Dataset Information

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.

SUBMITTER: Ansari M

PROVIDER: S-EPMC4849793 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Genetic Analysis of 'PAX6-Negative' Individuals with Aniridia or Gillespie Syndrome.

Ansari Morad M Rainger Jacqueline J Hanson Isabel M IM Williamson Kathleen A KA Sharkey Freddie F Harewood Louise L Sandilands Angela A Clayton-Smith Jill J Dollfus Helene H Bitoun Pierre P Meire Francoise F Fantes Judy J Franco Brunella B Lorenz Birgit B Taylor David S DS Stewart Fiona F Willoughby Colin E CE McEntagart Meriel M Khaw Peng Tee PT Clericuzio Carol C Van Maldergem Lionel L Williams Denise D Newbury-Ecob Ruth R Traboulsi Elias I EI Silva Eduardo D ED Madlom Mukhlis M MM Goudie David R DR Fleck Brian W BW Wieczorek Dagmar D Kohlhase Juergen J McTrusty Alice D AD Gardiner Carol C Yale Christopher C Moore Anthony T AT Russell-Eggitt Isabelle I Islam Lily L Lees Melissa M Beales Philip L PL Tuft Stephen J SJ Solano Juan B JB Splitt Miranda M Hertz Jens Michael JM Prescott Trine E TE Shears Deborah J DJ Nischal Ken K KK Doco-Fenzy Martine M Prieur Fabienne F Temple I Karen IK Lachlan Katherine L KL Damante Giuseppe G Morrison Danny A DA van Heyningen Veronica V FitzPatrick David R DR

PloS one 20160428 4

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. S ...[more]

PMID: 27124303

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Project description:To report the clinical and genetic study of patients with autosomal dominant aniridia.We studied ten patients with aniridia from three families of Egyptian origin. All patients underwent full ophthalmologic, general and neurological examination, and blood drawing. Cerebral magnetic resonance imaging was performed in the index case of each family. Genomic DNA was prepared from venous leukocytes, and direct sequencing of all the exons and intron-exon junctions of the Paired Box gene 6 (PAX6) was performed after PCR amplification. Phenotype description, including ophthalmic and cerebral anomalies, mutation detection in PAX6 and phenotype-genotype correlation was acquired.Common features observed in the three families included absence of iris tissue, corneal pannus with different degrees of severity, and foveal hypoplasia with severely reduced visual acuity. In Families 2 and 3, additional findings, such as lens dislocation, lens opacities or polar cataract, and glaucoma, were observed. We identified two novel (c.170-174delTGGGC [p.L57fs17] and c.475delC [p.R159fs47]) and one known (c.718C>T [p.R240X]) PAX6 mutations in the affected members of the three families. Systemic and neurological examination was normal in all ten affected patients. Cerebral magnetic resonance imaging showed absence of the pineal gland in all three index patients. Severe hypoplasia of the brain anterior commissure was associated with the p.L57fs17 mutation, absence of the posterior commissure with p.R159fs47, and optic chiasma atrophy and almost complete agenesis of the corpus callosum with p.R240X.We identified two novel PAX6 mutations in families with severe aniridia. In addition to common phenotype of aniridia and despite normal neurological examination, absence of the pineal gland and interhemispheric brain anomalies were observed in all three index patients. The heterogeneity of PAX6 mutations and brain anomalies are highlighted. This report emphasizes the association between aniridia and brain anomalies with or without functional impact, such as neurodevelopment delay or auditory dysfunction.

Dataset Information

Genetic Analysis of 'PAX6-Negative' Individuals with Aniridia or Gillespie Syndrome.

Publications

Genetic Analysis of 'PAX6-Negative' Individuals with Aniridia or Gillespie Syndrome.

Similar Datasets

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