Loss-of-function HDAC8 mutations cause a phenotypic spectrum of Cornelia de Lange syndrome-like features, ocular hypertelorism, large fontanelle and X-linked inheritance

Frank J. Kaiser, Morad Ansari, Diana Braunholz, María Concepción Gil-Rodríguez, Christophe Decroos, Jonathan J. Wilde, Christopher T. Fincher, Maninder Kaur, Masashige Bando, David J. Amor, P. S. Atwal, Melanie Bahlo, Christine M. Bowman, Jacquelyn J. Bradley, Han G. Brunner, Dinah Clark, Miguel Del Campo, Nataliya Di Donato, Peter Diakumis, Holly Dubbs & 64 others David A. Dyment, Juliane Eckhold, Sarah Ernst, Jose C. Ferreira, Lauren J. Francey, Ulrike Gehlken, Encarna Guillén-Navarro, Yolanda Gyftodimou, Bryan D. Hall, Raoul Hennekam, Louanne Hudgins, Melanie Hullings, Jennifer M. Hunter, Helger Yntema, A. Micheil Innes, Antonie D. Kline, Zita Krumina, Hane Lee, Kathleen Leppig, Sally Ann Lynch, Mark B. Mallozzi, Linda Mannini, Shane Mckee, Sarju G. Mehta, Ieva Micule, Care Rare Canada Consortium, Shehla Mohammed, Ellen Moran, Geert R. Mortier, Joe Ann S Moser, Sarah E. Noon, Naohito Nozaki, Luis Nunes, John G. Pappas, Lynette S. Penney, Antonio Pérez-Aytés, Michael B. Petersen, Beatriz Puisac, Nicole Revencu, Elizabeth Roeder, Sulagna Saitta, Angela E. Scheuerle, Karen L. Schindeler, Victoria M. Siu, Zornitza Stark, Samuel P. Strom, Heidi Thiese, Inga Vater, Patrick Willems, Kathleen Williamson, Louise C. Wilson, Hakon Hakonarson, Fabiola Quintero-Rivera, Jolanta Wierzba, Antonio Musio, Gabriele Gillessen-Kaesbach, Feliciano J. Ramos, Laird G. Jackson, Katsuhiko Shirahige, Juan Pié, David W. Christianson, Ian D. Krantz, David R. Fitzpatrick, Matthew A. Deardorff

Research output: Contribution to journalArticle

65 Citations (Scopus)

Abstract

Cornelia de Lange syndrome (CdLS) is amultisystemgenetic disorder with distinct facies, growth failure, intellectual disability, distal limb anomalies, gastrointestinal and neurological disease. Mutations in NIPBL, encoding a cohesin regulatory protein, account for >80% of cases with typical facies. Mutations in the core cohesin complex proteins, encoded by the SMC1A, SMC3 and RAD21 genes, together account for ̃5% of subjects, often with atypical CdLS features. Recently, we identified mutations in the X-linked gene HDAC8 as the cause of a small number of CdLS cases. Here, we report a cohort of 38 individuals with an emerging spectrum of features caused by HDAC8 mutations. For several individuals, the diagnosis of CdLS was not considered prior to genomic testing. Most mutations identified are missense and de novo. Many cases are heterozygous females, each with marked skewing of X-inactivation in peripheral blood DNA.Wealso identified eight hemizygous males who are more severely affected. The craniofacial appearance caused by HDAC8 mutations overlaps that of typical CdLS but often displays delayed anterior fontanelle closure, ocular hypertelorism, hooding of the eyelids, a broader nose and dental anomalies, which may be useful discriminating features. HDAC8 encodes the lysine deacetylase for the cohesin subunit SMC3 and analysis of the functional consequences of the missense mutations indicates that all cause a loss of enzymatic function. These data demonstrate that loss-of-function mutations in HDAC8 cause a range of overlapping human developmental phenotypes, including a phenotypically distinct subgroup of CdLS.

