Medical Genetics Summaries

Book. 2012

Authors: Pratt V, McLeod H, Dean L, Malheiro A, Rubinstein W

Abstract
Phenytoin is an antiseizure medication used for the prevention of focal seizures and generalized tonic-clonic convulsions (1). Phenytoin has a narrow therapeutic index—patients that have toxic blood concentrations of phenytoin have inreased risks of acute side effects. Dosing can be complex due to pharmacokinetic factors, including patient weight, age, sex, concomitant medications, plasma binding protein stats, the presence of uremia or hyperbilirubinemia, and specific pharmacogenetic variants. As such, therapeutic drug monitoring is often used to adjust dose and maintain serum concentrations within the therapeutic range (10–20 μg/mL). CYP2C9 is one of the main enzymes involved in the metabolism of phenytoin, and variant CYP2C9 alleles are known to influence phenytoin drug levels. Individuals who carry decreased activity CYP2C9 variants may have reduced clearance rates of phenytoin and be at greater risk for dose-related side effects (2). An individual’s human leukocyte antigen B (HLA-B) genotype is a known risk factor for drug-induced hypersensitivity reactions. HLA-B has an important immunological role in pathogen recognition and response, as well as to non-pathogens such as drugs. Carriers of the variant HLA-B*15:02 allele are at high risk of developing potentially life-threatening phenytoin-induced Stevens-Johnson syndrome (SJS) and the related toxic epidermal necrolysis (TEN). The HLA-B*15:02 variant is most commonly found among individuals of Southeast Asian descent, where there is a strong association between SJS/TEN and exposure to carbamazepine. Carbamazepine is an antiseizure medication used to treat the same types of seizures as phenytoin, as well as trigeminal neuralgia and bipolar disorder. The FDA-approved drug label for phenytoin states that consideration should be given to avoiding phenytoin as an alternative for carbamazepine in patients positive for HLA-B*15:02. The label also mentions that variant CYP2C9 alleles may contribute to unusually high levels of phenytoin (1). The Clinical Pharmacogenetics Implementation Consortium (CPIC) recommends the use of an antiseizure medication other than carbamazepine, phenytoin (or its prodrug fosphenytoin) for any HLA-B*15:02 carrier regardless of CYP2C9 genotype, patient ancestry or age. CPIC also recommends consideration of at least a 25% reduction in the starting maintenance dose for patients who are CYP2C9 intermediate metabolizers and HLA-B*15:02 negative, and at least a 50% reduction for CYP2C9 poor metabolizers and HLA-B*15:02 negative, with subsequent maintenance doses adjusted based on therapeutic drug monitoring and response (Table 1) (2).

PMID: 28520374

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Large-scale data-driven integrative framework for extracting essential targets and processes from disease-associated gene data sets.

Brief Bioinform. 2017 May 18;:

Authors: Mazandu GK, Chimusa ER, Rutherford K, Zekeng EG, Gebremariam ZZ, Onifade MY, Mulder NJ

Abstract
Populations worldwide currently face several public health challenges, including growing prevalence of infections and the emergence of new pathogenic organisms. The cost and risk associated with drug development make the development of new drugs for several diseases, especially orphan or rare diseases, unappealing to the pharmaceutical industry. Proof of drug safety and efficacy is required before market approval, and rigorous testing makes the drug development process slow, expensive and frequently result in failure. This failure is often because of the use of irrelevant targets identified in the early steps of the drug discovery process, suggesting that target identification and validation are cornerstones for the success of drug discovery and development. Here, we present a large-scale data-driven integrative computational framework to extract essential targets and processes from an existing disease-associated data set and enhance target selection by leveraging drug-target-disease association at the systems level. We applied this framework to tuberculosis and Ebola virus diseases combining heterogeneous data from multiple sources, including protein-protein functional interaction, functional annotation and pharmaceutical data sets. Results obtained demonstrate the effectiveness of the pipeline, leading to the extraction of essential drug targets and to the rational use of existing approved drugs. This provides an opportunity to move toward optimal target-based strategies for screening available drugs and for drug discovery. There is potential for this model to bridge the gap in the production of orphan disease therapies, offering a systematic approach to predict new uses for existing drugs, thereby harnessing their full therapeutic potential.

PMID: 28520909 [PubMed - as supplied by publisher]

Large-scale data-driven integrative framework for extracting essential targets and processes from disease-associated gene data sets.

