Q000235:genetics; D005820:Genetic Testing / Q000379:methods; D006655:Histone Deacetylases / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics*; D008297:Male; D009154:Mutation / Q000235:genetics; D000071841:PAX6 Transcription Factor / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics; D000097577:Homeobox Protein PITX2
chemical_list: D051858:Forkhead Transcription Factors; D020690:GTPase-Activating Proteins; D006655:Histone Deacetylases; D018398:Homeodomain Proteins; D000071841:PAX6 Transcription Factor; D014157:Transcription Factors; D000097577:Homeobox Protein PITX2; C109971:ARHGAP6 protein, human; C112743:FOXC1 protein, human; C000605730:PAX6 protein, human; C492634:PHF21A protein, human