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Genetic analysis of ‘PAX6-Negative’ individuals with aniridia or gillespie syndrome

Genetic analysis of ‘PAX6-Negative’ individuals with aniridia or gillespie syndrome
Genetic analysis of ‘PAX6-Negative’ individuals with aniridia or gillespie syndrome
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.
1932-6203
1-15
Ansari, Morad
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Sandilands, Angela
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Morrison, Danny A.
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van Heyningen, Veronica
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FitzPatrick, David R.
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Ansari, Morad, Rainger, Jacqueline, Hanson, Isabel M., Williamson, Kathleen A., Sharkey, Freddie, Harewood, Louise, Sandilands, Angela, Clayton-Smith, Jill, Dollfus, Helene, Bitoun, Pierre, Meire, Francoise, Fantes, Judy, Franco, Brunella, Lorenz, Birgit, Taylor, David S., Stewart, Fiona, Willoughby, Colin E., McEntagart, Meriel, Khaw, Peng Tee, Clericuzio, Carol, Van Maldergem, Lionel, Williams, Denise, Newbury-Ecob, Ruth, Traboulsi, Elias I., Silva, Eduardo D., Madlom, Mukhlis M., Goudie, David R., Fleck, Brian W., Wieczorek, Dagmar, Kohlhase, Juergen, McTrusty, Alice D., Gardiner, Carol, Yale, Christopher, Moore, Anthony T., Russell-Eggitt, Isabelle, Islam, Lily, Lees, Melissa, Beales, Philip L., Tuft, Stephen J., Solano, Juan B., Splitt, Miranda, Hertz, Jens Michael, Prescott, Trine E., Shears, Deborah J., Nischal, Ken K., Doco-Fenzy, Martine, Prieur, Fabienne, Temple, I. Karen, Lachlan, Katherine L., Damante, Giuseppe, Morrison, Danny A., van Heyningen, Veronica and FitzPatrick, David R. (2016) Genetic analysis of ‘PAX6-Negative’ individuals with aniridia or gillespie syndrome. PLoS ONE, 11 (4), 1-15. (doi:10.1371/journal.pone.0153757). (PMID:27124303)

Record type: Article

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.

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Accepted/In Press date: 19 April 2016
e-pub ahead of print date: 28 April 2016
Published date: 28 April 2016
Organisations: Human Development & Health

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Local EPrints ID: 393678
URI: https://eprints.soton.ac.uk/id/eprint/393678
ISSN: 1932-6203
PURE UUID: f4c663af-103e-47a8-b2bb-5d7588bf7952

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Date deposited: 29 Apr 2016 13:51
Last modified: 09 Jan 2018 18:09

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Contributors

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

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