Brief Bioinform. 2017 May 18;:

Authors: Mazandu GK, Chimusa ER, Rutherford K, Zekeng EG, Gebremariam ZZ, Onifade MY, Mulder NJ

Abstract
Populations worldwide currently face several public health challenges, including growing prevalence of infections and the emergence of new pathogenic organisms. The cost and risk associated with drug development make the development of new drugs for several diseases, especially orphan or rare diseases, unappealing to the pharmaceutical industry. Proof of drug safety and efficacy is required before market approval, and rigorous testing makes the drug development process slow, expensive and frequently result in failure. This failure is often because of the use of irrelevant targets identified in the early steps of the drug discovery process, suggesting that target identification and validation are cornerstones for the success of drug discovery and development. Here, we present a large-scale data-driven integrative computational framework to extract essential targets and processes from an existing disease-associated data set and enhance target selection by leveraging drug-target-disease association at the systems level. We applied this framework to tuberculosis and Ebola virus diseases combining heterogeneous data from multiple sources, including protein-protein functional interaction, functional annotation and pharmaceutical data sets. Results obtained demonstrate the effectiveness of the pipeline, leading to the extraction of essential drug targets and to the rational use of existing approved drugs. This provides an opportunity to move toward optimal target-based strategies for screening available drugs and for drug discovery. There is potential for this model to bridge the gap in the production of orphan disease therapies, offering a systematic approach to predict new uses for existing drugs, thereby harnessing their full therapeutic potential.

PMID: 28520909 [PubMed - as supplied by publisher]

Social/economic costs and health-related quality of life in patients with rare diseases in Europe.

Eur J Health Econ. 2016 Apr;17 Suppl 1:1-5

Authors: López-Bastida J, Oliva-Moreno J, Linertová R, Serrano-Aguilar P

PMID: 27023708 [PubMed - indexed for MEDLINE]

Uveal melanoma: From diagnosis to treatment and the science in between.

Cancer. 2016 Aug 01;122(15):2299-312

Authors: Chattopadhyay C, Kim DW, Gombos DS, Oba J, Qin Y, Williams MD, Esmaeli B, Grimm EA, Wargo JA, Woodman SE, Patel SP

Abstract
Melanomas of the choroid, ciliary body, and iris of the eye are collectively known as uveal melanomas. These cancers represent 5% of all melanoma diagnoses in the United States, and their age-adjusted risk is 5 per 1 million population. These less frequent melanomas are dissimilar to their more common cutaneous melanoma relative, with differing risk factors, primary treatment, anatomic spread, molecular changes, and responses to systemic therapy. Once uveal melanoma becomes metastatic, therapy options are limited and are often extrapolated from cutaneous melanoma therapies despite the routine exclusion of patients with uveal melanoma from clinical trials. Clinical trials directed at uveal melanoma have been completed or are in progress, and data from these well designed investigations will help guide future directions in this orphan disease. Cancer 2016;122:2299-2312. © 2016 American Cancer Society.

PMID: 26991400 [PubMed - indexed for MEDLINE]

Role of the endocannabinoid system in vertebrates: Emphasis on the zebrafish model.

Dev Growth Differ. 2017 May 17;:

Authors: Oltrabella F, Melgoza A, Nguyen B, Guo S

Abstract
The endocannabinoid system (eCBs), named after the plant Cannabis sativa, comprises cannabinoid receptors, endogenous ligands known as "endocannabinoids", and enzymes involved in the biosynthesis and degradation of these ligands, as well as putative transporters for these ligands. ECBs proteins and small molecules have been detected in early embryonic stages of many vertebrate models. As a result, cannabinoid receptors and endogenous as well as exogenous cannabinoids influence development and behavior in many vertebrate species. Understanding the precise mechanisms of action for the eCBs will provide an invaluable guide towards elucidation of vertebrate development and will also help delineate how developmental exposure to marijuana might impact health and cognitive/executive functioning in adulthood. Here we review the developmental roles of the eCBs in vertebrates, focusing our attention on the zebrafish model. Since little is known regarding the eCBs in zebrafish, we provide new data on the expression profiles of eCBs genes during development and in adult tissue types of this model organism. We also highlight exciting areas for future investigations, including the synaptic regulation of eCBs, its role in reward and addiction, and in nervous system development and plasticity.