Original languageEnglish (US)
Article numberddu002
Pages (from-to)2888-2900
Number of pages13
JournalHuman Molecular Genetics
Volume23
Issue number11
DOIs
StatePublished - 2014

Fingerprint

De Lange Syndrome
Hypertelorism
X-Linked Genes
Mutation
Missense Mutation
Cranial Fontanelles
X Chromosome Inactivation
Gastrointestinal Diseases
Eyelids
Nose
Intellectual Disability
Lysine
Tooth
Extremities
Phenotype
DNA
Growth
Genes

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology

Cite this

Kaiser, F. J., Ansari, M., Braunholz, D., Gil-Rodríguez, M. C., Decroos, C., Wilde, J. J., ... Deardorff, M. A. (2014). Loss-of-function HDAC8 mutations cause a phenotypic spectrum of Cornelia de Lange syndrome-like features, ocular hypertelorism, large fontanelle and X-linked inheritance. Human Molecular Genetics, 23(11), 2888-2900. [ddu002]. https://doi.org/10.1093/hmg/ddu002

Loss-of-function HDAC8 mutations cause a phenotypic spectrum of Cornelia de Lange syndrome-like features, ocular hypertelorism, large fontanelle and X-linked inheritance. / Kaiser, Frank J.; Ansari, Morad; Braunholz, Diana; Gil-Rodríguez, María Concepción; Decroos, Christophe; Wilde, Jonathan J.; Fincher, Christopher T.; Kaur, Maninder; Bando, Masashige; Amor, David J.; Atwal, P. S.; Bahlo, Melanie; Bowman, Christine M.; Bradley, Jacquelyn J.; Brunner, Han G.; Clark, Dinah; Campo, Miguel Del; Di Donato, Nataliya; Diakumis, Peter; Dubbs, Holly; Dyment, David A.; Eckhold, Juliane; Ernst, Sarah; Ferreira, Jose C.; Francey, Lauren J.; Gehlken, Ulrike; Guillén-Navarro, Encarna; Gyftodimou, Yolanda; Hall, Bryan D.; Hennekam, Raoul; Hudgins, Louanne; Hullings, Melanie; Hunter, Jennifer M.; Yntema, Helger; Innes, A. Micheil; Kline, Antonie D.; Krumina, Zita; Lee, Hane; Leppig, Kathleen; Lynch, Sally Ann; Mallozzi, Mark B.; Mannini, Linda; Mckee, Shane; Mehta, Sarju G.; Micule, Ieva; Consortium, Care Rare Canada; Mohammed, Shehla; Moran, Ellen; Mortier, Geert R.; Moser, Joe Ann S; Noon, Sarah E.; Nozaki, Naohito; Nunes, Luis; Pappas, John G.; Penney, Lynette S.; Pérez-Aytés, Antonio; Petersen, Michael B.; Puisac, Beatriz; Revencu, Nicole; Roeder, Elizabeth; Saitta, Sulagna; Scheuerle, Angela E.; Schindeler, Karen L.; Siu, Victoria M.; Stark, Zornitza; Strom, Samuel P.; Thiese, Heidi; Vater, Inga; Willems, Patrick; Williamson, Kathleen; Wilson, Louise C.; Hakonarson, Hakon; Quintero-Rivera, Fabiola; Wierzba, Jolanta; Musio, Antonio; Gillessen-Kaesbach, Gabriele; Ramos, Feliciano J.; Jackson, Laird G.; Shirahige, Katsuhiko; Pié, Juan; Christianson, David W.; Krantz, Ian D.; Fitzpatrick, David R.; Deardorff, Matthew A.

In: Human Molecular Genetics, Vol. 23, No. 11, ddu002, 2014, p. 2888-2900.

