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Recognition of patients with multiple diagnoses, and the unique challenges they pose to clinicians and laboratorians, is increasing rapidly as genome-wide genetic testing grows in prevalence. We describe a unique patient with dual diagnoses of PDCD10-related cerebral cavernous malformations and ETV6-related thrombocytopenia with associated neutropenia. She presented with brain abscesses as an infant, which is highly atypical for these disorders in isolation. Confirming her diagnoses depended on thorough phenotyping both during and after her acute illness. Furthermore, the causative variant in ETV6 is a novel single-exon deletion that required multiple modalities with manual review to confirm, including unique use of polymorphic nucleotides in trio exome data. She illustrates the special challenges of patients with multiple diagnoses, and the multiple tools clinicians and laboratorians must use to treat them.
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PURPOSE: Genome sequencing (GS) may shorten the diagnostic odyssey for patients, but clinical experience with this assay in nonresearch settings remains limited. Texas Children's Hospital began offering GS as a clinical test to admitted patients in 2020, providing an opportunity to study GS utilization, possibilities for test optimization, and testing outcomes. METHODS: We retrospectively reviewed GS orders for admitted patients for a nearly 3-year period from March 2020 through December 2022. We gathered anonymized clinical data from the electronic health record to answer the study questions. RESULTS: The diagnostic yield over 97 admitted patients was 35%. The majority of GS clinical indications were neurologic or metabolic (61%) and most patients were in intensive care (58%). Tests were often characterized as candidates for intervention/improvement (56%), frequently because of redundancy with prior testing. Patients receiving GS without prior exome sequencing (ES) had higher diagnostic rates (45%) than the cohort as a whole. In 2 cases, GS revealed a molecular diagnosis that is unlikely to be detected by ES. CONCLUSION: The performance of GS in clinical settings likely justifies its use as a first-line diagnostic test, but the incremental benefit for patients with prior ES may be limited.
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Pruebas Genéticas , Hospitales , Humanos , Niño , Estudios Retrospectivos , Secuenciación del Exoma , Mapeo CromosómicoRESUMEN
Stroke causes significant disability and is a common cause of death worldwide. Previous studies have estimated that 1%-5% of stroke is attributable to monogenic etiologies. We set out to assess the utility of clinical exome sequencing (ES) in the evaluation of stroke. We retrospectively analyzed 124 individuals who received ES at the Baylor Genetics reference lab between 2012 and 2021 who had stroke as a major part of their reported phenotype. Ages ranged from 10 days to 69 years. 8.9% of the cohort received a diagnosis, including 25% of infants less than 1 year old; an additional 10.5% of the cohort received a probable diagnosis. We identified several syndromes that predispose to stroke such as COL4A1-related brain small vessel disease, homocystinuria caused by CBS mutation, POLG-related disorders, TTC19-linked mitochondrial disease, and RNASEH2A associated Aicardi-Goutieres syndrome. We also observed pathogenic variants in NSD1, PKHD1, HRAS, and ATP13A2, which are genes rarely associated with stroke. Although stroke is a complex phenotype with varying pathologies and risk factors, these results show that use of exome sequencing can be highly relevant in stroke, especially for those presenting <1 year of age.
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Exoma , Accidente Cerebrovascular , Exoma/genética , Humanos , Fenotipo , Estudios Retrospectivos , Accidente Cerebrovascular/diagnóstico , Accidente Cerebrovascular/genética , Secuenciación del Exoma/métodosRESUMEN
The tumor suppressor p53 has well known roles in cancer development and germline cancer predisposition disorders, but increasing evidence supports the role of activation of this transcription factor in the pathogenesis of inherited bone marrow failure and chromosomal instability disorders. Here we report a patient with red cell aplasia, which was steroid responsive, as well as intellectual disability, seizures, microcephaly, short stature, cellular radiosensitivity, and normal telomere lengths, who had a germline heterozygous C-terminal frameshift variant in TP53 similar to others that activate the transcription factor. This is the third reported individual with a germline p53 activation syndrome, with several unique features that refine the clinical disease associated with these variants.
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Discapacidad Intelectual , Proteína p53 Supresora de Tumor , Predisposición Genética a la Enfermedad , Células Germinativas , Mutación de Línea Germinal/genética , Humanos , Discapacidad Intelectual/genética , Fenotipo , Síndrome , Factores de Transcripción/genética , Proteína p53 Supresora de Tumor/genéticaRESUMEN
Escape from nonsense mediated mRNA decay (NMD-) can produce activated or inactivated gene products, and bias in rates of escape can identify functionally important genes in germline disease. We hypothesized that the same would be true of cancer genes, and tested for NMD- bias within The Cancer Genome Atlas pan-cancer somatic mutation dataset. We identify 29 genes that show significantly elevated or suppressed rates of NMD-. This novel approach to cancer gene discovery reveals genes not previously cataloged as potentially tumorigenic, and identifies many potential driver mutations in known cancer genes for functional characterization.
