Supplementary Figures

Total Page：16

File Type：pdf, Size：1020Kb

Supplemental Figures Supplementary Figure 1. Top 10 most frequently mutated genes. Supplementary Figure 2. Frequency of missense and nonsense mutations in TP53 and RB1 and their distribution across all samples. Supplementary Figure 3. The distribution of APC mutations across different domains of the gene. Supplementary Figure 4. Amplifications in MYC. Supplementary Figure 5. TP53 mutations across SCLC samples with multiple mutations. Supplementary Figure 6. Oncoplot demonstrating distribution of the ten most frequently altered genes across samples collected at diagnosis. 0 50 150 250 350 72% TP53 18% RB1 14% EGFR 13% NF1 12% ARID1A 10% APC 8% PIK3CA 8% AR 8% BRCA1 8% KRAS Missense Mutation Nonsense Mutation SpliceSite Multi Hit Supplementary Figure 1. Top 10 most frequently mutated genes. Oncoplot demonstrating distribution of the ten most frequently altered genes across all samples. The right barplot represents the frequency of mutations in each gene. Multi Hit = presence of multiple types of mutation in same gene in a given sample. Each column represents an individual patient sample. 0 100 200 300 66% TP53 12% RB1 Missense Mutation Nonsense Mutation Multi Hit Supplementary Figure 2. Frequency of missense and nonsense mutations in TP53 and RB1 and their distribution across all samples. The right barplot represents the frequency of mutations in each gene. Multi-Hit = presence of multiple types of mutation in same gene in a given sample. Each column represents an individual patient sample. G1635E 2 1 # Mutations O ARDs S BASIC EB1 0 500 1000 1500 2000 2500 2846 Indel Missense Mutation Nonsense Mutation Splice Site Supplementary Figure 3. The distribution of APC mutations across different domains of the gene. O = oligomerization. ARDs = Armadillo Repeat Domains. S = Ser- Ala-Met-Pro (SAMP) motif. EB1 = EB1 binding domain. n.s. 100 80 r 60 40 Copy numbe 20 0 Diagnosis Relapse Supplementary Figure 4. Amplifications in MYC. The distribution of the number of copies of MYC across diagnosis and relapse samples in which they are amplified. Error bars represent Mean ± SEM. n.s = not significant. Y220C R273H/L/G R175H/P R282W V272M/L # Mutations Tad DNA-binding Tet 0 100 200 300 396 Indel Missense Mutation Nonsense Mutation Splice Site Supplementary Figure 5. TP53 mutations across SCLC samples with multiple mutations. Demonstrates mutation pattern of mutations in TP53 that were shed at lower allelic frequecies in samples showing multiple mutations. Tad = Transactivating domain. Tet = Tetrameriization domain. 0 10 20 30 67% TP53 24% RB1 22% PIK3CA 14% NOTCH1 12% ERBB2 10% EGFR 10% KIT 9% ARID1A 9% NF1 9% PDGFRA Missense Mutation Nonsense Mutation Multi Hit Splice Site Amp Supplementary Figure 6. Oncoplot demonstrating distribution of the ten most frequently altered genes across samples collected at diagnosis. Amp = amplification, Multi-Hit = presence of multiple types of mutation in same gene in a given sample. Each column represents an individual patient sample. The right barplot represents the frequency of mutations in each gene..

