Genetic variants associated with phenytoin-related severe cutaneous adverse reactions
Chung, W., Chang, W., Lee, Y., Wu, Y., Yang, C., Ho, H., & ... Hung, S. (2014). Genetic variants associated with phenytoin-related severe cutaneous adverse reactions. JAMA: The Journal Of The American Medical Association, 312(5), 525-534. doi:10.1001/jama.2014.7859
Breast-cancer risk in families with mutations in PALB2
Antoniou, A., Casadei, S., Heikkinen, T., Barrowdale, D., Pylkäs, K., Roberts, J., & ... Tischkowitz, M. (2014). Breast-cancer risk in families with mutations in PALB2. The New England Journal Of Medicine, 371(6), 497-506. doi:10.1056/NEJMoa1400382
PALB2 mutations and breast-cancer risk
Evans MK, Longo DL. (2014). PALB2 mutations and breast-cancer risk. N Engl J Med. 2014 Aug 7;371(6):566-8. doi: 10.1056/NEJMe1405784.
STING-associated vasculopathy with onset in infancy--a new interferonopathy
Crow, Y., & Casanova, J. (2014). STING-associated vasculopathy with onset in infancy--a new interferonopathy. The New England Journal Of Medicine, 371(6), 568-571. doi:10.1056/NEJMe1407246
Genotype-phenotype correlation--promiscuity in the era of next-generation sequencing
Lu JT, Campeau PM, Lee BH. (2014). Genotype-phenotype correlation--promiscuity in the era of next-generation sequencing. N Engl J Med. 2014 Aug 14;371(7):593-6. doi: 10.1056/NEJMp1400788.
Syndromes of thrombotic microangiopathy
George JN, Nester CM. (2014). Syndromes of thrombotic microangiopathy. N Engl J Med. 2014 Aug 14;371(7):654-66. doi: 10.1056/NEJMra1312353.
Loss-of-function mutations in APOC3, triglycerides, and coronary disease
Crosby, J., Peloso, G., Auer, P., Crosslin, D., Stitziel, N., Lange, L., & ... Kathiresan, S. (2014). Loss-of-function mutations in APOC3, triglycerides, and coronary disease. The New England Journal Of Medicine, 371(1), 22-31. doi:10.1056/NEJMoa1307095
Loss-of-function mutations in APOC3 and risk of ischemic vascular disease
Jørgensen, A., Frikke-Schmidt, R., Nordestgaard, B., & Tybjærg-Hansen, A. (2014). Loss-of-function mutations in APOC3 and risk of ischemic vascular disease. The New England Journal Of Medicine, 371(1), 32-41. doi:10.1056/NEJMoa1308027
Correspondence: Mutant COQ2 in Multiple-System Atrophy
Correspondence: Mutant COQ2 in Multiple-System Atrophy: NEJM: July 3, 2014: Vol 371, No. 3: pp 80-83
Resistance mechanisms for the Bruton's tyrosine kinase inhibitor ibrutinib
brutinib is an irreversible inhibitor of Bruton's tyrosine kinase (BTK) and is effective in chronic lymphocytic leukemia (CLL). Resistance to irreversible kinase inhibitors and resistance associated with BTK inhibition have not been characterized. Although only a small proportion of patients have had a relapse during ibrutinib therapy, an understanding of resistance mechanisms is important. We evaluated patients with relapsed disease to identify mutations that may mediate ibrutinib resistance...
Null Mutation in Hormone-Sensitive Lipase Gene and Risk of Type 2 Diabetes
Lipolysis regulates energy homeostasis through the hydrolysis of intracellular triglycerides and the release of fatty acids for use as energy substrates or lipid mediators in cellular processes. Genes encoding proteins that regulate energy homeostasis through lipolysis are thus likely to play an important role in determining susceptibility to metabolic disorders...
Translating the Genomic Revolution—Targeted Genome Editing in Primates
The promise of the genomics revolution is appealing, ambitious, and multipronged. Should this promise be delivered on, patients, equipped with interpretations of their genomes, will be able to gauge the risk of receiving a diagnosis of cancer or heart disease. Physicians will be able to quickly pinpoint the genetic basis of a disorder and take appropriate actions to treat the disease using specific “genome editing” tools...
New report offers a primer for doctors' use of clinical genome and exome sequencing
ooner than almost anyone expected, a new, genome-based technology for demystifying undiagnosed illnesses-particularly rare childhood diseases-is moving from research laboratories into general medical practice. Now, two leading scientists have sketched out what doctors need to know in order to use the new technology effectively...