PMID: 28516445 [PubMed - as supplied by publisher]

DNA Sequence Analysis in Clinical Medicine, Proceeding Cautiously.

Front Mol Biosci. 2017;4:24

Authors: Smith M

Abstract
Delineation of underlying genomic and genetic factors in a specific disease may be valuable in establishing a definitive diagnosis and may guide patient management and counseling. In addition, genetic information may be useful in identification of at risk family members. Gene mapping and initial genome sequencing data enabled the development of microarrays to analyze genomic variants. The goal of this review is to consider different generations of sequencing techniques and their application to exome sequencing and whole genome sequencing and their clinical applications. In recent decades, exome sequencing has primarily been used in patient studies. Discussed in some detail, are important measures that have been developed to standardize variant calling and to assess pathogenicity of variants. Examples of cases where exome sequencing has facilitated diagnosis and led to improved medical management are presented. Whole genome sequencing and its clinical relevance are presented particularly in the context of analysis of nucleotide and structural genomic variants in large population studies and in certain patient cohorts. Applications involving analysis of cell free DNA in maternal blood for prenatal diagnosis of specific autosomal trisomies are reviewed. Applications of DNA sequencing to diagnosis and therapeutics of cancer are presented. Also discussed are important recent diagnostic applications of DNA sequencing in cancer, including analysis of tumor derived cell free DNA and exosomes that are present in body fluids. Insights gained into underlying pathogenetic mechanisms of certain complex common diseases, including schizophrenia, macular degeneration, neurodegenerative disease are presented. The relevance of different types of variants, rare, uncommon, and common to disease pathogenesis, and the continuum of causality, are addressed. Pharmogenetic variants detected by DNA sequence analysis are gaining in importance and are particularly relevant to personalized and precision medicine.

PMID: 28516087 [PubMed - in process]

The WinCF Model - An Inexpensive and Tractable Microcosm of a Mucus Plugged Bronchiole to Study the Microbiology of Lung Infections.

J Vis Exp. 2017 May 08;(123):

Authors: Comstock WJ, Huh E, Weekes R, Watson C, Xu T, Dorrestein PC, Quinn RA

Abstract
Many chronic airway diseases result in mucus plugging of the airways. Lungs of an individual with cystic fibrosis are an exemplary case where their mucus-plugged bronchioles create a favorable habitat for microbial colonization. Various pathogens thrive in this environment interacting with each other and driving many of the symptoms associated with CF disease. Like any microbial community, the chemical conditions of their habitat have a significant impact on the community structure and dynamics. For example, different microorganisms thrive in differing levels of oxygen or other solute concentrations. This is also true in the CF lung, where oxygen concentrations are believed to drive community physiology and structure. The methods described here are designed to mimic the lung environment and grow pathogens in a manner more similar to that from which they cause disease. Manipulation of the chemical surroundings of these microbes is then used to study how the chemistry of lung infections governs its microbial ecology. The method, called the WinCF system, is based on artificial sputum medium and narrow capillary tubes meant to provide an oxygen gradient similar to that which exists in mucus-plugged bronchioles. Manipulating chemical conditions, such as the media pH of the sputum or antibiotics pressure, allows for visualization of the microbiological differences in those samples using colored indicators, watching for gas or biofilm production, or extracting and sequencing the nucleic acid contents of each sample.

PMID: 28518116 [PubMed - in process]

Body Sanctification and Sleep in Adolescents with Cystic Fibrosis: A Pilot Study.

J Relig Health. 2017 May 17;:

Authors: Kopp AT, Chini BA, Dimitriou SM, Grossoehme DH

Abstract
Imbuing one's body with divine significance is associated with health-protective behaviors. The purpose of this study was to determine whether adolescents with a life-shortening, chronic disease (cystic fibrosis) who sanctified their bodies also received adequate sleep. Data from Daily Phone Diaries and questionnaire replies from 45 adolescents with cystic fibrosis (ages 11-19 years) were analyzed. A significant relationship between body sanctification and sleep was found, with between-gender differences. Body sanctification is an understudied construct which is associated with healthy behaviors.

PMID: 28516396 [PubMed - as supplied by publisher]

Aspergillus Species in Bronchiectasis: Challenges in the Cystic Fibrosis and Non-cystic Fibrosis Airways.

