Mutations in NOTCH1 Cause Adams-Oliver Syndrome

Slides:

Advertisements

Similar presentations

Biallelic Mutations in TMTC3, Encoding a Transmembrane and TPR-Containing Protein, Lead to Cobblestone Lissencephaly Julie Jerber, Maha S. Zaki, Jumana.

Advertisements

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

Mesial temporal lobe epilepsy associated with KCNT1 mutation

Figure 1 Phenotype and genotype of an undiagnosed family with autosomal recessive spastic ataxia Phenotype and genotype of an undiagnosed family with autosomal.

A Novel Mutation and Large Size Polymorphism Affecting the V2 Domain of Keratin 1 in an African-American Family with Severe, Diffuse Palmoplantar Keratoderma.

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

Exome Sequencing in Brown-Vialetto-Van Laere Syndrome

Familial Deafness, Congenital Heart Defects, and Posterior Embryotoxon Caused by Cysteine Substitution in the First Epidermal-Growth-Factor–Like Domain.

Eija Siintola, Meral Topcu, Nina Aula, Hannes Lohi, Berge A

Disruptive SCYL1 Mutations Underlie a Syndrome Characterized by Recurrent Episodes of Liver Failure, Peripheral Neuropathy, Cerebellar Atrophy, and Ataxia

Biallelic Mutations in TMTC3, Encoding a Transmembrane and TPR-Containing Protein, Lead to Cobblestone Lissencephaly Julie Jerber, Maha S. Zaki, Jumana.

Deletion and Point Mutations of PTHLH Cause Brachydactyly Type E

De Novo Loss-of-Function Mutations in SETD5, Encoding a Methyltransferase in a 3p25 Microdeletion Syndrome Critical Region, Cause Intellectual Disability

Kimberly A. Aldinger, Stephen J. Mosca, Martine Tétreault, Jennifer C

Mutations in PADI6 Cause Female Infertility Characterized by Early Embryonic Arrest Yao Xu, Yingli Shi, Jing Fu, Min Yu, Ruizhi Feng, Qing Sang, Bo Liang,

Exome Sequencing Identifies Truncating Mutations in Human SERPINF1 in Autosomal- Recessive Osteogenesis Imperfecta Jutta Becker, Oliver Semler, Christian.

T. Ohta, K. Buiting, H. Kokkonen, S. McCandless, S. Heeger, H

Heterozygous Loss-of-Function Mutations in DLL4 Cause Adams-Oliver Syndrome Josephina A.N. Meester, Laura Southgate, Anna-Barbara Stittrich, Hanka Venselaar,

Autosomal-Recessive Congenital Cerebellar Ataxia Is Caused by Mutations in Metabotropic Glutamate Receptor 1 Velina Guergueltcheva, Dimitar N. Azmanov,

Pathogenicity Evaluation of BRCA1 and BRCA2 Unclassified Variants Identified in Portuguese Breast/Ovarian Cancer Families Catarina Santos, Ana Peixoto,

Alexander G. Marneros Journal of Investigative Dermatology

A Homozygous Mutation in the Tight-Junction Protein JAM3 Causes Hemorrhagic Destruction of the Brain, Subependymal Calcification, and Congenital Cataracts

Jong-Min Lee, Kyung-Hee Kim, Aram Shin, Michael J

Mutations in a Novel Gene with Transmembrane Domains Underlie Usher Syndrome Type 3 Tarja Joensuu, Riikka Hämäläinen, Bo Yuan, Cheryl Johnson, Saara.

Mutations in ABCB6 Cause Dyschromatosis Universalis Hereditaria

GCM2-Activating Mutations in Familial Isolated Hyperparathyroidism

A Recurrent Missense Mutation in ZP3 Causes Empty Follicle Syndrome and Female Infertility Tailai Chen, Yuehong Bian, Xiaoman Liu, Shigang Zhao, Keliang.

Mutations in the ZNF41 Gene Are Associated with Cognitive Deficits: Identification of a New Candidate for X-Linked Mental Retardation Sarah A. Shoichet,

RBPJ Mutations Identified in Two Families Affected by Adams-Oliver Syndrome Susan J. Hassed, Graham B. Wiley, Shaofeng Wang, Ji-Yun Lee, Shibo Li, Weihong.

Per M. Knappskog, Jacek Majewski, Avi Livneh, Per Torgeir E

Christian Gilissen, Heleen H

A Presenilin-1 Truncating Mutation Is Present in Two Cases with Autopsy-Confirmed Early-Onset Alzheimer Disease Carolyn Tysoe, Joanne Whittaker, John.

