Genetic analysis of ‘PAX6-negative’ individuals with Aniridia or Gillespie Syndrome

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

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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.
Original languageEnglish
Article numbere0153757
JournalPLoS ONE
Volume11
Issue number4
Early online date28 Apr 2016
DOIs
Publication statusPublished - Apr 2016

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Aniridia
genetic techniques and protocols
Genes
mutation
Mutation
Chromosomes
comparative genomic hybridization
reciprocal translocation
Chromosomes, Human, Pair 11
missense mutation
Comparative Genomic Hybridization
genes
gene deletion
Gene Deletion
X Chromosome
gene targeting
Iris
X chromosome
Missense Mutation
Ataxia

Keywords

  • molecular genetics
  • PAX6 mutations
  • locus heterogeneity

Cite this

Ansari, M., Rainger, J., Hanson, I., Williamson, K., Sharkey, F., Harewood, L., ... FitzPatrick, D. (2016). Genetic analysis of ‘PAX6-negative’ individuals with Aniridia or Gillespie Syndrome. PLoS ONE , 11(4), [e0153757]. https://doi.org/10.1371/journal.pone.0153757
Ansari, Morad ; Rainger, Jacqueline ; Hanson, Isabel ; Williamson, Kathleen ; Sharkey, Freddie ; Harewood, Louise ; Sandilands, Angela ; Clayton-Smith, Jill ; Dollfus, Helene ; Bitoun, Pierre ; Meire, Francoise ; Fantes, Judy ; Franco, Brunella ; Lorenz, Birgit ; Taylor, David ; Stewart, Fiona ; Willoughby, Colin ; McEntagar, Meriel ; Khaw, Peng Tee ; Clericuzio, Carol ; Van Maldergem, Lionel ; Williams, Denise ; Newbury-Ecob, Ruth ; Traboulsi, Elias ; Silva, Eduardo ; Madlom, Mukhlis ; Goudie, David ; Fleck, Brian ; Wieczore, Dagmar ; Kohlhase, Juergen ; McTrusty, Alice ; Gardiner, Carol ; Yale, Christopher ; Moore, Anthony ; Russell-Eggitt, Isabelle ; Islam, Lily ; Lees, Melissa ; Beales, Philip ; Tuft, Stephen ; Solano, Juan ; Splitt, Miranda ; Hertz, Jens ; Prescott, Trine ; Shears, Deborah ; Nischal, Ken ; Doco-Fenzy, Martine ; Prieur, Fabienne ; Temple, Karen ; Lachlan, Katherine ; Damante, Giuseppe ; Morrison, Danny ; van Heyningen, Veronica ; FitzPatrick, David. / Genetic analysis of ‘PAX6-negative’ individuals with Aniridia or Gillespie Syndrome. In: PLoS ONE . 2016 ; Vol. 11, No. 4.
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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.",
keywords = "molecular genetics , PAX6 mutations, locus heterogeneity",
author = "Morad Ansari and Jacqueline Rainger and Isabel Hanson and Kathleen Williamson and Freddie Sharkey and Louise Harewood and Angela Sandilands and Jill Clayton-Smith and Helene Dollfus and Pierre Bitoun and Francoise Meire and Judy Fantes and Brunella Franco and Birgit Lorenz and David Taylor and Fiona Stewart and Colin Willoughby and Meriel McEntagar and Khaw, {Peng Tee} and Carol Clericuzio and {Van Maldergem}, Lionel and Denise Williams and Ruth Newbury-Ecob and Elias Traboulsi and Eduardo Silva and Mukhlis Madlom and David Goudie and Brian Fleck and Dagmar Wieczore and Juergen Kohlhase and Alice McTrusty and Carol Gardiner and Christopher Yale and Anthony Moore and Isabelle Russell-Eggitt and Lily Islam and Melissa Lees and Philip Beales and Stephen Tuft and Juan Solano and Miranda Splitt and Jens Hertz and Trine Prescott and Deborah Shears and Ken Nischal and Martine Doco-Fenzy and Fabienne Prieur and Karen Temple and Katherine Lachlan and Giuseppe Damante and Danny Morrison and {van Heyningen}, Veronica and David FitzPatrick",
note = "Article found via WoS Accepted: 4-4-16 Online pub: 28-4-16 Gold OA MRC funded, compliant Data Availability Statement: All relevant data are within the paper and its Supporting Information files. ArrayCGH data have been deposited in the Database of Genomic Variants (accession ID estd228) and the DECIPHER database (decipher.sanger.ac.uk).",
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Ansari, M, Rainger, J, Hanson, I, Williamson, K, Sharkey, F, Harewood, L, Sandilands, A, Clayton-Smith, J, Dollfus, H, Bitoun, P, Meire, F, Fantes, J, Franco, B, Lorenz, B, Taylor, D, Stewart, F, Willoughby, C, McEntagar, M, Khaw, PT, Clericuzio, C, Van Maldergem, L, Williams, D, Newbury-Ecob, R, Traboulsi, E, Silva, E, Madlom, M, Goudie, D, Fleck, B, Wieczore, D, Kohlhase, J, McTrusty, A, Gardiner, C, Yale, C, Moore, A, Russell-Eggitt, I, Islam, L, Lees, M, Beales, P, Tuft, S, Solano, J, Splitt, M, Hertz, J, Prescott, T, Shears, D, Nischal, K, Doco-Fenzy, M, Prieur, F, Temple, K, Lachlan, K, Damante, G, Morrison, D, van Heyningen, V & FitzPatrick, D 2016, 'Genetic analysis of ‘PAX6-negative’ individuals with Aniridia or Gillespie Syndrome', PLoS ONE , vol. 11, no. 4, e0153757. https://doi.org/10.1371/journal.pone.0153757