Mycopathologia. 2017 May 17;:

Authors: Chotirmall SH, Martin-Gomez MT

Abstract
Bronchiectasis is a chronic irreversible airway abnormality associated with infectious agents that either cause or superinfect the airways. While the role of bacteria is well studied, much remains to be determined about fungi in both cystic fibrosis- and non-cystic fibrosis-related bronchiectasis. The airway is constantly exposed to inhaled ambient moulds of which Aspergillus represent the most ubiquitous. In a normal healthy host, this situation is of little consequence. The presence of anatomical or immunological abnormalities such as those in bronchiectasis leads to a range of fungal-related pathologies from asymptomatic airway colonization to fungal sensitization, allergic bronchopulmonary aspergillosis or chronic pulmonary aspergillosis. These entities are difficult to recognize, diagnose and treat due in part to a lack of validated biomarkers. Our true understanding of the complex relationships that regulate fungal-host interactions is still in its infancy and, several questions remain. This includes if fungal epidemiology in bronchiectasis is uniform across countries, and to what extent immunopathological mechanisms-related to fungal airway infections-occurs in different disease states. Specific triggers to allergic or infectious responses to Aspergillus require further exploration. How transition occurs between allergic and invasive phenotypes and their respective biomarkers is also important. Whether anti-fungal treatment is warranted in all cases and what the optimal management strategy is, particularly when treatment should commence and its expected duration remains unclear. Further research is clearly necessary and should be prioritized to better understand the clinical effects and impact of Aspergillus in the setting of bronchiectasis.

PMID: 28516246 [PubMed - as supplied by publisher]

A neutralizing anti-G-CSFR antibody blocks G-CSF-induced neutrophilia without inducing neutropenia in nonhuman primates.

J Leukoc Biol. 2017 May 17;:

Authors: Scalzo-Inguanti K, Monaghan K, Edwards K, Herzog E, Mirosa D, Hardy M, Sorto V, Huynh H, Rakar S, Kurtov D, Braley H, Wilson N, Busfield S, Nash A, Andrews A

Abstract
Neutrophils are the most abundant WBCs and have an essential role in the clearance of pathogens. Tight regulation of neutrophil numbers and their recruitment to sites of inflammation is critical in maintaining a balanced immune response. In various inflammatory conditions, such as rheumatoid arthritis, vasculitis, cystic fibrosis, and inflammatory bowel disease, increased serum G-CSF correlates with neutrophilia and enhanced neutrophil infiltration into inflamed tissues. We describe a fully human therapeutic anti-G-CSFR antibody (CSL324) that is safe and well tolerated when administered via i.v. infusion to cynomolgus macaques. CSL324 was effective in controlling G-CSF-mediated neutrophilia when administered either before or after G-CSF. A single ascending-dose study showed CSL324 did not alter steady-state neutrophil numbers, even at doses sufficient to completely prevent G-CSF-mediated neutrophilia. Weekly infusions of CSL324 (≤10 mg/kg) for 3 wk completely neutralized G-CSF-mediated pSTAT3 phosphorylation without neutropenia. Moreover, repeat dosing up to 100 mg/kg for 12 wk did not result in neutropenia at any point, including the 12-wk follow-up after the last infusion. In addition, CSL324 had no observable effect on basic neutrophil functions, such as phagocytosis and oxidative burst. These data suggest that targeting G-CSFR may provide a safe and effective means of controlling G-CSF-mediated neutrophilia as observed in various inflammatory diseases.

PMID: 28515226 [PubMed - as supplied by publisher]

Lung function imaging methods in Cystic Fibrosis pulmonary disease.