Aicardi-Goutières Syndrome Is Caused by IFIH1 Mutations

Mutation of Solute Carrier SLC16A12 Associates with a Syndrome Combining Juvenile Cataract with Microcornea and Renal Glucosuria Barbara Kloeckener-Gruissem,

Mutations in FAM20C Are Associated with Lethal Osteosclerotic Bone Dysplasia (Raine Syndrome), Highlighting a Crucial Molecule in Bone Development M.A.

Fatema Zahrani, Mohammed A. Aldahmesh, Muneera J. Alshammari, Selwa A

Joubert Syndrome 2 (JBTS2) in Ashkenazi Jews Is Associated with a TMEM216 Mutation Simon Edvardson, Avraham Shaag, Shamir Zenvirt, Yaniv Erlich, Gregory.

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.

A Novel Point Mutation Affecting the Tyrosine Kinase Domain of the TRKA Gene in a Family with Congenital Insensitivity to Pain with Anhidrosis Shinichi.

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,

Mutations in ECEL1 Cause Distal Arthrogryposis Type 5D

A Mutation in the Variable Repeat Region of the Aggrecan Gene (AGC1) Causes a Form of Spondyloepiphyseal Dysplasia Associated with Severe, Premature.

Biallelic Mutations in PATL2 Cause Female Infertility Characterized by Oocyte Maturation Arrest Biaobang Chen, Zhihua Zhang, Xiaoxi Sun, Yanping Kuang,

Exome Sequencing Identifies a DYNC1H1 Mutation in a Large Pedigree with Dominant Axonal Charcot-Marie-Tooth Disease Michael N. Weedon, Robert Hastings,

Next-Generation Sequencing Identifies Mutations of SMPX, which Encodes the Small Muscle Protein, X-Linked, as a Cause of Progressive Hearing Impairment

A Novel Dominant Mutation in Plakoglobin Causes Arrhythmogenic Right Ventricular Cardiomyopathy Angeliki Asimaki, Petros Syrris, Thomas Wichter, Paul.

Ryan McDaniell, Daniel M. Warthen, Pedro A

Mutations in FEZF1 Cause Kallmann Syndrome

Heterozygous Loss-of-Function Mutations in DLL4 Cause Adams-Oliver Syndrome Josephina A.N. Meester, Laura Southgate, Anna-Barbara Stittrich, Hanka Venselaar,

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

Volume 58, Issue 2, Pages (August 2000)

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

Compound Heterozygosity for Novel Splice Site Mutations in the BPAG2/COL17A1 Gene Underlies Generalized Atrophic Benign Epidermolysis Bullosa Leena Pulkkinen,

Volume 57, Issue 3, Pages (March 2000)

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

Mutations in POLR3A and POLR3B Encoding RNA Polymerase III Subunits Cause an Autosomal-Recessive Hypomyelinating Leukoencephalopathy Hirotomo Saitsu,

(A) yellow cDNA comparison among wild-type and ch mutants

Arun Kumar, Satish C. Girimaji, Mahesh R. Duvvari, Susan H. Blanton

Mutations in CHEK2 Associated with Prostate Cancer Risk

Germline Mutations in CDH23, Encoding Cadherin-Related 23, Are Associated with Both Familial and Sporadic Pituitary Adenomas Qilin Zhang, Cheng Peng,

Mutations in NEXN, a Z-Disc Gene, Are Associated with Hypertrophic Cardiomyopathy Hu Wang, Zhaohui Li, Jizheng Wang, Kai Sun, Qiqiong Cui, Lei Song, Yubao.

Mutations in POFUT1, Encoding Protein O-fucosyltransferase 1, Cause Generalized Dowling-Degos Disease Ming Li, Ruhong Cheng, Jianying Liang, Heng Yan,

Cole-Carpenter Syndrome Is Caused by a Heterozygous Missense Mutation in P4HB Frank Rauch, Somayyeh Fahiminiya, Jacek Majewski, Jian Carrot-Zhang, Sergei.

Frances R. Goodman, Frank Majewski, Amanda L. Collins, Peter J

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.