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Biomarcadores de Tumor/genética , Codón sin Sentido , Genoma Humano , Neoplasias/patología , Degradación de ARNm Mediada por Codón sin Sentido , Fenotipo , Humanos , Neoplasias/genética , PronósticoRESUMEN
Pathogenic variants in non-coding regions of genes encoding enzymes or transporters of the urea cycle can lead to urea cycle disorders (UCDs). However, not all commercially available testing platforms interrogate these regions. Here, we used a gene panel based on massively parallel sequencing (MPS) in 10 individuals with clinical or pedigree-based evidence of a proximal UCD but without a molecular confirmation of the diagnosis. We identified causal variant(s) in 5 of 10 individuals, including in 3 of 7 individuals in whom prior molecular testing was unrevealing. We show that a deep-intronic pathogenic variant in OTC, c.540+265G>A, is an important cause of ornithine transcarbamylase (OTC) deficiency.
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Enfermedad por Rasguño de Gato/diagnóstico , Parálisis Facial/microbiología , Fiebre de Origen Desconocido/microbiología , Bartonella henselae , Enfermedad por Rasguño de Gato/tratamiento farmacológico , Preescolar , Diagnóstico Diferencial , Parálisis Facial/tratamiento farmacológico , Femenino , Fiebre de Origen Desconocido/tratamiento farmacológico , HumanosRESUMEN
The original version of this Article contained errors in the depiction of confidence intervals in the NF1 BCSS data illustrated in Figure 3b. These have now been corrected in both the PDF and HTML versions of the Article. The incorrect version of Figure 3b is presented in the associated Author Correction.
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Here we report targeted sequencing of 83 genes using DNA from primary breast cancer samples from 625 postmenopausal (UBC-TAM series) and 328 premenopausal (MA12 trial) hormone receptor-positive (HR+) patients to determine interactions between somatic mutation and prognosis. Independent validation of prognostic interactions was achieved using data from the METABRIC study. Previously established associations between MAP3K1 and PIK3CA mutations with luminal A status/favorable prognosis and TP53 mutations with Luminal B/non-luminal tumors/poor prognosis were observed, validating the methodological approach. In UBC-TAM, NF1 frame-shift nonsense (FS/NS) mutations were also a poor outcome driver that was validated in METABRIC. For MA12, poor outcome associated with PIK3R1 mutation was also reproducible. DDR1 mutations were strongly associated with poor prognosis in UBC-TAM despite stringent false discovery correction (q = 0.0003). In conclusion, uncommon recurrent somatic mutations should be further explored to create a more complete explanation of the highly variable outcomes that typifies ER+ breast cancer.
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Neoplasias de la Mama/genética , Neoplasias de la Mama/mortalidad , Mutación , Adulto , Neoplasias de la Mama/metabolismo , Estudios de Casos y Controles , Fosfatidilinositol 3-Quinasa Clase I/genética , Fosfatidilinositol 3-Quinasa Clase Ia , Estudios de Cohortes , Receptor con Dominio Discoidina 1/genética , Femenino , Humanos , Quinasa 1 de Quinasa de Quinasa MAP/genética , Persona de Mediana Edad , Neurofibromina 1/genética , Fosfatidilinositol 3-Quinasas/genética , Posmenopausia , Pronóstico , Receptores de Estrógenos/metabolismo , Análisis de SupervivenciaRESUMEN
In this study we use somatic cancer mutations to identify important functional residues within sets of related genes. We focus on protein kinases, a superfamily of phosphotransferases that share homologous sequences and structural motifs and have many connections to cancer. We develop several statistical tests for identifying Significantly Mutated Positions (SMPs), which are positions in an alignment with mutations that show signs of selection. We apply our methods to 21,917 mutations that map to the alignment of human kinases and identify 23 SMPs. SMPs occur throughout the alignment, with many in the important A-loop region, and others spread between the N and C lobes of the kinase domain. Since mutations are pooled across the superfamily, these positions may be important to many protein kinases. We select eleven mutations from these positions for functional validation. All eleven mutations cause a reduction or loss of function in the affected kinase. The tested mutations are from four genes, including two tumor suppressors (TGFBR1 and CHEK2) and two oncogenes (KDR and ERBB2). They also represent multiple cancer types, and include both recurrent and non-recurrent events. Many of these mutations warrant further investigation as potential cancer drivers.
