Genetic Analysis of ‘PAX6-Negative’ Individuals with Aniridia or Gillespie Syndrome

Michael G Anderson, Morad Ansari, Jacqueline Rainger, Isabel M. Hanson, Kathleen A. Williamson, Freddie Sharkey, Louise Harewood, Angela Sandilands, Jill Clayton-Smith, Helene Dollfus, Pierre Bitoun, Francoise Meire, Judy Fantes, Brunella Franco, Birgit Lorenz, David S. Taylor, Fiona Stewart, Colin Willoughby, Meriel McEntagart, Peng Tee Khaw & 34 others Carol Clericuzio, Lionel Van Maldergem, Denise Williams, Ruth Newbury-Ecob, Elias I. Traboulsi, Eduardo D. Silva, Mukhlis M. Madlom, David R. Goudie, Brian W. Fleck, Dagmar Wieczorek, Juergen Kohlhase, Alice D. McTrusty, Carol Gardiner, Christopher Yale, Anthony T. Moore, Isabelle Russell-Eggitt, Lily Islam, Melissa Lees, Philip L. Beales, Stephen J. Tuft, Juan B. Solano, Miranda Splitt, Jens Michael Hertz, Trine E. Prescott, Deborah J. Shears, Ken K. Nischal, Martine Doco-Fenzy, Fabienne Prieur, I. Karen Temple, Katherine L. Lachlan, Giuseppe Damante, Danny A. Morrison, Veronica van Heyningen, David R. FitzPatrick

    Research output: Contribution to journalArticle

    21 Citations (Scopus)

    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.
    LanguageEnglish
    Pagese0153757
    JournalPLoS ONE
    Volume11
    Issue number4
    DOIs
    Publication statusAccepted/In press - 4 Apr 2016

    Fingerprint

    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

    • PAX6
    • aniridia
    • mutation
    • anterior segment dysgenesis

    Cite this

    Anderson, M. G., Ansari, M., Rainger, J., Hanson, I. M., Williamson, K. A., Sharkey, F., ... FitzPatrick, D. R. (Accepted/In press). Genetic Analysis of ‘PAX6-Negative’ Individuals with Aniridia or Gillespie Syndrome. PLoS ONE, 11(4), e0153757. https://doi.org/10.1371/journal.pone.0153757
    Anderson, Michael G ; 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 ; 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 ; FitzPatrick, David R. / Genetic Analysis of ‘PAX6-Negative’ Individuals with Aniridia or Gillespie Syndrome. In: PLoS ONE. 2016 ; Vol. 11, No. 4. pp. e0153757.
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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.",
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    author = "Anderson, {Michael G} and Morad Ansari and Jacqueline Rainger and Hanson, {Isabel M.} and Williamson, {Kathleen A.} 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 Taylor, {David S.} and Fiona Stewart and Colin Willoughby and Meriel McEntagart and Khaw, {Peng Tee} and Carol Clericuzio and {Van Maldergem}, Lionel and Denise Williams and Ruth Newbury-Ecob and Traboulsi, {Elias I.} and Silva, {Eduardo D.} and Madlom, {Mukhlis M.} and Goudie, {David R.} and Fleck, {Brian W.} and Dagmar Wieczorek and Juergen Kohlhase and McTrusty, {Alice D.} and Carol Gardiner and Christopher Yale and Moore, {Anthony T.} and Isabelle Russell-Eggitt and Lily Islam and Melissa Lees and Beales, {Philip L.} and Tuft, {Stephen J.} and Solano, {Juan B.} and Miranda Splitt and Hertz, {Jens Michael} and Prescott, {Trine E.} and Shears, {Deborah J.} and Nischal, {Ken K.} and Martine Doco-Fenzy and Fabienne Prieur and Temple, {I. Karen} and Lachlan, {Katherine L.} and Giuseppe Damante and Morrison, {Danny A.} and {van Heyningen}, Veronica and FitzPatrick, {David R.}",
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    Anderson, MG, 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, C, 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, KK, Doco-Fenzy, M, Prieur, F, Temple, IK, Lachlan, KL, Damante, G, Morrison, DA, van Heyningen, V & FitzPatrick, DR 2016, 'Genetic Analysis of ‘PAX6-Negative’ Individuals with Aniridia or Gillespie Syndrome', PLoS ONE, vol. 11, no. 4, pp. e0153757. https://doi.org/10.1371/journal.pone.0153757

    Genetic Analysis of ‘PAX6-Negative’ Individuals with Aniridia or Gillespie Syndrome. / Anderson, Michael G; 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; 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; FitzPatrick, David R.

    In: PLoS ONE, Vol. 11, No. 4, 04.04.2016, p. e0153757.

    Research output: Contribution to journalArticle

    TY - JOUR

    T1 - Genetic Analysis of ‘PAX6-Negative’ Individuals with Aniridia or Gillespie Syndrome

    AU - Anderson, Michael G

    AU - Ansari, Morad

    AU - Rainger, Jacqueline

    AU - Hanson, Isabel M.

    AU - Williamson, Kathleen A.

    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 S.

    AU - Stewart, Fiona

    AU - Willoughby, Colin

    AU - McEntagart, Meriel

    AU - Khaw, Peng Tee

    AU - Clericuzio, Carol

    AU - Van Maldergem, Lionel

    AU - Williams, Denise

    AU - Newbury-Ecob, Ruth

    AU - Traboulsi, Elias I.

    AU - Silva, Eduardo D.

    AU - Madlom, Mukhlis M.

    AU - Goudie, David R.

    AU - Fleck, Brian W.

    AU - Wieczorek, Dagmar

    AU - Kohlhase, Juergen

    AU - McTrusty, Alice D.

    AU - Gardiner, Carol

    AU - Yale, Christopher

    AU - Moore, Anthony T.

    AU - Russell-Eggitt, Isabelle

    AU - Islam, Lily

    AU - Lees, Melissa

    AU - Beales, Philip L.

    AU - Tuft, Stephen J.

    AU - Solano, Juan B.

    AU - Splitt, Miranda

    AU - Hertz, Jens Michael

    AU - Prescott, Trine E.

    AU - Shears, Deborah J.

    AU - Nischal, Ken K.

    AU - Doco-Fenzy, Martine

    AU - Prieur, Fabienne

    AU - Temple, I. Karen

    AU - Lachlan, Katherine L.

    AU - Damante, Giuseppe

    AU - Morrison, Danny A.

    AU - van Heyningen, Veronica

    AU - FitzPatrick, David R.

    PY - 2016/4/4

    Y1 - 2016/4/4

    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 - PAX6

    KW - aniridia

    KW - mutation

    KW - anterior segment dysgenesis

    U2 - 10.1371/journal.pone.0153757

    DO - 10.1371/journal.pone.0153757

    M3 - Article

    VL - 11

    SP - e0153757

    JO - PLoS ONE

    T2 - PLoS ONE

    JF - PLoS ONE

    SN - 1932-6203

    IS - 4

    ER -

    Anderson MG, Ansari M, Rainger J, Hanson IM, Williamson KA, Sharkey F et al. Genetic Analysis of ‘PAX6-Negative’ Individuals with Aniridia or Gillespie Syndrome. PLoS ONE. 2016 Apr 4;11(4):e0153757. https://doi.org/10.1371/journal.pone.0153757