Zhimiao Lin, Quan Chen, Lei Shi, Mingyang Lee, Kathrin A

BMPER Mutation in Diaphanospondylodysostosis Identified by Ancestral Autozygosity Mapping and Targeted High-Throughput Sequencing Vincent A. Funari,

Homozygous WNT3 Mutation Causes Tetra-Amelia in a Large Consanguineous Family Stephan Niemann, Chengfeng Zhao, Filon Pascu, Ulrich Stahl, Ute Aulepp,

Presentation transcript:

Mutations in NOTCH1 Cause Adams-Oliver Syndrome Anna-Barbara Stittrich, Anna Lehman, Dale L. Bodian, Justin Ashworth, Zheyuan Zong, Hong Li, Patricia Lam, Alina Khromykh, Ramaswamy K. Iyer, Joseph G. Vockley, Rajiv Baveja, Ermelinda Santos Silva, Joanne Dixon, Eyby L. Leon, Benjamin D. Solomon, Gustavo Glusman, John E. Niederhuber, Jared C. Roach, Millan S. Patel The American Journal of Human Genetics Volume 95, Issue 3, Pages 275-284 (September 2014) DOI: 10.1016/j.ajhg.2014.07.011 Copyright © 2014 The American Society of Human Genetics Terms and Conditions

Figure 1 Clinical Vignettes for AOS Individuals from Families 1, 2, and 4 (A–C) Family 1 proband (1-II-3): scarred aplasia cutis lesion affecting the scalp at age 5 years (A), calcific deposits in the subcutaneous tissue of the distal first toe (arrow, B), and terminal transverse defect of the toes and cutis marmorata in infancy (C). (D–F) Family 2 proband (2-III-1): distal hypoplasia of the digits of the left hand (D) and toes of the feet (E) and aplasia cutis of the scalp (F). (G and H) Family 2 father of the proband (2-II-1): aplasia cutis of the scalp (G) and terminal transverse defects of both feet (H). (I–K) Family 4 proband (4-II-1): MRI of the brain on day of life (DOL) 9 shows areas of infarcts (solid arrows) and an area of partial thrombus (outlined arrow) from axial sections on diffusion weighted MRI (I and J) and axial T2-weighted MRI (K). The American Journal of Human Genetics 2014 95, 275-284DOI: (10.1016/j.ajhg.2014.07.011) Copyright © 2014 The American Society of Human Genetics Terms and Conditions

Figure 2 Pedigrees of the AOS-Affected Families and the Respective NOTCH1 Variants (A) Affected males are represented by solid squares, affected females are represented by solid circles, and index individuals are indicated by arrows. For individuals tested by WGS and/or Sanger sequencing, the genotypes are noted below in boxes; WT indicates the wild-type genotype, and the five different mutations observed in NOTCH1 (RefSeq accession number NM_017617.3) are numbered as follows: (1) the 85 kb deletion, (2) c.743−1G>T (splice site), (3) c.1285T>C (p.Cys429Arg), (4) c.4487G>A (p.Cys1496Tyr), and (5) c.5965G>A (p.Asp1989Asn). (B) For family 1, analysis of sequencing coverage is shown and indicates a 85 kb deletion (chr9: 139,439,621–139,524,478) that overlaps with the promoter region and coding sequence of NOTCH1 (chr9: 139,388,896–139,440,238) in the proband. For families 2–5, Sanger sequencing chromatograms show the respective variants (red asterisks). (C) The exon-intron structure of NOTCH1 is shown. The red triangles indicate our reported mutations in NOTCH1: (1) the 85 kb deletion, (2) c.743−1G>T (splice site), (3) c.1285T>C (p.Cys429Arg), (4) c.4487G>A (p.Cys1496Tyr), and (5) c.5965G>A (p.Asp1989Asn). Blue dots indicate previously reported NOTCH1 variants associated with isolated cardiac defects. The American Journal of Human Genetics 2014 95, 275-284DOI: (10.1016/j.ajhg.2014.07.011) Copyright © 2014 The American Society of Human Genetics Terms and Conditions

Figure 3 Modeling the Effect of the NOTCH1 Variants p.Cys429Arg, p.Cys1496Tyr, and p.Asp1989Asn on Protein Structure and Energetics For each variant, the left and middle panels show 20 energy-minimized structures from Rosetta modeling (A, D, and G represent the wild-type proteins, and B, E, and H represent the simulated substitutions). In (C), (F), and (I), the predicted change in the free energy of protein folding and stability upon substitution (ΔΔG) is shown for each variant (blue, wild-type; pink, variant protein). Higher values indicate decreased domain stability. The American Journal of Human Genetics 2014 95, 275-284DOI: (10.1016/j.ajhg.2014.07.011) Copyright © 2014 The American Society of Human Genetics Terms and Conditions