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Mutación con Pérdida de Función , Neoplasias/genética , Fosfotransferasas/genética , Animales , Quinasa de Punto de Control 2/genética , Bases de Datos Genéticas , Humanos , Ratones , Células 3T3 NIH , Neoplasias/enzimología , Fosfotransferasas/química , Fosfotransferasas/metabolismo , Receptor ErbB-2/genética , Receptor Tipo I de Factor de Crecimiento Transformador beta/genética , Reproducibilidad de los Resultados , Receptor 2 de Factores de Crecimiento Endotelial Vascular/genéticaRESUMEN
Methods are needed to reliably prioritize biologically active driver mutations over inactive passengers in high-throughput sequencing cancer data sets. We present ParsSNP, an unsupervised functional impact predictor that is guided by parsimony. ParsSNP uses an expectation-maximization framework to find mutations that explain tumor incidence broadly, without using predefined training labels that can introduce biases. We compare ParsSNP to five existing tools (CanDrA, CHASM, FATHMM Cancer, TransFIC, and Condel) across five distinct benchmarks. ParsSNP outperformed the existing tools in 24 of 25 comparisons. To investigate the real-world benefit of these improvements, we applied ParsSNP to an independent data set of 30 patients with diffuse-type gastric cancer. ParsSNP identified many known and likely driver mutations that other methods did not detect, including truncation mutations in known tumor suppressors and the recurrent driver substitution RHOA p.Tyr42Cys. In conclusion, ParsSNP uses an innovative, parsimony-based approach to prioritize cancer driver mutations and provides dramatic improvements over existing methods.
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Aprendizaje Automático , Mutación , Neoplasias/genética , Polimorfismo de Nucleótido Simple , Algoritmos , Recolección de Datos/métodos , Humanos , Modelos Genéticos , Neoplasias Gástricas/genéticaRESUMEN
MOTIVATION: Several tools exist to identify cancer driver genes based on somatic mutation data. However, these tools do not account for subclasses of cancer genes: oncogenes, which undergo gain-of-function events, and tumor suppressor genes (TSGs) which undergo loss-of-function. A method which accounts for these subclasses could improve performance while also suggesting a mechanism of action for new putative cancer genes. RESULTS: We develop a panel of five complementary statistical tests and assess their performance against a curated set of 99 HiConf cancer genes using a pan-cancer dataset of 1.7 million mutations. We identify patient bias as a novel signal for cancer gene discovery, and use it to significantly improve detection of oncogenes over existing methods (AUROC = 0.894). Additionally, our test of truncation event rate separates oncogenes and TSGs from one another (AUROC = 0.922). Finally, a random forest integrating the five tests further improves performance and identifies new cancer genes, including CACNG3, HDAC2, HIST1H1E, NXF1, GPS2 and HLA-DRB1. AVAILABILITY AND IMPLEMENTATION: All mutation data, instructions, functions for computing the statistics and integrating them, as well as the HiConf gene panel, are available at www.github.com/Bose-Lab/Improved-Detection-of-Cancer-Genes. CONTACT: rbose@dom.wustl.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
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Bases de Datos Genéticas , Genes Supresores de Tumor , Genoma Humano , Neoplasias/genética , Oncogenes , Análisis de Secuencia de ADN/métodos , Estadística como Asunto , Área Bajo la Curva , Humanos , Modelos Genéticos , Mutación , Control de Calidad , Curva ROC , Reproducibilidad de los ResultadosRESUMEN
The Drug-Gene Interaction database (DGIdb) mines existing resources that generate hypotheses about how mutated genes might be targeted therapeutically or prioritized for drug development. It provides an interface for searching lists of genes against a compendium of drug-gene interactions and potentially 'druggable' genes. DGIdb can be accessed at http://dgidb.org/.
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Minería de Datos/métodos , Bases de Datos Genéticas , Descubrimiento de Drogas/métodos , Antineoplásicos/química , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Biología Computacional/métodos , Interacciones Farmacológicas , Regulación de la Expresión Génica/efectos de los fármacos , Variación Genética , Genoma , Genómica/métodos , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Mutación , Programas Informáticos , Tecnología Farmacéutica/métodosRESUMEN
A major goal of cancer genome sequencing is to identify mutations or other somatic alterations that can be targeted by selective and specific drugs. dGene is an annotation tool designed to rapidly identify genes belonging to one of ten druggable classes that are frequently targeted in cancer drug development. These classes were comprehensively populated by combining and manually curating data from multiple specialized and general databases. dGene was used by The Cancer Genome Atlas squamous cell lung cancer project, and here we further demonstrate its utility using recently released breast cancer genome sequencing data. dGene is designed to be usable by any cancer researcher without the need for support from a bioinformatics specialist. A full description of dGene and options for its implementation are provided here.