Research output: Contribution to journalArticle

Kaiser, FJ, Ansari, M, Braunholz, D, Gil-Rodríguez, MC, Decroos, C, Wilde, JJ, Fincher, CT, Kaur, M, Bando, M, Amor, DJ, Atwal, PS, Bahlo, M, Bowman, CM, Bradley, JJ, Brunner, HG, Clark, D, Campo, MD, Di Donato, N, Diakumis, P, Dubbs, H, Dyment, DA, Eckhold, J, Ernst, S, Ferreira, JC, Francey, LJ, Gehlken, U, Guillén-Navarro, E, Gyftodimou, Y, Hall, BD, Hennekam, R, Hudgins, L, Hullings, M, Hunter, JM, Yntema, H, Innes, AM, Kline, AD, Krumina, Z, Lee, H, Leppig, K, Lynch, SA, Mallozzi, MB, Mannini, L, Mckee, S, Mehta, SG, Micule, I, Consortium, CRC, Mohammed, S, Moran, E, Mortier, GR, Moser, JAS, Noon, SE, Nozaki, N, Nunes, L, Pappas, JG, Penney, LS, Pérez-Aytés, A, Petersen, MB, Puisac, B, Revencu, N, Roeder, E, Saitta, S, Scheuerle, AE, Schindeler, KL, Siu, VM, Stark, Z, Strom, SP, Thiese, H, Vater, I, Willems, P, Williamson, K, Wilson, LC, Hakonarson, H, Quintero-Rivera, F, Wierzba, J, Musio, A, Gillessen-Kaesbach, G, Ramos, FJ, Jackson, LG, Shirahige, K, Pié, J, Christianson, DW, Krantz, ID, Fitzpatrick, DR & Deardorff, MA 2014, 'Loss-of-function HDAC8 mutations cause a phenotypic spectrum of Cornelia de Lange syndrome-like features, ocular hypertelorism, large fontanelle and X-linked inheritance', Human Molecular Genetics, vol. 23, no. 11, ddu002, pp. 2888-2900. https://doi.org/10.1093/hmg/ddu002
Kaiser, Frank J. ; Ansari, Morad ; Braunholz, Diana ; Gil-Rodríguez, María Concepción ; Decroos, Christophe ; Wilde, Jonathan J. ; Fincher, Christopher T. ; Kaur, Maninder ; Bando, Masashige ; Amor, David J. ; Atwal, P. S. ; Bahlo, Melanie ; Bowman, Christine M. ; Bradley, Jacquelyn J. ; Brunner, Han G. ; Clark, Dinah ; Campo, Miguel Del ; Di Donato, Nataliya ; Diakumis, Peter ; Dubbs, Holly ; Dyment, David A. ; Eckhold, Juliane ; Ernst, Sarah ; Ferreira, Jose C. ; Francey, Lauren J. ; Gehlken, Ulrike ; Guillén-Navarro, Encarna ; Gyftodimou, Yolanda ; Hall, Bryan D. ; Hennekam, Raoul ; Hudgins, Louanne ; Hullings, Melanie ; Hunter, Jennifer M. ; Yntema, Helger ; Innes, A. Micheil ; Kline, Antonie D. ; Krumina, Zita ; Lee, Hane ; Leppig, Kathleen ; Lynch, Sally Ann ; Mallozzi, Mark B. ; Mannini, Linda ; Mckee, Shane ; Mehta, Sarju G. ; Micule, Ieva ; Consortium, Care Rare Canada ; Mohammed, Shehla ; Moran, Ellen ; Mortier, Geert R. ; Moser, Joe Ann S ; Noon, Sarah E. ; Nozaki, Naohito ; Nunes, Luis ; Pappas, John G. ; Penney, Lynette S. ; Pérez-Aytés, Antonio ; Petersen, Michael B. ; Puisac, Beatriz ; Revencu, Nicole ; Roeder, Elizabeth ; Saitta, Sulagna ; Scheuerle, Angela E. ; Schindeler, Karen L. ; Siu, Victoria M. ; Stark, Zornitza ; Strom, Samuel P. ; Thiese, Heidi ; Vater, Inga ; Willems, Patrick ; Williamson, Kathleen ; Wilson, Louise C. ; Hakonarson, Hakon ; Quintero-Rivera, Fabiola ; Wierzba, Jolanta ; Musio, Antonio ; Gillessen-Kaesbach, Gabriele ; Ramos, Feliciano J. ; Jackson, Laird G. ; Shirahige, Katsuhiko ; Pié, Juan ; Christianson, David W. ; Krantz, Ian D. ; Fitzpatrick, David R. ; Deardorff, Matthew A. / Loss-of-function HDAC8 mutations cause a phenotypic spectrum of Cornelia de Lange syndrome-like features, ocular hypertelorism, large fontanelle and X-linked inheritance. In: Human Molecular Genetics. 2014 ; Vol. 23, No. 11. pp. 2888-2900.
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title = "Loss-of-function HDAC8 mutations cause a phenotypic spectrum of Cornelia de Lange syndrome-like features, ocular hypertelorism, large fontanelle and X-linked inheritance",
