Spectrum of CHD7 Mutations in 110 Individuals with CHARGE Syndrome and Genotype-Phenotype Correlation Seema R. Lalani, Arsalan M. Safiullah, Susan D.

Slides:

Advertisements

Similar presentations

and its visual implications

Advertisements

ABCB6 Mutations Cause Ocular Coloboma

Rapid Molecular Analysis of the STAT3 Gene in Job Syndrome of Hyper-IgE and Recurrent Infectious Diseases Attila Kumánovics, Carl T. Wittwer, Robert.

High Incidence of Cardiac Malformations in Connexin40-Deficient Mice

by Yuka Morikawa, and Peter Cserjesi

A Mutation in HOXA2 Is Responsible for Autosomal-Recessive Microtia in an Iranian Family Fatemeh Alasti, Abdorrahim Sadeghi, Mohammad Hossein Sanati,

Jena Donovan, Anna Kordylewska, Yuh Nung Jan, Manuel F Utset

Arnd Heuser, Eva R. Plovie, Patrick T. Ellinor, Katja S

Ilse Feenstra, Lisenka E. L. M. Vissers, Ronald J. E

Volume 10, Issue 1, Pages (January 2006)

Jianbin Wang, H. Christina Fan, Barry Behr, Stephen R. Quake Cell

Mutation of IGFBP7 Causes Upregulation of BRAF/MEK/ERK Pathway and Familial Retinal Arterial Macroaneurysms Leen Abu-Safieh, Emad B. Abboud, Hisham Alkuraya,

Neurological Phenotype in Waardenburg Syndrome Type 4 Correlates with Novel SOX10 Truncating Mutations and Expression in Developing Brain Renaud L. Touraine,

Tracy Dixon-Salazar, Jennifer L. Silhavy, Sarah E. Marsh, Carrie M

The Molecular Basis of Vascular Disorders

Inactivating Mutations in ESCO2 Cause SC Phocomelia and Roberts Syndrome: No Phenotype-Genotype Correlation Birgitt Schüle, Angelica Oviedo, Kathreen.

Spectrum of CHD7 Mutations in 110 Individuals with CHARGE Syndrome and Genotype-Phenotype Correlation Seema R. Lalani, Arsalan M. Safiullah, Susan D.

Margaret J. McMillin, Anita E. Beck, Jessica X. Chong, Kathryn M

Warsaw Breakage Syndrome, a Cohesinopathy Associated with Mutations in the XPD Helicase Family Member DDX11/ChlR1 Petra van der Lelij, Krystyna H. Chrzanowska,

Loss of MAFB Function in Humans and Mice Causes Duane Syndrome, Aberrant Extraocular Muscle Innervation, and Inner-Ear Defects Jong G. Park, Max A. Tischfield,

Cohen Syndrome Is Caused by Mutations in a Novel Gene, COH1, Encoding a Transmembrane Protein with a Presumed Role in Vesicle-Mediated Sorting and Intracellular.

High-Resolution Mapping of Genotype-Phenotype Relationships in Cri du Chat Syndrome Using Array Comparative Genomic Hybridization Xiaoxiao Zhang, Antoine.

A Novel Alu-Like Element Rearranged in the Dystrophin Gene Causes a Splicing Mutation in a Family with X-Linked Dilated Cardiomyopathy Alessandra Ferlini,

Silvia E. Racedo, Donna M. McDonald-McGinn, Jonathan H

Michael Field, Patrick S

Germline BHD-Mutation Spectrum and Phenotype Analysis of a Large Cohort of Families with Birt-Hogg-Dubé Syndrome Laura S. Schmidt, Michael L. Nickerson,

Volume 126, Issue 6, Pages (September 2006)

Mutations in SMG9, Encoding an Essential Component of Nonsense-Mediated Decay Machinery, Cause a Multiple Congenital Anomaly Syndrome in Humans and Mice

SAMS, a Syndrome of Short Stature, Auditory-Canal Atresia, Mandibular Hypoplasia, and Skeletal Abnormalities Is a Unique Neurocristopathy Caused by Mutations.

Capillary Malformation–Arteriovenous Malformation, a New Clinical and Genetic Disorder Caused by RASA1 Mutations Iiro Eerola, Laurence M. Boon, John.

Elizabeth R. Heller, Sikandar G

Mutations in TCF4, Encoding a Class I Basic Helix-Loop-Helix Transcription Factor, Are Responsible for Pitt-Hopkins Syndrome, a Severe Epileptic Encephalopathy.

Mutations in ASPH Cause Facial Dysmorphism, Lens Dislocation, Anterior-Segment Abnormalities, and Spontaneous Filtering Blebs, or Traboulsi Syndrome

Genotype/Phenotype Analysis of a Photoreceptor-Specific ATP-Binding Cassette Transporter Gene, ABCR, in Stargardt Disease Richard Alan Lewis, Noah F.

John D. Rioux, Valerie A. Stone, Mark J

Bassem A. Bejjani, Lisa G. Shaffer

A Nonsense Mutation in CRYBB1 Associated with Autosomal Dominant Cataract Linked to Human Chromosome 22q Donna S. Mackay, Olivera B. Boskovska, Harry.