Respir Res. 2017 May 17;18(1):96

Authors: Kołodziej M, de Veer MJ, Cholewa M, Egan GF, Thompson BR

Abstract
Monitoring of pulmonary physiology is fundamental to the clinical management of patients with Cystic Fibrosis. The current standard clinical practise uses spirometry to assess lung function which delivers a clinically relevant functional readout of total lung function, however does not supply any visible or localised information. High Resolution Computed Tomography (HRCT) is a well-established current 'gold standard' method for monitoring lung anatomical changes in Cystic Fibrosis patients. HRCT provides excellent morphological information, however, the X-ray radiation dose can become significant if multiple scans are required to monitor chronic diseases such as cystic fibrosis. X-ray phase-contrast imaging is another emerging X-ray based methodology for Cystic Fibrosis lung assessment which provides dynamic morphological and functional information, albeit with even higher X-ray doses than HRCT. Magnetic Resonance Imaging (MRI) is a non-ionising radiation imaging method that is garnering growing interest among researchers and clinicians working with Cystic Fibrosis patients. Recent advances in MRI have opened up the possibilities to observe lung function in real time to potentially allow sensitive and accurate assessment of disease progression. The use of hyperpolarized gas or non-contrast enhanced MRI can be tailored to clinical needs. While MRI offers significant promise it still suffers from poor spatial resolution and the development of an objective scoring system especially for ventilation assessment.

PMID: 28514950 [PubMed - in process]

Induced pluripotent stem cell modelling of HLHS underlines the contribution of dysfunctional NOTCH signalling to impaired cardiogenesis.

Hum Mol Genet. 2017 May 17;:

Authors: Yang C, Xu Y, Yu M, Lee D, Alharti S, Hellen N, Ahmad Shaik N, Banaganapalli B, Sheikh HAM, Ramu E, Przyborski S, Tenin G, Williams S, O'Sullivan J, Al-Radi OO, Atta J, Harding SE, Keavney B, Lako M, Armstrong L

Abstract
Hypoplastic left heart syndrome (HLHS) is among the most severe forms of congenital heart disease. Although the consensus view is that reduced flow through the left heart during development is a key factor in the development of the condition, the molecular mechanisms leading to hypoplasia of left heart structures are unknown. We have generated induced pluripotent stem cells (iPSC) from five HLHS patients and two unaffected controls, differentiated these to cardiomyocytes and identified reproducible in vitro cellular and functional correlates of the HLHS phenotype. Our data indicate that HLHS-iPSC have a reduced ability to give rise to mesodermal, cardiac progenitors and mature cardiomyocytes and an enhanced ability to differentiate to smooth muscle cells. HLHS-iPSC derived cardiomyocytes are characterised by a lower beating rate, disorganised sarcomeres and sarcoplasmic reticulum and a blunted response to isoprenaline. Whole exome sequencing of HLHS fibroblasts identified deleterious variants in NOTCH receptors and other genes involved in the NOTCH signalling pathway. Our data indicate that the expression of NOTCH receptors was significantly downregulated in HLHS-iPSC derived cardiomyocytes alongside NOTCH target genes confirming downregulation of NOTCH signalling activity. Activation of NOTCH signalling via addition of Jagged peptide ligand during the differentiation of HLHS-iPSC restored their cardiomyocyte differentiation capacity and beating rate and suppressed the smooth muscle cell formation. Together our data provide firm evidence for involvement of NOTCH signalling in HLHS pathogenesis, reveal novel genetic insights important for HLHS pathology and shed new insights into the role of this pathway during human cardiac development.

PMID: 28521042 [PubMed - as supplied by publisher]

GeMSTONE: orchestrated prioritization of human germline mutations in the cloud.

Nucleic Acids Res. 2017 May 18;:

Authors: Chen S, Beltrán JF, Esteban-Jurado C, Franch-Expósito S, Castellví-Bel S, Lipkin S, Wei X, Yu H

Abstract
Integrative analysis of whole-genome/exome-sequencing data has been challenging, especially for the non-programming research community, as it requires simultaneously managing a large number of computational tools. Even computational biologists find it unexpectedly difficult to reproduce results from others or optimize their strategies in an end-to-end workflow. We introduce Germline Mutation Scoring Tool fOr Next-generation sEquencing data (GeMSTONE), a cloud-based variant prioritization tool with high-level customization and a comprehensive collection of bioinformatics tools and data libraries (http://gemstone.yulab.org/). GeMSTONE generates and readily accepts a shareable 'recipe' file for each run to either replicate previous results or analyze new data with identical parameters and provides a centralized workflow for prioritizing germline mutations in human disease within a streamlined workflow rather than a pool of program executions.

PMID: 28521008 [PubMed - as supplied by publisher]

VCF.Filter: interactive prioritization of disease-linked genetic variants from sequencing data.