Copy Link

Recommended publications

Bio 102 Practice Problems Genetic Code and Mutation
Bio 102 Practice Problems Genetic Code and Mutation Multiple choice: Unless otherwise directed, circle the one best answer: 1. Choose the one best answer: Beadle and Tatum mutagenized Neurospora to find strains that required arginine to live. Based on the classification of their mutants, they concluded that: A. one gene corresponds to one protein. B. DNA is the genetic material. C. "inborn errors of metabolism" were responsible for many diseases. D. DNA replication is semi-conservative. E. protein cannot be the genetic material. 2. Choose the one best answer. Which one of the following is NOT part of the definition of a gene? A. A physical unit of heredity B. Encodes a protein C. Segement of a chromosome D. Responsible for an inherited characteristic E. May be linked to other genes 3. A mutation converts an AGA codon to a TGA codon (in DNA). This mutation is a: A. Termination mutation B. Missense mutation C. Frameshift mutation D. Nonsense mutation E. Non-coding mutation 4. Beadle and Tatum performed a series of complex experiments that led to the idea that one gene encodes one enzyme. Which one of the following statements does not describe their experiments? A. They deduced the metabolic pathway for the synthesis of an amino acid. B. Many different auxotrophic mutants of Neurospora were isolated. C. Cells unable to make arginine cannot survive on minimal media. D. Some mutant cells could survive on minimal media if they were provided with citrulline or ornithine. E. Homogentisic acid accumulates and is excreted in the urine of diseased individuals. 5.
[Show full text]
Truncating Mutations in Severe Intellectual Disability
European Journal of Human Genetics (2014) 22, 289–292 & 2014 Macmillan Publishers Limited All rights reserved 1018-4813/14 www.nature.com/ejhg SHORT REPORT Expanding the phenotype of IQSEC2 mutations: truncating mutations in severe intellectual disability Frederic Tran Mau-Them1, Marjolaine Willems*,1, Beate Albrecht2, Elodie Sanchez1, Jacques Puechberty1, Sabine Endele3, Anouck Schneider4, Nathalie Ruiz Pallares4,5, Chantal Missirian6, Francois Rivier7, Manon Girard4, Muriel Holder8, Sylvie Manouvrier8, Isabelle Touitou5, Genevieve Lefort4, Pierre Sarda1, Anne Moncla7, Severine Drunat9, Dagmar Wieczorek2 and David Genevieve1 Intellectual disability (ID) is frequent in the general population, with 1 in 50 individuals directly affected worldwide. The multiple etiologies include X-linked ID (XLID). Among syndromic XLID, few syndromes present severe ID associated with postnatal microcephaly and midline stereotypic hand movements. We report on three male patients with ID, midline stereotypic hand movements, hypotonia, hyperkinesia, strabismus, as well as seizures (2/3), and non-inherited and postnatal onset microcephaly (2/3). Using array CGH and exome sequencing we characterised two truncating mutations in IQSEC2, namely two de novo intragenic duplication mapped to the Xp11.22 region and a nonsense mutation in exon 7. We propose that truncating mutations in IQSEC2 are responsible for syndromic severe ID in male patients and should be screened in patients without mutations in MECP2, FOXG1, CDKL5 and MEF2C. European Journal of Human Genetics (2014) 22, 289–292; doi:10.1038/ejhg.2013.113; published online 15 May 2013 Keywords: syndromic X-linked intellectual disability; microcephaly; IQSEC2-truncating mutations INTRODUCTION native to the south of France. Pregnancy was uneventful. The boy was born at Intellectual disability (ID) is deﬁned by substantial limitations in 37 ½ weeks of gestation full term by caesarean section due to an abnormal cognitive functioning (intellectual quotient o70) coupled with a deﬁcit presentation.
[Show full text]
Variegate Porphyria: Identification of a Nonsense Mutation in The
View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector MUTATION REPORTS Variegate Porphyria: Identification of a Nonsense Mutation in the Protoporphyrinogen Oxidase Gene Jorge Frank, Frank K. Jugert,* Katrin Kalka,† Gu¨nter Goerz,† Hans F. Merk,* and Angela M. Christiano Department of Dermatology, Columbia University, New York, New York, U.S.A.; *Department of Dermatology, University Clinic of the RWTH, Aachen, Germany; †Department of Dermatology, Heinrich Heine University, Du¨sseldorf, Germany The porphyrias are disorders of porphyrin metabolism protoporphyrinogen oxidase gene, resulting in the substi- that result from inherited or acquired aberrations in the tution of glutamic acid by a nonsense codon, designated control of the heme biosynthetic pathway. Variegate E133X. Our investigation establishes that a nonsense porphyria is characterized by a partial reduction in the mutation in the protoporphyrinogen oxidase gene is activity of protoporphyrinogen oxidase. In this study, we the underlying mutation in this family with variegate identified the first nonsense mutation in a family with porphyria. Key words: bullous diseases/genodermatosis/photo- variegate porphyria. The mutation consisted of a previ- sensitivity/porphyrin-heme biosynthetic pathway. J Invest ously unreported G-to-T transversion in exon 5 of the Dermatol 110:449–451, 1998 he porphyrias are disorders of heme metabolism resulting in the PPO gene in the clinically affected patient and one of her sons from the inherited or acquired dysregulation of one of by heteroduplex analysis, automated sequencing, and allele specific the eight enzymes that control the porphyrin-heme oligonucleotide (ASO) hybridization. The mutation consisted of a biosynthetic pathway.
