Mutations in ZIC2 in human holoprosencephaly

Description of a Novel ZIC2 specific phenotype and comprehensive analysis of 157 individuals

Benjamin D. Solomon, Felicitas Lacbawan, Sandra Mercier, Nancy J. Clegg, Mauricio R. Delgado, Kenneth Rosenbaum, Christèle Dubourg, Veronique David, Ann Haskins Olney, Lars Erik Wehner, Ute Hehr, Sherri Bale, Aimee Paulussen, Hubert J. Smeets, Emily Hardisty, Anna Tylki-Szymanska, Ewa Pronicka, Michelle Clemens, Elizabeth McPherson, Raoul C M Hennekam & 21 others Jin Hahn, Elaine Stashinko, Eric Levey, Dagmar Wieczorek, Elizabeth Roeder, Chayim Can Schell-Apacik, Carol W. Booth, Ronald L. Thomas, Sue Kenwrick, Derek A T Cummings, Sophia M. Bous, Amelia Keaton, Joan Z. Balog, Donald Hadley, Nan Zhou, Robert Long, Jorge I. Vélez, Daniel E. Pineda-Alvarez, Sylvie Odent, Erich Roessler, Maximilian Muenke

Research output: Contribution to journalArticle

51 Citations (Scopus)

Abstract

Background: Holoprosencephaly (HPE), the most common malformation of the human forebrain, may be due to mutations in genes associated with non-syndromic HPE. Mutations in ZIC2, located on chromosome 13q32, are a common cause of non-syndromic, non-chromosomal HPE. Objective: To characterise genetic and clinical findings in patients with ZIC2 mutations. Methods: Through the National Institutes of Health and collaborating centres, DNA from approximately 1200 individuals with HPE spectrum disorders was analysed for sequence variations in ZIC2. Clinical details were examined and all other known cases of mutations in ZIC2 were included through a literature search. Results: By direct sequencing of DNA samples of an unselected group of unrelated patients with HPE in our NIH laboratory, ZIC2 mutations were found in 8.4% (49/ 582) of probands. A total of 157 individuals from 119 unrelated kindreds are described, including 141 patients with intragenic sequence determined mutations in ZIC2. Only 39/157 patients have previously been clinically described. Unlike HPE due to mutations in other genes, most mutations occur de novo and the distribution of HPE types differs significantly from that of non-ZIC2 related HPE. Evidence is presented for the presence of a novel facial phenotype which includes bitemporal narrowing, upslanting palpebral fissures, a short nose with anteverted nares, a broad and well demarcated philtrum, and large ears. Conclusions: HPE due to ZIC2 mutations is distinct from that due to mutations in other genes. This may shed light on the mechanisms involved in formation of the forebrain and face and will help direct genetic counselling and diagnostic strategies.

Original languageEnglish (US)
Pages (from-to)513-524
Number of pages12
JournalJournal of Medical Genetics
Volume47
Issue number8
DOIs
StatePublished - Aug 2010

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Holoprosencephaly
Phenotype
Mutation
Prosencephalon
Genes
Genetic Counseling
National Institutes of Health (U.S.)
Eyelids
Lip
DNA Sequence Analysis
Nose
Ear
Chromosomes

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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Mutations in ZIC2 in human holoprosencephaly : Description of a Novel ZIC2 specific phenotype and comprehensive analysis of 157 individuals. / Solomon, Benjamin D.; Lacbawan, Felicitas; Mercier, Sandra; Clegg, Nancy J.; Delgado, Mauricio R.; Rosenbaum, Kenneth; Dubourg, Christèle; David, Veronique; Olney, Ann Haskins; Wehner, Lars Erik; Hehr, Ute; Bale, Sherri; Paulussen, Aimee; Smeets, Hubert J.; Hardisty, Emily; Tylki-Szymanska, Anna; Pronicka, Ewa; Clemens, Michelle; McPherson, Elizabeth; Hennekam, Raoul C M; Hahn, Jin; Stashinko, Elaine; Levey, Eric; Wieczorek, Dagmar; Roeder, Elizabeth; Schell-Apacik, Chayim Can; Booth, Carol W.; Thomas, Ronald L.; Kenwrick, Sue; Cummings, Derek A T; Bous, Sophia M.; Keaton, Amelia; Balog, Joan Z.; Hadley, Donald; Zhou, Nan; Long, Robert; Vélez, Jorge I.; Pineda-Alvarez, Daniel E.; Odent, Sylvie; Roessler, Erich; Muenke, Maximilian.

In: Journal of Medical Genetics, Vol. 47, No. 8, 08.2010, p. 513-524.