Nucleic Acids Res. 2017 May 17;:

Authors: Müller H, Jimenez-Heredia R, Krolo A, Hirschmugl T, Dmytrus J, Boztug K, Bock C

Abstract
Next generation sequencing is widely used to link genetic variants to diseases, and it has massively accelerated the diagnosis and characterization of rare genetic diseases. After initial bioinformatic data processing, the interactive analysis of genome, exome, and panel sequencing data typically starts from lists of genetic variants in VCF format. Medical geneticists filter and annotate these lists to identify variants that may be relevant for the disease under investigation, or to select variants that are reported in a clinical diagnostics setting. We developed VCF.Filter to facilitate the search for disease-linked variants, providing a standalone Java program with a user-friendly interface for interactive variant filtering and annotation. VCF.Filter allows the user to define a broad range of filtering criteria through a graphical interface. Common workflows such as trio analysis and cohort-based filtering are pre-configured, and more complex analyses can be performed using VCF.Filter's support for custom annotations and filtering criteria. All filtering is documented in the results file, thus providing traceability of the interactive variant prioritization. VCF.Filter is an open source tool that is freely and openly available at http://vcffilter.rarediseases.at.

PMID: 28520890 [PubMed - as supplied by publisher]

Using high-resolution variant frequencies to empower clinical genome interpretation.

Genet Med. 2017 May 18;:

Authors: Whiffin N, Minikel E, Walsh R, O'Donnell-Luria AH, Karczewski K, Ing AY, Barton PJR, Funke B, Cook SA, MacArthur D, Ware JS

Abstract
PurposeWhole-exome and whole-genome sequencing have transformed the discovery of genetic variants that cause human Mendelian disease, but discriminating pathogenic from benign variants remains a daunting challenge. Rarity is recognized as a necessary, although not sufficient, criterion for pathogenicity, but frequency cutoffs used in Mendelian analysis are often arbitrary and overly lenient. Recent very large reference datasets, such as the Exome Aggregation Consortium (ExAC), provide an unprecedented opportunity to obtain robust frequency estimates even for very rare variants.MethodsWe present a statistical framework for the frequency-based filtering of candidate disease-causing variants, accounting for disease prevalence, genetic and allelic heterogeneity, inheritance mode, penetrance, and sampling variance in reference datasets.ResultsUsing the example of cardiomyopathy, we show that our approach reduces by two-thirds the number of candidate variants under consideration in the average exome, without removing true pathogenic variants (false-positive rate<0.001).ConclusionWe outline a statistically robust framework for assessing whether a variant is "too common" to be causative for a Mendelian disorder of interest. We present precomputed allele frequency cutoffs for all variants in the ExAC dataset.GENETICS in MEDICINE advance online publication, 18 May 2017; doi:10.1038/gim.2017.26.

PMID: 28518168 [PubMed - as supplied by publisher]

DNA Sequence Analysis in Clinical Medicine, Proceeding Cautiously.

Front Mol Biosci. 2017;4:24

Authors: Smith M

Abstract
Delineation of underlying genomic and genetic factors in a specific disease may be valuable in establishing a definitive diagnosis and may guide patient management and counseling. In addition, genetic information may be useful in identification of at risk family members. Gene mapping and initial genome sequencing data enabled the development of microarrays to analyze genomic variants. The goal of this review is to consider different generations of sequencing techniques and their application to exome sequencing and whole genome sequencing and their clinical applications. In recent decades, exome sequencing has primarily been used in patient studies. Discussed in some detail, are important measures that have been developed to standardize variant calling and to assess pathogenicity of variants. Examples of cases where exome sequencing has facilitated diagnosis and led to improved medical management are presented. Whole genome sequencing and its clinical relevance are presented particularly in the context of analysis of nucleotide and structural genomic variants in large population studies and in certain patient cohorts. Applications involving analysis of cell free DNA in maternal blood for prenatal diagnosis of specific autosomal trisomies are reviewed. Applications of DNA sequencing to diagnosis and therapeutics of cancer are presented. Also discussed are important recent diagnostic applications of DNA sequencing in cancer, including analysis of tumor derived cell free DNA and exosomes that are present in body fluids. Insights gained into underlying pathogenetic mechanisms of certain complex common diseases, including schizophrenia, macular degeneration, neurodegenerative disease are presented. The relevance of different types of variants, rare, uncommon, and common to disease pathogenesis, and the continuum of causality, are addressed. Pharmogenetic variants detected by DNA sequence analysis are gaining in importance and are particularly relevant to personalized and precision medicine.