Genetic analysis of ‘PAX6-negative’ individuals with Aniridia or Gillespie Syndrome. / Ansari, Morad; Rainger, Jacqueline; Hanson, Isabel; Williamson, Kathleen; Sharkey, Freddie; Harewood, Louise; Sandilands, Angela; Clayton-Smith, Jill; Dollfus, Helene; Bitoun, Pierre ; Meire, Francoise; Fantes, Judy ; Franco, Brunella; Lorenz, Birgit ; Taylor, David ; Stewart, Fiona ; Willoughby, Colin; McEntagar, Meriel; Khaw, Peng Tee; Clericuzio, Carol; Van Maldergem, Lionel; Williams, Denise; Newbury-Ecob, Ruth; Traboulsi, Elias; Silva, Eduardo; Madlom, Mukhlis; Goudie, David; Fleck, Brian ; Wieczore, Dagmar; Kohlhase, Juergen; McTrusty, Alice; Gardiner, Carol ; Yale, Christopher; Moore, Anthony ; Russell-Eggitt, Isabelle; Islam, Lily ; Lees, Melissa; Beales, Philip; Tuft, Stephen; Solano, Juan ; Splitt, Miranda ; Hertz, Jens; Prescott, Trine; Shears, Deborah; Nischal, Ken; Doco-Fenzy, Martine; Prieur, Fabienne; Temple, Karen; Lachlan, Katherine; Damante, Giuseppe; Morrison, Danny; van Heyningen, Veronica ; FitzPatrick, David.

In: PLoS ONE , Vol. 11, No. 4, e0153757, 04.2016.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Genetic analysis of ‘PAX6-negative’ individuals with Aniridia or Gillespie Syndrome

AU - Ansari, Morad

AU - Rainger, Jacqueline

AU - Hanson, Isabel

AU - Williamson, Kathleen

AU - Sharkey, Freddie

AU - Harewood, Louise

AU - Sandilands, Angela

AU - Clayton-Smith, Jill

AU - Dollfus, Helene

AU - Bitoun, Pierre

AU - Meire, Francoise

AU - Fantes, Judy

AU - Franco, Brunella

AU - Lorenz, Birgit

AU - Taylor, David

AU - Stewart, Fiona

AU - Willoughby, Colin

AU - McEntagar, Meriel

AU - Khaw, Peng Tee

AU - Clericuzio, Carol

AU - Van Maldergem, Lionel

AU - Williams, Denise

AU - Newbury-Ecob, Ruth

AU - Traboulsi, Elias

AU - Silva, Eduardo

AU - Madlom, Mukhlis

AU - Goudie, David

AU - Fleck, Brian

AU - Wieczore, Dagmar

AU - Kohlhase, Juergen

AU - McTrusty, Alice

AU - Gardiner, Carol

AU - Yale, Christopher

AU - Moore, Anthony

AU - Russell-Eggitt, Isabelle

AU - Islam, Lily

AU - Lees, Melissa

AU - Beales, Philip

AU - Tuft, Stephen

AU - Solano, Juan

AU - Splitt, Miranda

AU - Hertz, Jens

AU - Prescott, Trine

AU - Shears, Deborah

AU - Nischal, Ken

AU - Doco-Fenzy, Martine

AU - Prieur, Fabienne

AU - Temple, Karen

AU - Lachlan, Katherine

AU - Damante, Giuseppe

AU - Morrison, Danny

AU - van Heyningen, Veronica

AU - FitzPatrick, David

N1 - Article found via WoS Accepted: 4-4-16 Online pub: 28-4-16 Gold OA MRC funded, compliant Data Availability Statement: All relevant data are within the paper and its Supporting Information files. ArrayCGH data have been deposited in the Database of Genomic Variants (accession ID estd228) and the DECIPHER database (decipher.sanger.ac.uk).

PY - 2016/4

Y1 - 2016/4

N2 - 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.

AB - 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.

KW - molecular genetics

KW - PAX6 mutations

KW - locus heterogeneity

U2 - 10.1371/journal.pone.0153757

DO - 10.1371/journal.pone.0153757

M3 - Article

VL - 11

JO - PLoS ONE

JF - PLoS ONE

SN - 1932-6203

IS - 4

M1 - e0153757

ER -

Ansari M, Rainger J, Hanson I, Williamson K, Sharkey F, Harewood L et al. Genetic analysis of ‘PAX6-negative’ individuals with Aniridia or Gillespie Syndrome. PLoS ONE . 2016 Apr;11(4). e0153757. https://doi.org/10.1371/journal.pone.0153757