[Show full text]
Excess of Rare Novel Loss-Of-Function Variants in Synaptic Genes in Schizophrenia and Autism Spectrum Disorders
Molecular Psychiatry (2014) 19, 872–879 & 2014 Macmillan Publishers Limited All rights reserved 1359-4184/14 www.nature.com/mp ORIGINAL ARTICLE Excess of rare novel loss-of-function variants in synaptic genes in schizophrenia and autism spectrum disorders EM Kenny1,3, P Cormican1,3, S Furlong1,3, E Heron1, G Kenny1, C Fahey1, E Kelleher1, S Ennis2, D Tropea1, R Anney1, AP Corvin1, G Donohoe1, L Gallagher1, M Gill1 and DW Morris1 Schizophrenia (SZ) and autism spectrum disorders (ASDs) are complex neurodevelopmental disorders that may share an underlying pathology suggested by shared genetic risk variants. We sequenced the exonic regions of 215 genes in 147 ASD cases, 273 SZ cases and 287 controls, to identify rare risk mutations. Genes were primarily selected for their function in the synapse and were categorized as: (1) Neurexin and Neuroligin Interacting Proteins, (2) Post-synaptic Glutamate Receptor Complexes, (3) Neural Cell Adhesion Molecules, (4) DISC1 and Interactors and (5) Functional and Positional Candidates. Thirty-one novel loss-of-function (LoF) variants that are predicted to severely disrupt protein-coding sequence were detected among 2 861 rare variants. We found an excess of LoF variants in the combined cases compared with controls (P ¼ 0.02). This effect was stronger when analysis was limited to singleton LoF variants (P ¼ 0.0007) and the excess was present in both SZ (P ¼ 0.002) and ASD (P ¼ 0.001). As an individual gene category, Neurexin and Neuroligin Interacting Proteins carried an excess of LoF variants in cases compared with controls (P ¼ 0.05). A de novo nonsense variant in GRIN2B was identiﬁed in an ASD case adding to the growing evidence that this is an important risk gene for the disorder.
[Show full text]
Nonsense and Missense Mutations in Hemophilia A: Estimate of the Relative Mutation Rate at CG Dinucleotides Hagop Youssoufian,* Stylianos E
Am. J. Hum. Genet. 42:718-725, 1988 Nonsense and Missense Mutations in Hemophilia A: Estimate of the Relative Mutation Rate at CG Dinucleotides Hagop Youssoufian,* Stylianos E. Antonarakis,* William Bell,t Anne M. Griffin,4 and Haig H. Kazazian, Jr.* *Genetics Unit, Department of Pediatrics, and tDivision of Hematology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore; and tDivision of Hematology, Department of Medicine, University of North Carolina School of Medicine, Chapel Hill Summary Hemophilia A is an X-linked disease of coagulation caused by deficiency of factor VIII. Using cloned cDNA and synthetic oligonucleotide probes, we have now screened 240 patients and found CG-to-TG transitions in an exon in nine. We have previously reported four of these patients; and here we report the remaining five, all of whom were severely affected. In one patient a TaqI site was lost in exon 23, and in the other four it was lost in exon 24. The novel exon 23 mutation is a CG-to-TG substitution at the codon for amino acid residue 2166, producing a nonsense codon in place of the normal codon for arginine. Simi- larly, the exon 24 mutations are also generated by CG-to-TG transitions, either on the sense strand produc- ing nonsense mutations or on the antisense strand producing missense mutations (Arg to Gln) at position 2228. The novel missense mutations are the first such mutations observed in association with severe hemo- philia A. These results provide further evidence that recurrent mutations are not uncommon in hemophilia A, and they also allow us to estimate that the extent of hypermutability of CG dinucleotides is 10-20 times greater than the average mutation rate for hemophilia A.
