title: Improving molecular diagnosis of aniridia and WAGR syndrome using customized targeted array-based CGH.
abstract: Chromosomal deletions at 11p13 are a frequent cause of congenital Aniridia, a rare pan-ocular genetic disease, and of WAGR syndrome, accounting up to 30% of cases. First-tier genetic testing for newborn with aniridia, to detect 11p13 rearrangements, includes Multiplex Ligation-dependent Probe Amplification (MLPA) and karyotyping. However, neither of these approaches allow obtaining a complete picture of the high complexity of chromosomal deletions and breakpoints in aniridia. Here, we report the development and validation of a customized targeted array-based comparative genomic hybridization, so called WAGR-array, for comprehensive high-resolution analysis of CNV in the WAGR locus. Our approach increased the detection rate in a Spanish cohort of 38 patients with aniridia, WAGR syndrome and other related ocular malformations, allowing to characterize four undiagnosed aniridia cases, and to confirm MLPA findings in four additional patients. For all patients, breakpoints were accurately established and a contiguous deletion syndrome, involving a large number of genes, was identified in three patients. Moreover, we identified novel microdeletions affecting 3' PAX6 regulatory regions in three families with isolated aniridia. This tool represents a good strategy for the genetic diagnosis of aniridia and associated syndromes, allowing for a more accurate CNVs detection, as well as a better delineation of breakpoints. Our results underline the clinical importance of performing exhaustive and accurate analysis of chromosomal rearrangements for patients with aniridia, especially newborns and those without defects in PAX6 after diagnostic screening.
authors.affiliation: Department of Genetics & Genomics, Instituto de Investigación Sanitaria-Fundación Jiménez Díaz University Hospital- Universidad Autónoma de Madrid (IIS-FJD, UAM), Madrid, Spain.|Centre for Biomedical Network Research on Rare Diseases (CIBERER), ISCIII, Madrid, Spain.
authors.forename: Fiona
authors.initials: F
authors.lastname: Blanco-Kelly
authors.affiliation: Centre for Biomedical Network Research on Rare Diseases (CIBERER), ISCIII, Madrid, Spain.|Institute of Medical & Molecular Genetics (INGEMM), Hospital Universitario La Paz, Universidad Autónoma de Madrid, IdiPAZ, Madrid, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Palomares
authors.affiliation: Centre for Biomedical Network Research on Rare Diseases (CIBERER), ISCIII, Madrid, Spain.|Institute of Medical & Molecular Genetics (INGEMM), Hospital Universitario La Paz, Universidad Autónoma de Madrid, IdiPAZ, Madrid, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Vallespín
authors.affiliation: Department of Genetics & Genomics, Instituto de Investigación Sanitaria-Fundación Jiménez Díaz University Hospital- Universidad Autónoma de Madrid (IIS-FJD, UAM), Madrid, Spain.|Centre for Biomedical Network Research on Rare Diseases (CIBERER), ISCIII, Madrid, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Villaverde
authors.affiliation: Centre for Biomedical Network Research on Rare Diseases (CIBERER), ISCIII, Madrid, Spain.|Institute of Medical & Molecular Genetics (INGEMM), Hospital Universitario La Paz, Universidad Autónoma de Madrid, IdiPAZ, Madrid, Spain.
authors.forename: Rubén
authors.initials: R
authors.lastname: Martín-Arenas
authors.affiliation: Department of Genetics & Genomics, Instituto de Investigación Sanitaria-Fundación Jiménez Díaz University Hospital- Universidad Autónoma de Madrid (IIS-FJD, UAM), Madrid, Spain.|Centre for Biomedical Network Research on Rare Diseases (CIBERER), ISCIII, Madrid, Spain.
authors.forename: Camilo
authors.initials: C
authors.lastname: Vélez-Monsalve
authors.affiliation: Department of Genetics & Genomics, Instituto de Investigación Sanitaria-Fundación Jiménez Díaz University Hospital- Universidad Autónoma de Madrid (IIS-FJD, UAM), Madrid, Spain.|Centre for Biomedical Network Research on Rare Diseases (CIBERER), ISCIII, Madrid, Spain.
authors.forename: Isabel
authors.initials: I
authors.lastname: Lorda-Sánchez
authors.affiliation: Centre for Biomedical Network Research on Rare Diseases (CIBERER), ISCIII, Madrid, Spain.|Institute of Medical & Molecular Genetics (INGEMM), Hospital Universitario La Paz, Universidad Autónoma de Madrid, IdiPAZ, Madrid, Spain.
authors.forename: Julián
authors.initials: J
authors.lastname: Nevado
authors.affiliation: Department of Genetics & Genomics, Instituto de Investigación Sanitaria-Fundación Jiménez Díaz University Hospital- Universidad Autónoma de Madrid (IIS-FJD, UAM), Madrid, Spain.|Centre for Biomedical Network Research on Rare Diseases (CIBERER), ISCIII, Madrid, Spain.
authors.forename: María José
authors.initials: MJ
authors.lastname: Trujillo-Tiebas
authors.affiliation: Centre for Biomedical Network Research on Rare Diseases (CIBERER), ISCIII, Madrid, Spain.|Institute of Medical & Molecular Genetics (INGEMM), Hospital Universitario La Paz, Universidad Autónoma de Madrid, IdiPAZ, Madrid, Spain.
authors.forename: Pablo
authors.initials: P
authors.lastname: Lapunzina
authors.affiliation: Department of Genetics & Genomics, Instituto de Investigación Sanitaria-Fundación Jiménez Díaz University Hospital- Universidad Autónoma de Madrid (IIS-FJD, UAM), Madrid, Spain.|Centre for Biomedical Network Research on Rare Diseases (CIBERER), ISCIII, Madrid, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Ayuso
authors.affiliation: Department of Genetics & Genomics, Instituto de Investigación Sanitaria-Fundación Jiménez Díaz University Hospital- Universidad Autónoma de Madrid (IIS-FJD, UAM), Madrid, Spain.|Centre for Biomedical Network Research on Rare Diseases (CIBERER), ISCIII, Madrid, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Corton
mesh_terms: D015783:Aniridia / Q000235:genetics*; D002872:Chromosome Deletion; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics*; D055028:Comparative Genomic Hybridization / Q000379:methods*; D005260:Female; D006801:Humans; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D000071841:PAX6 Transcription Factor / Q000235:genetics; D017624:WAGR Syndrome / Q000235:genetics*
chemical_list: D000071841:PAX6 Transcription Factor; C000605730:PAX6 protein, human