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Genetic analysis of 'PAX6-negative' individuals with aniridia or Gillespie Syndrome

Ansari, M and Rainger, J and Hanson, IM and Williamson, KA and Sharkey, F and Harewood, L and Sandilands, A and Clayton-Smith, J and Dollfus, H and Bitoun, P and Meire, F and Fantes, J and Franco, B and Lorenz, B and Taylor, DS and Stewart, F and Willoughby, CE and McEntagart, M and Khaw, PT and Clericuzio, C and Van Maldergem, L and Williams, D and Newbury-Ecob, R and Traboulsi, EI and Silva, ED and Madlom, MM and Goudie, DR and Fleck, BW and Wieczorek, D and Kohlhase, J and McTrusty, AD and Gardiner, C and Yale, C and Moore, AT and Russell-Eggitt, I and Islam, L and Lees, M and Beales, PL and Tuft, SJ and Solano, JB and Splitt, M and Hertz, JM and Prescott, TE and Shears, DJ and Nischal, KK and Doco-Fenzy, M and Prieur, F and Temple, IK and Lachlan, KL and Damante, G and Morrison, DA and Van Heyningen, V and Fitzpatrick, DR (2016) Genetic analysis of 'PAX6-negative' individuals with aniridia or Gillespie Syndrome. PLoS ONE, 11 (4).

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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.


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Item Type: Article
Status: Published
CreatorsEmailPitt UsernameORCID
Ansari, M
Rainger, J
Hanson, IM
Williamson, KA
Sharkey, F
Harewood, L
Sandilands, A
Clayton-Smith, J
Dollfus, H
Bitoun, P
Meire, F
Fantes, J
Franco, B
Lorenz, B
Taylor, DS
Stewart, F
Willoughby, CE
McEntagart, M
Khaw, PT
Clericuzio, C
Van Maldergem, L
Williams, D
Newbury-Ecob, R
Traboulsi, EI
Silva, ED
Madlom, MM
Goudie, DR
Fleck, BW
Wieczorek, D
Kohlhase, J
McTrusty, AD
Gardiner, C
Yale, C
Moore, AT
Russell-Eggitt, I
Islam, L
Lees, M
Beales, PL
Tuft, SJ
Solano, JB
Splitt, M
Hertz, JM
Prescott, TE
Shears, DJ
Nischal, KKkan72@pitt.eduKAN72
Doco-Fenzy, M
Prieur, F
Temple, IK
Lachlan, KL
Damante, G
Morrison, DA
Van Heyningen, V
Fitzpatrick, DR
ContributionContributors NameEmailPitt UsernameORCID
Date: 1 April 2016
Date Type: Publication
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Journal or Publication Title: PLoS ONE
Volume: 11
Number: 4
DOI or Unique Handle: 10.1371/journal.pone.0153757
Institution: University of Pittsburgh
Refereed: Yes
Date Deposited: 31 Aug 2016 17:32
Last Modified: 30 Mar 2021 13:56


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