[Show full text]
Cancer Genomics Terminology
Cancer Genomics Terminology Acquired Susceptibility Mutation: A mutation in a gene that occurs after birth from a carcinogenic insult. Allele: One of the variant forms of a gene. Different alleles may produce variation in inherited characteristics. Allele Heterogeneity: A phenotype that can be produced by different genetic mechanisms. Amino Acid: The building blocks of protein, for which DNA carries the genetic code. Analytical Sensitivity: The proportion of positive test results correctly reported by the laboratory among samples with a mutation(s) that the laboratory’s test is designed to detect. Analytic Specificity: The proportion of negative test results correctly reported among samples when no detectable mutation is present. Analytic Validity: A test’s ability to accurately and reliably measure the genotype of interest. Apoptosis: Programmed cell death. Ashkenazi: Individuals of Eastern European Jewish ancestry/decent (For example-Germany and Poland). Non-assortative mating occurred in this population. Association: When significant differences in allele frequencies are found between a disease and control population, the disease and allele are said to be in association. Assortative Mating: In population genetics, selective mating in a population between individuals that are genetically related or have similar characteristics. Autosome: Any chromosome other than a sex chromosome. Humans have 22 pairs numbered 1-22. Base Excision Repair Gene: The gene responsible for the removal of a damaged base and replacing it with the correct nucleotide. Base Pair: Two bases, which form a “rung on the DNA ladder”. Bases are the “letters” (Adenine, Thymine, Cytosine, Guanine) that spell out the genetic code. Normally adenine pairs with thymine and cytosine pairs with guanine.
[Show full text]
Genetics 101: What's in a CDKL5 Mutation?
JULY 21, 2018 Genetics 101: SCN1A Katie Angione, MS CGC Certified Genetic Counselor CHCO Neurology Disclosures: I have no financial interests or relationships to disclose. Objectives 1. Review genetic concepts and terminology 2. Discuss the genetics of Dravet Syndrome 3. Understand how to interpret a genetic testing report Who Are Genetic Counselors? • Master’s-trained health care professionals who combine their knowledge of: - Basic science - Medical genetics - Epidemiological principles - Counseling theory • With their skills in: - Genetic risk assessment - Education - Interpersonal communication and counseling • To provide services to clients and their families for a diverse set of genetic or genomic indications Dravet Syndrome • Seizures beginning in the first year • Developmental delays • Normal development prior to seizure onset • Developmental slowing, plateau, or regression • Other common features: • Movement/ balance issues, orthopedic conditions, growth and nutrition issues, sleeping difficulties, behavioral problems • Incidence of 1:16,000 – 1:20,000 www.dravetfoundation.org Greenwood Genetic Center Genetic Counseling Aids, 2013 Genes and Proteins • A gene is a segment of DNA that codes for a protein • A protein is a molecule that can have many different important roles in the body • provide structure and support • transport materials and sending signals • protect the body from viruses and bacteria • carry out chemical reactions • Proteins are made up of smaller units called amino acids • 20 different types of amino acids •
[Show full text]
DNA Mutation Worksheetkey
Name: ________________________ BIO300/CMPSC300 Mutation - Spring 2016 As you know from lecture, there are several types of mutation: DELETION (a base is lost) INSERTION (an extra base is inserted) Deletion and insertion may cause what’s called a FRAMESHIFT, meaning the reading “frame” changes, changing the amino acid sequence. POINT MUTATION (one base is substituted for another) If a point mutation changes the amino acid, it’s called a MISSENSE mutation. If a point mutation does not change the amino acid, it’s called a SILENT mutation. If a point mutation changes the amino acid to a “stop,” it’s called a NONSENSE mutation. Complete the boxes below. Classify each as either Deletion, Insertion, or Substitution AND as either frameshift, missense, silent or