Genetic Background of Congenital Chloride Diarrhea in High-Incidence Populations: Finland, Poland, and Saudi Arabia and Kuwait Pia Höglund, Mari Auranen,

Splitting p63 The American Journal of Human Genetics

High-Resolution Molecular Characterization of 15q11-q13 Rearrangements by Array Comparative Genomic Hybridization (Array CGH) with Detection of Gene Dosage

ABCB6 Mutations Cause Ocular Coloboma

A Missense Mutation in the Zinc-Finger Domain of the Human Hairless Gene Underlies Congenital Atrichia in a Family of Irish Travellers Wasim Ahmad, Alan.

Christina A. Gurnett, Farhang Alaee, Lisa M. Kruse, David M

Ataxia with Isolated Vitamin E Deficiency: Heterogeneity of Mutations and Phenotypic Variability in a Large Number of Families Laurent Cavalier, Karim.

Dominant Mutations in KAT6A Cause Intellectual Disability with Recognizable Syndromic Features Emma Tham, Anna Lindstrand, Avni Santani, Helena Malmgren,

Bilineal Disease and Trans-Heterozygotes in Autosomal Dominant Polycystic Kidney Disease York Pei, Andrew D. Paterson, Kai Rong Wang, Ning He, Donna.

Identification of Mutations in TRAPPC9, which Encodes the NIK- and IKK-β-Binding Protein, in Nonsyndromic Autosomal-Recessive Mental Retardation Asif.

De Novo Mutations of RERE Cause a Genetic Syndrome with Features that Overlap Those Associated with Proximal 1p36 Deletions Brieana Fregeau, Bum Jun.

Ryan McDaniell, Daniel M. Warthen, Pedro A

Dominique J. Verlaan, Adrian M. Siegel, Guy A. Rouleau

Opitz G/BBB Syndrome in Xp22: Mutations in the MID1 Gene Cluster in the Carboxy- Terminal Domain Karin Gaudenz, Erich Roessler, Nandita Quaderi, Brunella.

Functional Redundancy of ERK1 and ERK2 MAP Kinases during Development

A Unique Point Mutation in the PMP22 Gene Is Associated with Charcot-Marie-Tooth Disease and Deafness Margaret J. Kovach, Jing-Ping Lin, Simeon Boyadjiev,

Tracy Dixon-Salazar, Jennifer L. Silhavy, Sarah E. Marsh, Carrie M

Spectrum of Mutations in the RPGR Gene That Are Identified in 20% of Families with X- Linked Retinitis Pigmentosa Monika Buraczynska, Weiping Wu, Ricardo.

Deletions and Point Mutations of LRRC50 Cause Primary Ciliary Dyskinesia Due to Dynein Arm Defects Niki Tomas Loges, Heike Olbrich, Anita Becker-Heck,

Early Onset of Severe Familial Amyotrophic Lateral Sclerosis with a SOD-1 Mutation: Potential Impact of CNTF as a Candidate Modifier Gene Ralf Giess,

Identification of Somatic Chromosomal Abnormalities in Hypothalamic Hamartoma Tissue at the GLI3 Locus David W. Craig, Abraham Itty, Corrie Panganiban,

Mutations in HPSE2 Cause Urofacial Syndrome

Biljana Ilkovski, Sandra T. Cooper, Kristen Nowak, Monique M

Mutations in CHEK2 Associated with Prostate Cancer Risk

NSD1 Mutations Are the Major Cause of Sotos Syndrome and Occur in Some Cases of Weaver Syndrome but Are Rare in Other Overgrowth Phenotypes Jenny Douglas,

Mutations in UNC80, Encoding Part of the UNC79-UNC80-NALCN Channel Complex, Cause Autosomal-Recessive Severe Infantile Encephalopathy Hanan E. Shamseldin,

C. E. Browne, N. R. Dennis, E. Maher, F. L. Long, J. C. Nicholson, J

Cohen Syndrome Is Caused by Mutations in a Novel Gene, COH1, Encoding a Transmembrane Protein with a Presumed Role in Vesicle-Mediated Sorting and Intracellular.

Identification of a New Splice Form of the EDA1 Gene Permits Detection of Nearly All X- Linked Hypohidrotic Ectodermal Dysplasia Mutations Alex W. Monreal,

Identification of Novel pro-α2(IX) Collagen Gene Mutations in Two Families with Distinctive Oligo-Epiphyseal Forms of Multiple Epiphyseal Dysplasia Paul.