abstract = "Cornelia de Lange syndrome (CdLS) is amultisystemgenetic disorder with distinct facies, growth failure, intellectual disability, distal limb anomalies, gastrointestinal and neurological disease. Mutations in NIPBL, encoding a cohesin regulatory protein, account for >80{\%} of cases with typical facies. Mutations in the core cohesin complex proteins, encoded by the SMC1A, SMC3 and RAD21 genes, together account for ̃5{\%} of subjects, often with atypical CdLS features. Recently, we identified mutations in the X-linked gene HDAC8 as the cause of a small number of CdLS cases. Here, we report a cohort of 38 individuals with an emerging spectrum of features caused by HDAC8 mutations. For several individuals, the diagnosis of CdLS was not considered prior to genomic testing. Most mutations identified are missense and de novo. Many cases are heterozygous females, each with marked skewing of X-inactivation in peripheral blood DNA.Wealso identified eight hemizygous males who are more severely affected. The craniofacial appearance caused by HDAC8 mutations overlaps that of typical CdLS but often displays delayed anterior fontanelle closure, ocular hypertelorism, hooding of the eyelids, a broader nose and dental anomalies, which may be useful discriminating features. HDAC8 encodes the lysine deacetylase for the cohesin subunit SMC3 and analysis of the functional consequences of the missense mutations indicates that all cause a loss of enzymatic function. These data demonstrate that loss-of-function mutations in HDAC8 cause a range of overlapping human developmental phenotypes, including a phenotypically distinct subgroup of CdLS.",
author = "Kaiser, {Frank J.} and Morad Ansari and Diana Braunholz and Gil-Rodr{\'i}guez, {Mar{\'i}a Concepci{\'o}n} and Christophe Decroos and Wilde, {Jonathan J.} and Fincher, {Christopher T.} and Maninder Kaur and Masashige Bando and Amor, {David J.} and Atwal, {P. S.} and Melanie Bahlo and Bowman, {Christine M.} and Bradley, {Jacquelyn J.} and Brunner, {Han G.} and Dinah Clark and Campo, {Miguel Del} and {Di Donato}, Nataliya and Peter Diakumis and Holly Dubbs and Dyment, {David A.} and Juliane Eckhold and Sarah Ernst and Ferreira, {Jose C.} and Francey, {Lauren J.} and Ulrike Gehlken and Encarna Guill{\'e}n-Navarro and Yolanda Gyftodimou and Hall, {Bryan D.} and Raoul Hennekam and Louanne Hudgins and Melanie Hullings and Hunter, {Jennifer M.} and Helger Yntema and Innes, {A. Micheil} and Kline, {Antonie D.} and Zita Krumina and Hane Lee and Kathleen Leppig and Lynch, {Sally Ann} and Mallozzi, {Mark B.} and Linda Mannini and Shane Mckee and Mehta, {Sarju G.} and Ieva Micule and Consortium, {Care Rare Canada} and Shehla Mohammed and Ellen Moran and Mortier, {Geert R.} and Moser, {Joe Ann S} and Noon, {Sarah E.} and Naohito Nozaki and Luis Nunes and Pappas, {John G.} and Penney, {Lynette S.} and Antonio P{\'e}rez-Ayt{\'e}s and Petersen, {Michael B.} and Beatriz Puisac and Nicole Revencu and Elizabeth Roeder and Sulagna Saitta and Scheuerle, {Angela E.} and Schindeler, {Karen L.} and Siu, {Victoria M.} and Zornitza Stark and Strom, {Samuel P.} and Heidi Thiese and Inga Vater and Patrick Willems and Kathleen Williamson and Wilson, {Louise C.} and Hakon Hakonarson and Fabiola Quintero-Rivera and Jolanta Wierzba and Antonio Musio and Gabriele Gillessen-Kaesbach and Ramos, {Feliciano J.} and Jackson, {Laird G.} and Katsuhiko Shirahige and Juan Pi{\'e} and Christianson, {David W.} and Krantz, {Ian D.} and Fitzpatrick, {David R.} and Deardorff, {Matthew A.}",
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doi = "10.1093/hmg/ddu002",
language = "English (US)",
volume = "23",
pages = "2888--2900",
journal = "Human Molecular Genetics",
issn = "0964-6906",
publisher = "Oxford University Press",
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TY - JOUR