Research output: Contribution to journalArticle

Solomon, BD, Lacbawan, F, Mercier, S, Clegg, NJ, Delgado, MR, Rosenbaum, K, Dubourg, C, David, V, Olney, AH, Wehner, LE, Hehr, U, Bale, S, Paulussen, A, Smeets, HJ, Hardisty, E, Tylki-Szymanska, A, Pronicka, E, Clemens, M, McPherson, E, Hennekam, RCM, Hahn, J, Stashinko, E, Levey, E, Wieczorek, D, Roeder, E, Schell-Apacik, CC, Booth, CW, Thomas, RL, Kenwrick, S, Cummings, DAT, Bous, SM, Keaton, A, Balog, JZ, Hadley, D, Zhou, N, Long, R, Vélez, JI, Pineda-Alvarez, DE, Odent, S, Roessler, E & Muenke, M 2010, 'Mutations in ZIC2 in human holoprosencephaly: Description of a Novel ZIC2 specific phenotype and comprehensive analysis of 157 individuals', Journal of Medical Genetics, vol. 47, no. 8, pp. 513-524. https://doi.org/10.1136/jmg.2009.073049
Solomon, Benjamin D. ; Lacbawan, Felicitas ; Mercier, Sandra ; Clegg, Nancy J. ; Delgado, Mauricio R. ; Rosenbaum, Kenneth ; Dubourg, Christèle ; David, Veronique ; Olney, Ann Haskins ; Wehner, Lars Erik ; Hehr, Ute ; Bale, Sherri ; Paulussen, Aimee ; Smeets, Hubert J. ; Hardisty, Emily ; Tylki-Szymanska, Anna ; Pronicka, Ewa ; Clemens, Michelle ; McPherson, Elizabeth ; Hennekam, Raoul C M ; Hahn, Jin ; Stashinko, Elaine ; Levey, Eric ; Wieczorek, Dagmar ; Roeder, Elizabeth ; Schell-Apacik, Chayim Can ; Booth, Carol W. ; Thomas, Ronald L. ; Kenwrick, Sue ; Cummings, Derek A T ; Bous, Sophia M. ; Keaton, Amelia ; Balog, Joan Z. ; Hadley, Donald ; Zhou, Nan ; Long, Robert ; Vélez, Jorge I. ; Pineda-Alvarez, Daniel E. ; Odent, Sylvie ; Roessler, Erich ; Muenke, Maximilian. / Mutations in ZIC2 in human holoprosencephaly : Description of a Novel ZIC2 specific phenotype and comprehensive analysis of 157 individuals. In: Journal of Medical Genetics. 2010 ; Vol. 47, No. 8. pp. 513-524.
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title = "Mutations in ZIC2 in human holoprosencephaly: Description of a Novel ZIC2 specific phenotype and comprehensive analysis of 157 individuals",
abstract = "Background: Holoprosencephaly (HPE), the most common malformation of the human forebrain, may be due to mutations in genes associated with non-syndromic HPE. Mutations in ZIC2, located on chromosome 13q32, are a common cause of non-syndromic, non-chromosomal HPE. Objective: To characterise genetic and clinical findings in patients with ZIC2 mutations. Methods: Through the National Institutes of Health and collaborating centres, DNA from approximately 1200 individuals with HPE spectrum disorders was analysed for sequence variations in ZIC2. Clinical details were examined and all other known cases of mutations in ZIC2 were included through a literature search. Results: By direct sequencing of DNA samples of an unselected group of unrelated patients with HPE in our NIH laboratory, ZIC2 mutations were found in 8.4{\%} (49/ 582) of probands. A total of 157 individuals from 119 unrelated kindreds are described, including 141 patients with intragenic sequence determined mutations in ZIC2. Only 39/157 patients have previously been clinically described. Unlike HPE due to mutations in other genes, most mutations occur de novo and the distribution of HPE types differs significantly from that of non-ZIC2 related HPE. Evidence is presented for the presence of a novel facial phenotype which includes bitemporal narrowing, upslanting palpebral fissures, a short nose with anteverted nares, a broad and well demarcated philtrum, and large ears. Conclusions: HPE due to ZIC2 mutations is distinct from that due to mutations in other genes. This may shed light on the mechanisms involved in formation of the forebrain and face and will help direct genetic counselling and diagnostic strategies.",
author = "Solomon, {Benjamin D.} and Felicitas Lacbawan and Sandra Mercier and Clegg, {Nancy J.} and Delgado, {Mauricio R.} and Kenneth Rosenbaum and Christ{\`e}le Dubourg and Veronique David and Olney, {Ann Haskins} and Wehner, {Lars Erik} and Ute Hehr and Sherri Bale and Aimee Paulussen and Smeets, {Hubert J.} and Emily Hardisty and Anna Tylki-Szymanska and Ewa Pronicka and Michelle Clemens and Elizabeth McPherson and Hennekam, {Raoul C M} and Jin Hahn and Elaine Stashinko and Eric Levey and Dagmar Wieczorek and Elizabeth Roeder and Schell-Apacik, {Chayim Can} and Booth, {Carol W.} and Thomas, {Ronald L.} and Sue Kenwrick and Cummings, {Derek A T} and Bous, {Sophia M.} and Amelia Keaton and Balog, {Joan Z.} and Donald Hadley and Nan Zhou and Robert Long and V{\'e}lez, {Jorge I.} and Pineda-Alvarez, {Daniel E.} and Sylvie Odent and Erich Roessler and Maximilian Muenke",
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T1 - Mutations in ZIC2 in human holoprosencephaly

T2 - Description of a Novel ZIC2 specific phenotype and comprehensive analysis of 157 individuals

AU - Solomon, Benjamin D.