nonsense (hint: deletion or insertion will always be frameshift). Original DNA Sequence: T A C A C C T T G G C G A C G A C T mRNA Sequence: A U G U G G A A C C G C U G C U G A Amino Acid Sequence: MET -TRP- ASN - ARG- CYS - (STOP) Mutated DNA Sequence #1: T A C A T C T T G G C G A C G A C T What’s the mRNA sequence? A U G U A G A A C C G C U G C U G A What will be the amino acid sequence? MET -(STOP) Will there likely be effects? YES What kind of mutation is this? POINT MUTATION- NONSENSE Mutated DNA Sequence #2: T A C G A C C T T G G C G A C G A C T What’s the mRNA sequence? A U G C U G G A A C C G C U G C U G A What will be the amino acid sequence? MET - LEU -GLU– PRO-LEU-LEU Will there likely be effects? YES What kind of mutation is this? INSERTION - FRAME SHIFT Mutated DNA Sequence
[Show full text]
Mutation & Mutagenesis
MUTATION & MUTAGENESIS WHAT IS MUTATION? Any change in the DNA sequence of an organism is a mutation. - Mutation is the ultimate source of the altered versions of genes that provide the raw material for evolution. An organism exhibiting a novel phenotype as a result of the presence of a mutation is referred to as a “MUTANT”. - Most mutations have no effect on the organism, especially among the eukaryotes, because a large portion of the DNA is not in genes and thus does not affect the organism’s phenotype. - Of the mutations that do affect the phenotype, the most common effect of mutations is lethality, because most genes are necessary for life. Only a small percentage of mutations causes a visible but non-lethal change in the phenotype. *** Without mutation, all genes would exist in only one form- alleles would not exist and thus genetic analysis would not be possible. Organisms will not be able to evolve and adapt to environmental changes. Mutations can be : • Substitution, deletion, or insertion of a base pair(s) in DNA. • Chromosomal deletion, insertion, or rearrangement. Somatic mutations occur in somatic cells and only affect the individual in which the mutation arises. For e.g., the Delicious apple & Navel orange, originally were mosaics in somatic tissues. The desirable traits were due to spontaneous mutation in single cells. In each case the cell carrying the mutant gene reproduced, eventually producing an entire branch with the mutant phenotype. Fortunately vegetative propagation was feasible for both, and today numerous progenies from grafts and buds have perpetuated the original mutation.
[Show full text]
Thesis Had an Intellectual Developmental Disorder
From the Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden GENETIC STUDIES OF NEURODEVELOPMENTAL DISORDERS Josephine Wincent Stockholm 2012 All previously published papers were reproduced with permission from the publisher. Published by Karolinska Institutet. Printed by Larseric Digital Print AB © Josephine Wincent, 2012 ISBN 978-91-7457-715-0 ”Om du inte var en sån där liten rar och ful bleknosing med skeva ben, så var du ju inte min Skorpa, den som jag tycker om.” Jonatan till Skorpan i Bröderna Lejonhjärta av Astrid Lindgren. 4 ABSTRACT Neurodevelopmental disorders (NDDs) constitute a heterogeneous group of disorders that adversely impacts a child’s behavioural and learning processes. Developmental delay (DD) and mental retardation are included among the NDDs and are frequently associated with a wide range of accompanying disabilities such as multiple congenital anomalies and dysmorphic features. Despite extensive clinical and laboratory investigation, the cause of the patient’s symptoms remains unknown in approximately half of the cases. For the children’s families this is often frustrating since an aetiological diagnosis not only gives an explanation of why the child has symptoms but may also provide better prognosis evaluation, adequate genetic counselling and enable prenatal diagnosis. In approximately 20% of patients, a clear genetic cause can be found, including both single-gene disorders and chromosomal disorders. In paper I a NIPBL and SMC1L1 mutation screening by direct sequencing and MLPA was performed in a group of nine index patients diagnosed with Cornelia de Lange syndrome (CdLS), which is characterized by severe mental and growth retardation and distinctive dysmorphic facial features.