T1 - Loss-of-function HDAC8 mutations cause a phenotypic spectrum of Cornelia de Lange syndrome-like features, ocular hypertelorism, large fontanelle and X-linked inheritance

AU - Kaiser, Frank J.

AU - Ansari, Morad

AU - Braunholz, Diana

AU - Gil-Rodríguez, María Concepción

AU - Decroos, Christophe

AU - Wilde, Jonathan J.

AU - Fincher, Christopher T.

AU - Kaur, Maninder

AU - Bando, Masashige

AU - Amor, David J.

AU - Atwal, P. S.

AU - Bahlo, Melanie

AU - Bowman, Christine M.

AU - Bradley, Jacquelyn J.

AU - Brunner, Han G.

AU - Clark, Dinah

AU - Campo, Miguel Del

AU - Di Donato, Nataliya

AU - Diakumis, Peter

AU - Dubbs, Holly

AU - Dyment, David A.

AU - Eckhold, Juliane

AU - Ernst, Sarah

AU - Ferreira, Jose C.

AU - Francey, Lauren J.

AU - Gehlken, Ulrike

AU - Guillén-Navarro, Encarna

AU - Gyftodimou, Yolanda

AU - Hall, Bryan D.

AU - Hennekam, Raoul

AU - Hudgins, Louanne

AU - Hullings, Melanie

AU - Hunter, Jennifer M.

AU - Yntema, Helger

AU - Innes, A. Micheil

AU - Kline, Antonie D.

AU - Krumina, Zita

AU - Lee, Hane

AU - Leppig, Kathleen

AU - Lynch, Sally Ann

AU - Mallozzi, Mark B.

AU - Mannini, Linda

AU - Mckee, Shane

AU - Mehta, Sarju G.

AU - Micule, Ieva

AU - Consortium, Care Rare Canada

AU - Mohammed, Shehla

AU - Moran, Ellen

AU - Mortier, Geert R.

AU - Moser, Joe Ann S

AU - Noon, Sarah E.

AU - Nozaki, Naohito

AU - Nunes, Luis

AU - Pappas, John G.

AU - Penney, Lynette S.

AU - Pérez-Aytés, Antonio

AU - Petersen, Michael B.

AU - Puisac, Beatriz

AU - Revencu, Nicole

AU - Roeder, Elizabeth

AU - Saitta, Sulagna

AU - Scheuerle, Angela E.