AU - Lacbawan, Felicitas

AU - Mercier, Sandra

AU - Clegg, Nancy J.

AU - Delgado, Mauricio R.

AU - Rosenbaum, Kenneth

AU - Dubourg, Christèle

AU - David, Veronique

AU - Olney, Ann Haskins

AU - Wehner, Lars Erik

AU - Hehr, Ute

AU - Bale, Sherri

AU - Paulussen, Aimee

AU - Smeets, Hubert J.

AU - Hardisty, Emily

AU - Tylki-Szymanska, Anna

AU - Pronicka, Ewa

AU - Clemens, Michelle

AU - McPherson, Elizabeth

AU - Hennekam, Raoul C M

AU - Hahn, Jin

AU - Stashinko, Elaine

AU - Levey, Eric

AU - Wieczorek, Dagmar

AU - Roeder, Elizabeth

AU - Schell-Apacik, Chayim Can

AU - Booth, Carol W.

AU - Thomas, Ronald L.

AU - Kenwrick, Sue

AU - Cummings, Derek A T

AU - Bous, Sophia M.

AU - Keaton, Amelia

AU - Balog, Joan Z.

AU - Hadley, Donald

AU - Zhou, Nan

AU - Long, Robert

AU - Vélez, Jorge I.

AU - Pineda-Alvarez, Daniel E.

AU - Odent, Sylvie

AU - Roessler, Erich

AU - Muenke, Maximilian

PY - 2010/8

Y1 - 2010/8

N2 - Background: Holoprosencephaly (HPE), the most common malformation of the human forebrain, may be due to mutations in genes associated with non-syndromic HPE. Mutations in ZIC2, located on chromosome 13q32, are a common cause of non-syndromic, non-chromosomal HPE. Objective: To characterise genetic and clinical findings in patients with ZIC2 mutations. Methods: Through the National Institutes of Health and collaborating centres, DNA from approximately 1200 individuals with HPE spectrum disorders was analysed for sequence variations in ZIC2. Clinical details were examined and all other known cases of mutations in ZIC2 were included through a literature search. Results: By direct sequencing of DNA samples of an unselected group of unrelated patients with HPE in our NIH laboratory, ZIC2 mutations were found in 8.4% (49/ 582) of probands. A total of 157 individuals from 119 unrelated kindreds are described, including 141 patients with intragenic sequence determined mutations in ZIC2. Only 39/157 patients have previously been clinically described. Unlike HPE due to mutations in other genes, most mutations occur de novo and the distribution of HPE types differs significantly from that of non-ZIC2 related HPE. Evidence is presented for the presence of a novel facial phenotype which includes bitemporal narrowing, upslanting palpebral fissures, a short nose with anteverted nares, a broad and well demarcated philtrum, and large ears. Conclusions: HPE due to ZIC2 mutations is distinct from that due to mutations in other genes. This may shed light on the mechanisms involved in formation of the forebrain and face and will help direct genetic counselling and diagnostic strategies.

AB - Background: Holoprosencephaly (HPE), the most common malformation of the human forebrain, may be due to mutations in genes associated with non-syndromic HPE. Mutations in ZIC2, located on chromosome 13q32, are a common cause of non-syndromic, non-chromosomal HPE. Objective: To characterise genetic and clinical findings in patients with ZIC2 mutations. Methods: Through the National Institutes of Health and collaborating centres, DNA from approximately 1200 individuals with HPE spectrum disorders was analysed for sequence variations in ZIC2. Clinical details were examined and all other known cases of mutations in ZIC2 were included through a literature search. Results: By direct sequencing of DNA samples of an unselected group of unrelated patients with HPE in our NIH laboratory, ZIC2 mutations were found in 8.4% (49/ 582) of probands. A total of 157 individuals from 119 unrelated kindreds are described, including 141 patients with intragenic sequence determined mutations in ZIC2. Only 39/157 patients have previously been clinically described. Unlike HPE due to mutations in other genes, most mutations occur de novo and the distribution of HPE types differs significantly from that of non-ZIC2 related HPE. Evidence is presented for the presence of a novel facial phenotype which includes bitemporal narrowing, upslanting palpebral fissures, a short nose with anteverted nares, a broad and well demarcated philtrum, and large ears. Conclusions: HPE due to ZIC2 mutations is distinct from that due to mutations in other genes. This may shed light on the mechanisms involved in formation of the forebrain and face and will help direct genetic counselling and diagnostic strategies.

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