PMID: 28516087 [PubMed - in process]

Carrier frequency of Wilson's disease in the Korean population: a DNA-based approach.

J Hum Genet. 2017 May 18;:

Authors: Jang JH, Lee T, Bang S, Kim YE, Cho EH

Abstract
Wilson's disease (WD) is an autosomal recessive disorder caused by ATP7B gene mutation. The frequency of WD is about 1 in 30 000 worldwide. In the present study, we screened 14 835 dried blood spots (DBSs) from asymptomatic Korean neonates and retrospectively reviewed massively parallel sequencing of 1090 control individuals to estimate carrier frequency. TaqMan real-time PCR assays were conducted to detect six mutations that account for 58.3% of mutations in Korean WD patients: c.2333G>T (p.Arg778Leu), c.2621C>T (p.Ala874Val), c.3086C>T (p.Thr1029Ile), c.3247C>T (p.Leu1083Phe), c.3556G>A (p.Gly1186Ser) and c.3809A>G (p.Asn1270Ser). We also retrospectively reviewed data from 1090 individuals with various indications other than WD for whom whole-exome or panel sequencing data were available. Mutant allele frequency based on the six most common mutations was 0.0067 among the total of 14 835 DBSs screened. Given that these six mutations account for 58.3% of mutations in Korean WD patients, the corrected mutant allele frequency is 0.0115 (95% confidence interval (CI): 0.0103-0.0128). Corresponding incidence (q(2)) and carrier frequency (2pq) were estimated to be 1:7561 and 1:44, respectively. In retrospective data analysis of 1090 control individuals, allele frequency of pathogenic or likely pathogenic variants was 0.0096 (95% CI: 0.0063-0.0146). Corresponding carrier frequency was estimated to be 1:53. Estimated allele and carrier frequencies based on DNA screening were relatively higher than those reported previously based on clinical ascertainment.Journal of Human Genetics advance online publication, 18 May 2017; doi:10.1038/jhg.2017.49.

PMID: 28515472 [PubMed - as supplied by publisher]

Identification of somatic mutations using whole-exome sequencing in Korean patients with acute myeloid leukemia.

BMC Med Genet. 2017 Mar 01;18(1):23

Authors: Heo SG, Koh Y, Kim JK, Jung J, Kim HL, Yoon SS, Park JW

Abstract
BACKGROUND: Acute myeloid leukemia (AML) is a biologically and clinically heterogeneous cancer of the bone marrow that is characterized by the rapid growth of abnormal myeloid cells.
METHODS: We performed a mutational analysis to identify AML somatic mutations using the whole-exome sequencing data of 36 tumor-normal sample pairs from Korean patients with de novo AML. We explored the functional impact of the genes identified in the mutational analyses through an integrated Gene Ontology (GO) and pathway analysis.
RESULTS: A total of 11 genes, including NEFH (p = 6.27 × 10(-13) and q = 1.18 × 10(-8)) and TMPRSS13 (p = 1.40 × 10(-10) and q = 1.32 × 10(-6)), also demonstrated q values less than 0.1 in 36 Korean AML patients. Five out of the 11 novel genes have previously been reported to be associated with other cancers. Two gene mutations, CEBPA (p = 5.22 × 10(-5)) and ATXN3 (p = 9.75 × 10(-4)), showed statistical significance exclusively in the M2 and M3 subtypes of the French-American-British classifications, respectively. A total of 501 genes harbored 478 missense, 22 nonsense, 93 frameshift indels, and/or three stop codon deletions and these gene mutations significantly enriched GO terms for signal transduction (GO:0007165, p = 1.77 × 10(-3)), plasma membrane (GO:0005886, p = 3.07 × 10(-4)), and scaffold protein binding (GO:0097110, p = 8.65 × 10(-4)). The mitogen-activated protein kinase (hsa04010, 7.67 × 10(-4)) was the most enriched Kyoto Encyclopedia of Genes and Genomes pathway.
CONCLUSIONS: Morphological AML subtypes may in part reflect subtype specific patterns of genomic alterations. Following validation, future studies to evaluate the usefulness of these genes in genetic testing for the early diagnosis and prognostic prediction of AML patients would be worthwhile.

PMID: 28249600 [PubMed - indexed for MEDLINE]