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Antineoplásicos/farmacología , Anotación de Secuencia Molecular , Mutación , Neoplasias/genética , Biología Computacional , Genoma Humano , Humanos , Polimorfismo de Nucleótido SimpleRESUMEN
Various post-translational modifications (PTMs) fine-tune the functions of almost all eukaryotic proteins, and co-regulation of different types of PTMs has been shown within and between a number of proteins. Aiming at a more global view of the interplay between PTM types, we collected modifications for 13 frequent PTM types in 8 eukaryotes, compared their speed of evolution and developed a method for measuring PTM co-evolution within proteins based on the co-occurrence of sites across eukaryotes. As many sites are still to be discovered, this is a considerable underestimate, yet, assuming that most co-evolving PTMs are functionally associated, we found that PTM types are vastly interconnected, forming a global network that comprise in human alone >50,000 residues in about 6000 proteins. We predict substantial PTM type interplay in secreted and membrane-associated proteins and in the context of particular protein domains and short-linear motifs. The global network of co-evolving PTM types implies a complex and intertwined post-translational regulation landscape that is likely to regulate multiple functional states of many if not all eukaryotic proteins.
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Procesamiento Proteico-Postraduccional/fisiología , Proteínas/metabolismo , Proteómica/métodos , Animales , Bovinos , Pollos , Evolución Molecular , Humanos , Macaca mulatta , Ratones , Filogenia , Proteínas/genética , Ratas , Biología de Sistemas/métodosRESUMEN
Protein post-translational modifications (PTMs) represent important regulatory states that when combined have been hypothesized to act as molecular codes and to generate a functional diversity beyond genome and transcriptome. We systematically investigate the interplay of protein phosphorylation with other post-transcriptional regulatory mechanisms in the genome-reduced bacterium Mycoplasma pneumoniae. Systematic perturbations by deletion of its only two protein kinases and its unique protein phosphatase identified not only the protein-specific effect on the phosphorylation network, but also a modulation of proteome abundance and lysine acetylation patterns, mostly in the absence of transcriptional changes. Reciprocally, deletion of the two putative N-acetyltransferases affects protein phosphorylation, confirming cross-talk between the two PTMs. The measured M. pneumoniae phosphoproteome and lysine acetylome revealed that both PTMs are very common, that (as in Eukaryotes) they often co-occur within the same protein and that they are frequently observed at interaction interfaces and in multifunctional proteins. The results imply previously unreported hidden layers of post-transcriptional regulation intertwining phosphorylation with lysine acetylation and other mechanisms that define the functional state of a cell.
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Acetilesterasa/metabolismo , Tamaño del Genoma/genética , Lisina/metabolismo , Redes y Vías Metabólicas/genética , Neumonía por Mycoplasma/genética , Proteínas Quinasas/metabolismo , Acetilación , Dominio Catalítico/genética , Evolución Molecular , Redes Reguladoras de Genes/genética , Redes Reguladoras de Genes/fisiología , Genoma Bacteriano/genética , Redes y Vías Metabólicas/fisiología , Modelos Biológicos , Organismos Modificados Genéticamente , Fosforilación/fisiología , Neumonía por Mycoplasma/metabolismo , Procesamiento Proteico-Postraduccional/genética , Proteoma/genética , Proteoma/metabolismoRESUMEN
We report an interaction between poxA, encoding a paralog of lysyl tRNA-synthetase, and the closely linked yjeK gene, encoding a putative 2,3-beta-lysine aminomutase, that is critical for virulence and stress resistance in Salmonella enterica. Salmonella poxA and yjeK mutants share extensive phenotypic pleiotropy, including attenuated virulence in mice, an increased ability to respire under nutrient-limiting conditions, hypersusceptibility to a variety of diverse growth inhibitors, and altered expression of multiple proteins, including several encoded on the SPI-1 pathogenicity island. PoxA mediates posttranslational modification of bacterial elongation factor P (EF-P), analogous to the modification of the eukaryotic EF-P homolog, eIF5A, with hypusine. The modification of EF-P is a mechanism of regulation whereby PoxA acts as an aminoacyl-tRNA synthetase that attaches an amino acid to a protein resembling tRNA rather than to a tRNA.