Diagnostic Clinical Genome and Exome Sequencing
Sequencing of the genome or exome for clinical applications, hereafter referred to as clinical genome and exome sequencing (CGES), has now entered medical practice. Several thousand CGES tests have already been ordered for patients, with the goal of establishing diagnoses for rare, clinically unrecognizable, or puzzling disorders that are suspected to be genetic in origin. We anticipate increases in the use of CGES, the key attribute of which — its breadth — distinguishes it from other forms of laboratory testing. The interrogation of variation in about 20,000 genes simultaneously can be a powerful and effective diagnostic method...
A Form of the Metabolic Syndrome Associated with Mutations in DYRK1B
Genetic analysis has been successful in identifying causative mutations for individual cardiovascular risk factors. Success has been more limited in mapping susceptibility genes for clusters of cardiovascular risk traits, such as those in the metabolic syndrome.
A Notch for Noncoding RNA in Melanoma
In recent years, improved knowledge of the molecular basis of melanoma has transformed the care of patients with this disease. Metastatic melanoma is now an exemplar of the effect that scientific discovery can have in the clinic. Advances in immunobiology have brought forth a powerful new class of immunotherapeutic agents capable of providing durable disease control for a substantial fraction of patients with melanoma. For tumors that do not respond to immunotherapy but harbor specific mutations in the BRAF oncogene (about half of all cases), targeted therapy with pharmacologic inhibitors of the mitogen-activated protein kinase (MAPK) effectors RAF and MEK has proved highly (albeit transiently) beneficial. Ongoing clinical trials also hint at the promise of targeted therapy in other molecular subtypes of melanoma. In a cancer once considered a scourge even within oncology, scientific discoveries with potential clinical importance now seem almost commonplace.
Using Multiplexed Assays of Oncogenic Drivers in Lung Cancers to Select Targeted Drugs
Targeting oncogenic drivers (genomic alterations critical to cancer development and maintenance) has transformed the care of patients with lung adenocarcinomas. The Lung Cancer Mutation Consortium was formed to perform multiplexed assays testing adenocarcinomas of the lung for drivers in 10 genes to enable clinicians to select targeted treatments and enroll patients into clinical trials.
Non–Small Cell Lung Cancer and Precision Medicine A Model for the Incorporation of Genomic Features Into Clinical Trial Design
Lung cancer remains the leading cause of cancer death in the United States. It is estimated that 228 190 patients were diagnosed with the disease and 159 480 died of lung cancer in 2013. Historically, lung cancer has been categorized, based on histology, into non–small cell lung cancer (NSCLC) constituting approximately 85% of cases and small cell lung cancer accounting for approximately 15% of the cases. Treatment for advanced NSCLC has been associated with relatively low response rates and significant toxicity, and only in the last 20 years has an agreement been reached that chemotherapy for this disease confers a survival benefit. At the same time, no distinction was made in treatment between the various subtypes of NSCLC3 until 2008 when a randomized trial demonstrated differences in response rates to specific chemotherapy regimens between squamous and nonsquamous lung carcinomas. Addition of the antiangiogenic agent bevacizumab resulted in a 2-month improvement in median ...
Multitarget Stool DNA Testing for Colorectal-Cancer Screening
An accurate, noninvasive test could improve the effectiveness of colorectal-cancer screening.
Editorial: Stool DNA and Colorectal-Cancer Screening
Colorectal-cancer screening in the United States is a success story. The American Cancer Society recently reported that rates of death from colorectal cancer are down by 46% from their peak.1 There is good evidence that screening efforts have played an important role in the trend.2 However, work remains to be done, since approximately one third of Americans report not being current with screening.3 One approach to increase screening uptake is to broaden the available test options. On the basis of current U.S. Preventive Services Task Force guidelines, there are three recommended options: fecal occult blood testing, flexible sigmoidoscopy, and colonoscopy.4 Other screening tests, such as computed tomographic colonography and stool DNA testing, were not recommended because of insufficient evidence to assess the benefits and harms...
Autophagy, p53, and Pancreatic Cancer
In this age of environmental awareness and being green, one can take a lesson from eukaryotic cells. An efficient process called autophagy involves the formation of intracellular vesicles, called autophagosomes, which deliver long-lived proteins and excess organelles to lysosomes for degradation. The macromolecule products of this degradation are then used in a variety of cellular processes.1 Not surprisingly, the dysregulation of autophagy plays a major role in several human diseases, including cancer...
Mutant ZP1 in Familial Infertility
The human zona pellucida is composed of four glycoproteins (ZP1, ZP2, ZP3, and ZP4) and has an important role in reproduction. Here we describe a form of infertility with an autosomal recessive mode of inheritance, characterized by abnormal eggs that lack a zona pellucida. We identified a homozygous frameshift mutation in ZP1 in six family members. In vitro studies showed that defective ZP1 proteins and normal ZP3 proteins colocalized throughout the cells and were not expressed at the cell surface, suggesting that the aberrant ZP1 results in the sequestration of ZP3 in the cytoplasm, thereby preventing the formation of the zona pellucida around the oocyte.