D. M. Hagan, A. J. Ross, T. Strachan, S. A. Lynch, V. Ruiz-Perez, Y. M

Identification and Functional Analysis of ZIC3 Mutations in Heterotaxy and Related Congenital Heart Defects Stephanie M. Ware, Jianlan Peng, Lirong Zhu,

PRRT2 Mutations Cause Benign Familial Infantile Epilepsy and Infantile Convulsions with Choreoathetosis Syndrome Sarah E. Heron, Bronwyn E. Grinton,

Presentation transcript:

Spectrum of CHD7 Mutations in 110 Individuals with CHARGE Syndrome and Genotype-Phenotype Correlation Seema R. Lalani, Arsalan M. Safiullah, Susan D. Fernbach, Karine G. Harutyunyan, Christina Thaller, Leif E. Peterson, John D. McPherson, Richard A. Gibbs, Lisa D. White, Margaret Hefner, Sandra L.H. Davenport, John M. Graham, Carlos A. Bacino, Nancy L. Glass, Jeffrey A. Towbin, William J. Craigen, Steven R. Neish, Angela E. Lin, John W. Belmont The American Journal of Human Genetics Volume 78, Issue 2, Pages 303-314 (February 2006) DOI: 10.1086/500273 Copyright © 2006 The American Society of Human Genetics Terms and Conditions

Figure 1 Individuals with CHARGE syndrome who have CHD7 mutations. A and a, A 17-year-old girl with retinal coloboma, characteristic ear malformation, hearing loss, partial atrioventricular canal defect, growth retardation, and delayed puberty who has a frameshift mutation in exon 37. B and b, An 11-year-old boy with colobomas of the iris and the macula, choanal stenosis, characteristic ear malformation, bilateral Mondini malformation, profound hearing loss, submucous cleft palate, bilateral facial palsy, undescended testes, and pulmonary atresia with ventricular septal defect who has a de novo frameshift mutation in exon 18. C and c, A 3-year-old boy with bilateral iris coloboma, choanal stenosis, ear malformation, hearing loss, facial palsy, and abnormal cochlea but without cardiovascular malformation who has a nonsense mutation in exon 13. D and d, A 12-year-old boy with coloboma involving the optic nerve, choanal atresia, characteristic ear malformation, profound hearing loss, abnormal inner ear, patent ductus arteriosus, and genital abnormalities who has a frameshift mutation in exon 2. Note that the individuals in panels B and D illustrate the characteristic facial appearance of CHARGE syndrome. The American Journal of Human Genetics 2006 78, 303-314DOI: (10.1086/500273) Copyright © 2006 The American Society of Human Genetics Terms and Conditions

Figure 2 Microarray gene-expression profile and the resulting cluster analysis. Patterns of gene expression were assessed on Affymetrix U133Plus2.0 arrays (see “Material and Methods” section for details). After identification of a subset of transcripts with apparently significant differences in expression between the individuals with CHARGE syndrome with CHD7 mutations and the controls, the combined data were used to produce a hierarchical cluster analysis. Expression values shown were standardized using the gene-specific mean and SD of log2 expression. Note that the profile of CHA230 (who had no detectable CHD7 mutation) is highly similar to those of individuals with CHD7 mutations. The American Journal of Human Genetics 2006 78, 303-314DOI: (10.1086/500273) Copyright © 2006 The American Society of Human Genetics Terms and Conditions

Figure 3 Genomic and protein map of CHD7, indicating the spectrum of mutations in CHARGE syndrome. On the protein map, blackened circles signify nonsense mutations, blackened diamonds signify frameshift mutations, unblackened squares signify missense mutations, and the unblackened circle specifies a mutation with an in-frame deletion of 3 aa. On the genomic sequence, triangles represent splice-site mutations. The American Journal of Human Genetics 2006 78, 303-314DOI: (10.1086/500273) Copyright © 2006 The American Society of Human Genetics Terms and Conditions

Figure 4 Five pedigrees with CHARGE syndrome illustrating four familial cases and an affected pair of MZ twins. CHD7 mutations were identified in pedigrees CHA76, CHA166, and CHA172. Germline mosaicism is suggested in CHA76, whereas CHA166 indicates autosomal dominant transmission of the missense mutation in this mildly affected family. CHA172 shows a nonsense mutation in MZ twins. Mutations in CHD7 were not identified in families CHA192 and CHA88. Probands are indicated by arrows. The American Journal of Human Genetics 2006 78, 303-314DOI: (10.1086/500273) Copyright © 2006 The American Society of Human Genetics Terms and Conditions

Figure 5 Mouse embryo whole-mount and section in situ hybridization showing the expression of Chd7. A, Whole-mount in situ hybridization of the embryo at 10.5 dpc, demonstrating expression of Chd7 in the craniofacial region. B, Expression of Chd7 observed in cardiac outflow tract (OFT). LA = left atrium; RA = right atrium. C, Sagittal section of embryo at 10.5 dpc, showing expression in the facio-acoustic (VII–VIII) preganglion complex (FA), hindbrain (HB), forebrain (FB), mandibular component of the first branchial arch (BA), and otic vesicle (OV). D and F, Sagittal section of embryo with expression in optic stalk/optic vesicle (OPV) and olfactory pit (OP). E and G, Magnified images of panel C, indicating expression of Chd7 in facio-acoustic preganglion complex and otic vesicle, with hematoxylin and eosin stain. H, Sagittal section of the embryo, demonstrating expression in truncus arteriosus (TA) at 10.5 dpc. The American Journal of Human Genetics 2006 78, 303-314DOI: (10.1086/500273) Copyright © 2006 The American Society of Human Genetics Terms and Conditions