AU - Schindeler, Karen L.

AU - Siu, Victoria M.

AU - Stark, Zornitza

AU - Strom, Samuel P.

AU - Thiese, Heidi

AU - Vater, Inga

AU - Willems, Patrick

AU - Williamson, Kathleen

AU - Wilson, Louise C.

AU - Hakonarson, Hakon

AU - Quintero-Rivera, Fabiola

AU - Wierzba, Jolanta

AU - Musio, Antonio

AU - Gillessen-Kaesbach, Gabriele

AU - Ramos, Feliciano J.

AU - Jackson, Laird G.

AU - Shirahige, Katsuhiko

AU - Pié, Juan

AU - Christianson, David W.

AU - Krantz, Ian D.

AU - Fitzpatrick, David R.

AU - Deardorff, Matthew A.

PY - 2014

Y1 - 2014

N2 - Cornelia de Lange syndrome (CdLS) is amultisystemgenetic disorder with distinct facies, growth failure, intellectual disability, distal limb anomalies, gastrointestinal and neurological disease. Mutations in NIPBL, encoding a cohesin regulatory protein, account for >80% of cases with typical facies. Mutations in the core cohesin complex proteins, encoded by the SMC1A, SMC3 and RAD21 genes, together account for ̃5% of subjects, often with atypical CdLS features. Recently, we identified mutations in the X-linked gene HDAC8 as the cause of a small number of CdLS cases. Here, we report a cohort of 38 individuals with an emerging spectrum of features caused by HDAC8 mutations. For several individuals, the diagnosis of CdLS was not considered prior to genomic testing. Most mutations identified are missense and de novo. Many cases are heterozygous females, each with marked skewing of X-inactivation in peripheral blood DNA.Wealso identified eight hemizygous males who are more severely affected. The craniofacial appearance caused by HDAC8 mutations overlaps that of typical CdLS but often displays delayed anterior fontanelle closure, ocular hypertelorism, hooding of the eyelids, a broader nose and dental anomalies, which may be useful discriminating features. HDAC8 encodes the lysine deacetylase for the cohesin subunit SMC3 and analysis of the functional consequences of the missense mutations indicates that all cause a loss of enzymatic function. These data demonstrate that loss-of-function mutations in HDAC8 cause a range of overlapping human developmental phenotypes, including a phenotypically distinct subgroup of CdLS.

AB - Cornelia de Lange syndrome (CdLS) is amultisystemgenetic disorder with distinct facies, growth failure, intellectual disability, distal limb anomalies, gastrointestinal and neurological disease. Mutations in NIPBL, encoding a cohesin regulatory protein, account for >80% of cases with typical facies. Mutations in the core cohesin complex proteins, encoded by the SMC1A, SMC3 and RAD21 genes, together account for ̃5% of subjects, often with atypical CdLS features. Recently, we identified mutations in the X-linked gene HDAC8 as the cause of a small number of CdLS cases. Here, we report a cohort of 38 individuals with an emerging spectrum of features caused by HDAC8 mutations. For several individuals, the diagnosis of CdLS was not considered prior to genomic testing. Most mutations identified are missense and de novo. Many cases are heterozygous females, each with marked skewing of X-inactivation in peripheral blood DNA.Wealso identified eight hemizygous males who are more severely affected. The craniofacial appearance caused by HDAC8 mutations overlaps that of typical CdLS but often displays delayed anterior fontanelle closure, ocular hypertelorism, hooding of the eyelids, a broader nose and dental anomalies, which may be useful discriminating features. HDAC8 encodes the lysine deacetylase for the cohesin subunit SMC3 and analysis of the functional consequences of the missense mutations indicates that all cause a loss of enzymatic function. These data demonstrate that loss-of-function mutations in HDAC8 cause a range of overlapping human developmental phenotypes, including a phenotypically distinct subgroup of CdLS.

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