Overcoming Drug Resistance in ALK-Rearranged Lung Cancer
Approximately 4 to 15% of lung adenocarcinomas harbor a genomic rearrangement in the anaplastic lymphoma kinase gene (ALK) that creates a gene fusion activating the tyrosine kinase ALK.1-4 Treatment of patients with ALK-rearranged lung cancer with the MET and ALK inhibitor crizotinib induces responses5 and confers a benefit in progression-free survival.6 In a nonrandomized registry study, crizotinib also improved overall survival.
Ceritinib in ALK-rearranged non–small-cell lung cancer
Non–small-cell lung cancer (NSCLC) harboring the anaplastic lymphoma kinase gene (ALK) rearrangement is sensitive to the ALK inhibitor crizotinib, but resistance invariably develops. Ceritinib (LDK378) is a new ALK inhibitor that has shown greater antitumor potency than crizotinib in preclinical studies.
Genetic variants in C5 and poor response to eculizumab
Eculizumab is a humanized monoclonal antibody that targets complement protein C5 and inhibits terminal complement–mediated hemolysis associated with paroxysmal nocturnal hemoglobinuria (PNH). The molecular basis for the poor response to eculizumab in a small population of Japanese patients is unclear.
Vitamin B12 and Pernicious Anemia — The Dawn of Molecular Medicine
“From bedside to bench and back again” is a time-honored trajectory to which many medical students, residents, and fellows aspire. Arguably the earliest and most celebrated completion of this circuit was the dietary cure of pernicious anemia that drove the discovery of vitamin B12 (cobalamin) and its physiologic role.
Early-Onset Stroke and Vasculopathy Associated with Mutations in ADA2
"We observed a syndrome of intermittent fevers, early-onset lacunar strokes and other neurovascular manifestations, livedoid rash, hepatosplenomegaly, and systemic vasculopathy in three unrelated patients. We suspected a genetic cause because the disorder presented in early childhood."
Mutant Adenosine Deaminase 2 in a Polyarteritis Nodosa Vasculopathy
"Polyarteritis nodosa is a systemic necrotizing vasculitis with a pathogenesis that is poorly understood. We identified six families with multiple cases of systemic and cutaneous polyarteritis nodosa, consistent with autosomal recessive inheritance. In most cases, onset of the disease occurred during childhood."
APOL1 risk variants, race, and progression of chronic kidney disease
Background: Among patients in the United States with chronic kidney disease, black patients are at increased risk for end-stage renal disease, as compared with white patients.
Health disparities in kidney disease--emerging data from the human genome
Racial disparity in end-stage renal disease in the United States is well documented; hypertensive kidney disease has long been considered to be a leading cause of this disorder among black patients... Overall, nondiabetic chronic kidney disease afflicts black patients disproportionately...Research into health disparities has focused on the basis of these differences for more than 20 years, and the main emphasis in many relevant and important studies has been on social determinants of health. Yet, other observations have hinted at a role for biologic determinants, since many black patients with end-stage renal disease had close relatives who were receiving dialysis and had other family members who had so-called silent kidney disease, characterized by decreased kidney function and proteinuria. Such observations have led to the pressing question of whether there were undiscovered genetic determinants.
PLS3 mutations in X-linked osteoporosis with fractures
Plastin 3 (PLS3), a protein involved in the formation of filamentous actin (F-actin) bundles, appears to be important in human bone health, on the basis of pathogenic variants in PLS3 in five families with X-linked osteoporosis and osteoporotic fractures that we report here. The bone-regulatory properties of PLS3 were supported by in vivo analyses in zebrafish. Furthermore, in an additional five families (described in less detail) referred for diagnosis or ruling out of osteogenesis imperfecta type I, a rare variant (rs140121121) in PLS3 was found. This variant was also associated with a risk of fracture among elderly heterozygous women that was two times as high as that among noncarriers, which indicates that genetic variation in PLS3 is a novel etiologic factor involved in common, multi-factorial osteoporosis.
Next-Generation Sequencing for Clinical Diagnostics
Yang et al.1 report in the Journal the results of using whole-exome sequencing to make a molecular diagnosis in 62 of 250 cases (25%) sequenced by the clinical sequencing laboratory at the Baylor College of Medicine, which is accredited by the College of American Pathologists and certified through the Clinical Laboratory Improvement Amendments program. This level of success is a marked improvement over that obtained by testing single genes or gene panels currently used in standard care. The exome is the portion of the genome known to encode proteins (approximately 1% of the human genome2). Whole-exome sequencing has the advantage of reduced cost and analysis of a much smaller data set than that obtained by sequencing the entire genome. The other advantage of whole-exome sequencing is that current knowledge about functional genetic variation is largely limited to the coding sequences of genes (i.e., exons).
Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer
tients with metastatic colorectal cancer that harbors KRAS mutations in exon 2 do not benefit from anti–epidermal growth factor receptor (EGFR) therapy. Other activating RAS mutations may also be negative predictive biomarkers for anti-EGFR therapy.
Beyond exon 2--the developing story of RAS mutations in colorectal cancer
Initial single-agent studies of anti–epidermal growth factor receptor (anti-EGFR) antibodies in the treatment of colorectal cancer showed that these agents were marginally effective.1,2 The minority of patients derived benefit, as evidenced by progression-free survival curves that had no inflection until well after the 50% mark. However, after the determination that activating mutations in exon 2 of the gene KRAS predicted the inefficacy of anti-EGFR antibodies, reanalyses of multiple trials suggested that these agents could be more effective when administered to a more limited cohort of patients.3 Thus, mutations in exon 2 of KRAS became the first biomarkers of colorectal cancer. Even with testing of KRAS exon 2, however, a cohort of patients with colorectal cancer still do not benefit from anti-EGFR antibody therapy. Also, since the KRAS exon 2 mutations are common (appearing in approximately 40% of patients with colorectal cancer), they are the “low-hanging fruit” for analysis
Safety and efficacy of RNAi therapy for transthyretin amyloidosis
Transthyretin amyloidosis is caused by the deposition of hepatocyte-derived transthyretin amyloid in peripheral nerves and the heart. A therapeutic approach mediated by RNA interference (RNAi) could reduce the production of transthyretin.
A new era in the treatment of amyloidosis?
Amyloidosis is a diverse group of diseases caused by extracellular accumulation of protein in a highly ordered, abnormal, insoluble fibrillar form. These diseases can be hereditary or acquired and localized or systemic. Most are progressive and fatal. Among the almost 30 different proteins that have been found to form amyloid in humans, transthyretin, a carrier molecule of thyroxine and vitamin A, is of particular interest because it may cause both hereditary and acquired amyloidosis with a diverse range of symptoms. In addition, transthyretin amyloid may be more prevalent than previously thought, and several potential new treatments are on the horizon.
Mutations in DSTYK and dominant urinary tract malformations
ongenital abnormalities of the kidney and the urinary tract are the most common cause of pediatric kidney failure. These disorders are highly heterogeneous, and the etiologic factors are poorly understood.
Characterization of uterine leiomyomas by whole-genome sequencing
Uterine leiomyomas are benign but affect the health of millions of women. A better understanding of the molecular mechanisms involved may provide clues to the prevention and treatment of these lesions. We performed whole-genome sequencing and gene-expression profiling of 38 uterine leiomyomas and the corresponding myometrium from 30 women.
Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia
The treatment of relapsed chronic lymphocytic leukemia (CLL) has resulted in few durable remissions. Bruton's tyrosine kinase (BTK), an essential component of B-cell–receptor signaling, mediates interactions with the tumor microenvironment and promotes the survival and proliferation of CLL cells.
A mechanism-driven treatment for chronic lymphocytic leukemia?
Chronic lymphocytic leukemia (CLL) is the most common form of leukemia in the Western world. Its prevalence is increasing largely because of extended life expectancies. CLL has a highly heterogeneous clinical course: some patients live for years or decades, never require treatment, and eventually die from a cause other than CLL, whereas others have a slowly progressive clinical picture and others have an aggressive disease course of 2 years or less. Since 1975, clinicians have relied on clinical staging systems to define prognosis and make treatment decisions. Over the past 12 years, a number of biologic markers have allowed a more refined prognostic stratification...
Delayed puberty and estrogen resistance in a woman with estrogen receptor α variant
Although androgen resistance has been characterized in men with a normal chromosome complement and mutations in the androgen-receptor gene, a mutation in the gene encoding estrogen receptor α (ESR1) was previously described only in one man and not, to our knowledge, in a woman. We now describe an 18-year-old woman without breast development and with markedly elevated serum levels of estrogens and bilateral multicystic ovaries. She was found to have a homozygous loss-of-function ESR1 mutation in a completely conserved residue that interferes with estrogen signaling. Her clinical presentation was similar to that in the mouse orthologue knockout. This case shows that disruption of ESR1 causes profound estrogen resistance in women. (Funded by the National Institutes of Health.).
||Charles J. Macri, MD, FACOG, FACMG, FACS
Professor of Obstetrics & Gynecology
Director, Division of Maternal Fetal Medicine
Director, Student Education in Obstetrics and Gynecology
GWUMC Genetics - Current, Basic & Advanced Information about Genetics
This virtual journal club is intended to provide a way for health care practitioners to see new literature in genetics and to learn about developments in the field.
Articles on topics in medical genetics will be posted monthly, or more often if
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