[Show full text]
Basic Molecular Genetics for Epidemiologists F Calafell, N Malats
398 GLOSSARY Basic molecular genetics for epidemiologists F Calafell, N Malats ............................................................................................................................. J Epidemiol Community Health 2003;57:398–400 This is the first of a series of three glossaries on CHROMOSOME molecular genetics. This article focuses on basic Linear or (in bacteria and organelles) circular DNA molecule that constitutes the basic physical molecular terms. block of heredity. Chromosomes in diploid organ- .......................................................................... isms such as humans come in pairs; each member of a pair is inherited from one of the parents. general increase in the number of epide- Humans carry 23 pairs of chromosomes (22 pairs miological research articles that apply basic of autosomes and two sex chromosomes); chromo- science methods in their studies, resulting somes are distinguished by their length (from 48 A to 257 million base pairs) and by their banding in what is known as both molecular and genetic epidemiology, is evident. Actually, genetics has pattern when stained with appropriate methods. come into the epidemiological scene with plenty Homologous chromosome of new sophisticated concepts and methodologi- cal issues. Each of the chromosomes in a pair with respect to This fact led the editors of the journal to offer the other. Homologous chromosomes carry the you a glossary of terms commonly used in papers same set of genes, and recombine with each other applying genetic methods to health problems to during meiosis. facilitate your “walking” around the journal Sex chromosome issues and enjoying the articles while learning. Sex determining chromosome. In humans, as in Obviously, the topics are so extensive and inno- all other mammals, embryos carrying XX sex vative that a single short glossary would not be chromosomes develop as females, whereas XY sufﬁcient to provide you with the minimum embryos develop as males.
[Show full text]
Frequent Hsnf5/INI1 Germline Mutations in Patients with Rhabdoid Tumor
Clinical Cancer Human Cancer Biology Research Frequent hSNF5/INI1 Germline Mutations in Patients with Rhabdoid Tumor Franck Bourdeaut1,2, Delphine Lequin3, Laurence Brugieres 4,Stephanie Reynaud3, Christelle Dufour4, Francois¸ Doz5,6, Nicolas Andre7, Jean-Louis Stephan8,9, Yves Perel 10,11, Odile Oberlin4, Daniel Orbach5, Christophe Bergeron12, Xavier Rialland13, Paul Freneaux 14, Dominique Ranchere15, Dominique Figarella-Branger16, Georges Audry17,18, Stephanie Puget6,19, D. Gareth Evans20, Joan Carles Ferreres Pinas21, Valeria Capra22,Veronique Mosseri23, Isabelle Coupier24, Marion Gauthier-Villars25,Gaelle€ Pierron3, and Olivier Delattre2,3 Abstract Purpose: Germline hSNF5/INI1 mutations are responsible for hereditary cases of rhabdoid tumors (RT) that constitute the rhabdoid predisposition syndrome (RPS). Our study provides the first precise overview of the prevalence of RPS within a large cohort of RT. Experimental Design: hSNF5/INI1 coding exons were investigated by sequencing and by multiplex ligation-dependent probe amplification. Results: Seventy-four constitutional DNAs from 115 apparently sporadic RT were analyzed from 1999 to 2009. Germline mutations were found in 26 patients (35%). Data from 9 individuals from 5 RPS families (siblings) were also studied. The median age at diagnosis was much lower (6 months) in patients with germline mutation (P < 0.01) than in patients without (18 months). Nevertheless, 7 of 35 patients with germline mutation (20%) developed the disease after 2 years of age. The mutation could be detected in only 1 parent whereas germline blood DNA was wild type in the 20 other parent pairs, therefore indicating the very high proportion of germ-cell mosaicism or of de novo mutations in RPS. The former hypothesis could be clearly documented in 1 case in which prenatal diagnosis was positive in a new pregnancy.
[Show full text]