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Mutations in ZIC2 in Human Holoprosencephaly: Description of a Novel ZIC2 Specific Phenotype and Comprehensive Analysis of 157 Individuals

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Mutations in ZIC2 in Human Holoprosencephaly: Description of a Novel ZIC2 Specific Phenotype and Comprehensive Analysis of 157 Individuals Mutations in ZIC2 in human holoprosencephaly: description of a novel ZIC2 specific phenotype and comprehensive analysis of 157 individuals. Benjamin Solomon, Felicitas Lacbawan, Sandra Mercier, Nancy Clegg, Mauricio Delgado, Kenneth Rosenbaum, Christèle Dubourg, Véronique David, Ann Haskins Olney, Lars-Erik Wehner, et al. To cite this version: Benjamin Solomon, Felicitas Lacbawan, Sandra Mercier, Nancy Clegg, Mauricio Delgado, et al.. Mu- tations in ZIC2 in human holoprosencephaly: description of a novel ZIC2 specific phenotype and comprehensive analysis of 157 individuals.. Journal of Medical Genetics, BMJ Publishing Group, 2010, 47 (8), pp.513-24. 10.1136/jmg.2009.073049. inserm-00439659 HAL Id: inserm-00439659 https://www.hal.inserm.fr/inserm-00439659 Submitted on 9 Dec 2009 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Mutations in ZIC2 in Human Holoprosencephaly: Comprehensive Analysis of 153 Individuals and Description of a Novel ZIC2-Specfic Phenotype Benjamin D. Solomon1#, Felicitas Lacbawan1,2#, Sandra Mercier3,4, Nancy J. Clegg5, Mauricio R. Delgado5, Kenneth Rosenbaum6, Christèle Dubourg3, Veronique David3, Ann Haskins Olney7, Lars-Erik Wehner8,9, Ute Hehr8,9, Sherri Bale10, Aimee Paulussen11, Hubert J. Smeets11, Emily Hardisty12, Anna Tylki-Szymanska13, Ewa Pronicka13, Michelle Clemens14, Elizabeth McPherson15, Raoul C.M. Hennekam16, Jin Hahn17, Elaine Stashinko18, Eric Levey18, Dagmar Wieczorek19, Elizabeth Roeder20, Kiyoshi Imaizumi21, Chayim Can Schell-Apacik22,23, Carol W. Booth24, Ronald L. Thomas25, Sue Kenwrick26, Amelia Keaton1, Joan Z. Balog1, Donald Hadley1, Nan Zhou1, Robert Long1, Jorge I. Vélez1, Daniel E. Pineda-Alvarez1, Sylvie Odent3,4, Erich Roessler1, Maximilian Muenke1* 1National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA; 2Department of Pathology, State University of New York-Downstate Medical Center, Brooklyn, NY 11203, USA; 3CNRS Génétique et Développement, Université de Rennes, 35042 Rennes Cedex, France; 4Service de génétique clinique, CHU Hôpital Sud, 35042 Rennes Cedex, France 5Department of Neurology, Texas Scottish Rite Hospital for Children, University of Texas Southwestern Medical Center, Dallas, TX 75219, USA; 6Department of Genetics, Children’s National Medical Center, Washington, DC 20010, USA; 7Department of Genetics, Munroe-Meyer Institute for Genetics and Rehabilitation, University of Nebraska Medical Center, Omaha, NE 68109, USA; 8Center for Human Genetics Regensburg, Regensburg 93053, Germany, 9Department of Human Genetics, University of Regensburg, Regensburg 93053, Germany; 10GeneDx, Gaithersburg, MD 20877, USA; 11Department of Clinical Genetics, Academic Hospital Maastricht, 6229 GR Maastricht, Netherlands; 12Department of Obstetrics and Gynecology, University of Chapel Hill School of Medicine, Chapel Hill, NC 27514, USA; 13Clinic of Metabolic Diseases, Endocrinology and Diabetology, The Children's Memorial Health Institute, 02-004 Warsaw, Poland; 14Department of Genetics, University of Pittsburgh Medical Center, Pittsburgh, PA 15219, USA; 15Department of Genetics, Marshfield Clinic, Marshfield, WI 54449, USA; 16Department of Clinical Genetics, Academic Medical Center, 1105 AZ, Amsterdam, Netherlands; 17Department of Neurology, Stanford University School of Medicine, Palo Alto, CA 94305, USA; 18Kennedy Krieger Institute, Johns Hopkins University, Baltimore, MD 21218, USA, 19Institute of Human Genetics, University Duisburg-Essen, 174, 45147 Essen, Germany, 20Department of Pediatrics, Division of Genetics and Metabolic Disorders, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA, 21Division of Medical Genetics, Kanagawa Children’s Medical Center, Yokohama City, Kanagawa 232-8555, Japan, 22Institute of Social Pediatric and Adolescent Medicine of the University of Munich, D-81377 Munich, Germany; 23Practice of Human Genetics, 14050 Berlin, Germany, 24Department of Genetics, Lutheran General Hospital, Park Ridge, IL 60068, USA; 25Department of Obstetrics and Gynecology, Drexel School of Medicine, Philadelphia, PA 19129, USA; 26Cambridge University Hospitals, Cambridge CB2 0QQ, UK. #These authors contributed equally. *Corresponding author: National Institutes of Health, Building 35, Room 1B-203 Bethesda, MD 20892 USA Phone: (301)594-7487 Fax: (301)496-7184 e-mail: [email protected] Abstract Holoprosencephaly (HPE) is the most common malformation of the human forebrain, and may be due to cytogenetic anomalies, teratogens, occur in the context of a syndrome, or be due to mutations in single genes associated with non-syndromic HPE. Mutations in ZIC2, a transcription factor located on chromosome 13q32, are the second- most common cause of non-syndromic, non-chromosomal HPE. Blood samples from over 1000 individuals with HPE-spectrum disorders and their relatives were analyzed for sequence variations in ZIC2. We examined clinical details and included all other known previously published and unpublished cases of mutations in ZIC2 through a literature search and collaboration with other centers. We find mutations in ZIC2 in 8% of probands with HPE, and describe 153 individuals from 116 unrelated kindreds, including 137 patients with molecularly-determined mutations in ZIC2 and 16 patients with deletions of the ZIC2 locus. Unlike HPE due to mutations in other genes, the vast majority of cases are sporadic and the proportional distribution of HPE types differs significantly from previously published analyses of non-chromosomal non-syndromic HPE. Furthermore, we describe a novel facial phenotype in patients with mutations in ZIC2 which includes bitemporal narrowing, upsplanting palpebral fissures, a short nose with anteverted nares, and a broad and well-demarcated philtrum, and large ears. This phenotype is distinct from the standard facial dysmorphisms associated with non- chromosomal, non-syndromic HPE. Our findings show that HPE due to mutations in ZIC2 is distinct from that due to mutations in other genes. This may shed light on the mechanisms that contribute to the formation of the face and the forebrain and may help direct genetic counseling and diagnostic strategies. Manuscript Holoprosencephaly (HPE) is the most common malformation of the human forebrain, and results from failed or incomplete forebrain cleavage early in gestation. HPE occurs in 1 in 250 gestations, though the vast majority of conceptions with HPE do not survive to birth1,2. HPE is categorized by the degree of forebrain separation into alobar, in which there is no interhemispheric division, semilobar, and lobar HPE, from the most to least severe type. More recently, middle interhemispheric variant (MIHV) HPE has also been described, which includes failed separation of the posterior frontal and parietal lobes3-6. The distribution of HPE types in both living patients and deceased fetuses with non-chromosomal, non-syndromic HPE has been estimated to be 22% alobar, 45% semilobar, and 33% lobar HPE7. Common clinical features among patients with HPE include neurological impairment (often severe), seizures, diabetes insipidus, and characteristic dysmorphic facies. Traditionally, it is thought that in HPE “the face predicts the brain”: in other words, more severe craniofacial anomalies correlate with more severe neuroanatomic findings.4 At the most severe end of the spectrum, facial features in patients with alobar HPE may include cyclopia and a proboscis (a tubular nasal structure located above the fused eyes). Other, more common facial dysmorphisms in less-severely affected patients include microcephaly (though hydrocephalus can lead to macrocephaly), hypotelorism, a flat nasal bridge, and cleft lip and/or palate. At the least severe end of the spectrum, termed microform HPE, patients may have subtle features such as mild microcephaly, hypotelorism, single maxillary central incisors (SMCI) without appreciable CNS anomalies on conventional neuroimaging. These individuals are often identified due to the presence of a severely affected relative6,8-9. HPE is etiologically heterogeneous, and may be caused by cytogenetic anomalies, teratogenic influences, occur in the context of a syndrome, or be due to mutations in one of over 10 HPE-associated genes6-8,10-12. In patients with HPE who have a normal chromosome analysis, a typical initial diagnostic strategy is to screen for mutations in four genes: SHH [MIM 600725], ZIC2 [MIM 603073], SIX3 [MIM 603714], and TGIF [MIM 602630]. Mutations in these genes can arise de novo or may be found in multiple members of large families segregating HPE-spectrum anomalies. In large kindreds, family studies demonstrate the incomplete penetrance and highly variable expressivity of these mutations3-4,6,13. ZIC2, located at chromosome 13q32, was first identified as an HPE candidate gene due to individuals with brain anomalies who were found to have deletions involving the long arm of chromosome 13. Subsequent analysis of patients with HPE identified mutations in ZIC214-16. Mutations in this gene have previously been thought
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