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Genetics Journal Club: 2011-2012

A journal club for GWUMC faculty, fellows, residents and students interested in genetics.

March 2012

Patel, J. P., Gönen, M., Figueroa, M. E., Fernandez, H., Sun, Z., Racevskis, J., . . . Levine, R. L. (2012). Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. N Engl J Med, 366(12), 1079-1089. doi:10.1056/NEJMoa1112304


Acute myeloid leukemia (AML) is a heterogeneous disease with respect to presentation and clinical outcome. The prognostic value of recently identified somatic mutations has not been systematically evaluated in a phase 3 trial of treatment for AML.

We performed a mutational analysis of 18 genes in 398 patients younger than 60 years of age who had AML and who were randomly assigned to receive induction therapy with high-dose or standard-dose daunorubicin. We validated our prognostic findings in an independent set of 104 patients.

We identified at least one somatic alteration in 97.3% of the patients. We found that internal tandem duplication in FLT3 (FLT3-ITD), partial tandem duplication in MLL (MLL-PTD), and mutations in ASXL1 and PHF6 were associated with reduced overall survival (P=0.001 for FLT3-ITD, P=0.009 for MLL-PTD, P=0.05 for ASXL1, and P=0.006 for PHF6); CEBPA and IDH2 mutations were associated with improved overall survival (P=0.05 for CEBPA and P=0.01 for IDH2). The favorable effect of NPM1 mutations was restricted to patients with co-occurring NPM1 and IDH1 or IDH2 mutations. We identified genetic predictors of outcome that improved risk stratification among patients with AML, independently of age, white-cell count, induction dose, and post-remission therapy, and validated the significance of these predictors in an independent cohort. High-dose daunorubicin, as compared with standard-dose daunorubicin, improved the rate of survival among patients with DNMT3A or NPM1 mutations or MLL translocations (P=0.001) but not among patients with wild-type DNMT3A, NPM1, and MLL (P=0.67).

We found that DNMT3A and NPM1 mutations and MLL translocations predicted an improved outcome with high-dose induction chemotherapy in patients with AML. These findings suggest that mutational profiling could potentially be used for risk stratification and to inform prognostic and therapeutic decisions regarding patients with AML. (Funded by the National Cancer Institute and others.).

Godley, L. A. (2012). Profiles in leukemia. N Engl J Med, 366(12), 1152-1153. doi:10.1056/NEJMe1200409

For years, scientists have postulated the evolution of a cancer as a series of acquired mutations and epigenetic alterations that accumulate in a progressive way, beginning with a single transformed cell. Within this process, subclones of cells develop that acquire new properties, giving cells advantages, such as the ability to resist chemotherapy or to metastasize...

Koopman, W. J. H., Willems, P. H. G. M., & Smeitink, J. A. M. (2012). Monogenic mitochondrial disorders. N Engl J Med, 366(12), 1132-1141. doi:10.1056/NEJMra1012478

To function normally, human cells require energy in the form of ATP. In many cell types, ATP is primarily generated by mitochondria, which are also key players in other important cellular processes, such as adaptive thermogenesis, ion homeostasis, innate immune responses, production of reactive oxygen species, and programmed cell death (apoptosis).  Mitochondria contain their own DNA (mtDNA), which encodes 13 mitochondrial proteins, 2 ribosomal RNAs (rRNAs), and 22 transfer RNAs (tRNAs). The replication, transcription, translation, and repair of mtDNA are controlled by proteins encoded by nuclear DNA (nDNA)...

February 2012

Anheim, M., Tranchant, C., & Koenig, M. (2012). The autosomal recessive cerebellar ataxias. N Engl J Med, 366(7), 636-646. doi:10.1056/NEJMra1006610

The autosomal recessive cerebellar ataxias are a group of little known and often neglected diseases that are best understood by following a practical, multidisciplinary approach that focuses on clinical rather than molecular considerations...

Topaloglu, A. K., Tello, J. A., Kotan, L. D., Ozbek, M. N., Yilmaz, M. B., Erdogan, S., . . . Yuksel, B. (2012). Inactivating KISS1 mutation and hypogonadotropic hypogonadism. The New England Journal of Medicine, 366(7), 629-635. doi:10.1056/NEJMoa1111184

Gonadotropin-releasing hormone (GnRH) is the central regulator of gonadotropins, which stimulate gonadal function. Hypothalamic neurons that produce kisspeptin and neurokinin B stimulate GnRH release. Inactivating mutations in the genes encoding the human kisspeptin receptor (KISS1R, formerly called GPR54), neurokinin B (TAC3), and the neurokinin B receptor (TACR3) result in pubertal failure. However, human kisspeptin loss-of-function mutations have not been described, and contradictory findings have been reported in Kiss1-knockout mice. We describe an inactivating mutation in KISS1 in a large consanguineous family that results in failure of pubertal progression, indicating that functional kisspeptin is important for puberty and reproduction in humans. (Funded by the Scientific and Technological Research Council of Turkey [TÜBİTAK] and others.).

Herman, D. S., Lam, L., Taylor, M. R., Wang, L., Teekakirikul, P., Christodoulou, D., . . . Seidman, C. E. (2012). Truncations of titin causing dilated cardiomyopathy. The New England Journal of Medicine, 366(7), 619-628. doi:10.1056/NEJMoa1110186

BACKGROUND:  Dilated cardiomyopathy and hypertrophic cardiomyopathy arise from mutations in many genes. TTN, the gene encoding the sarcomere protein titin, has been insufficiently analyzed for cardiomyopathy mutations because of its enormous size.
METHODS:  We analyzed TTN in 312 subjects with dilated cardiomyopathy, 231 subjects with hypertrophic cardiomyopathy, and 249 controls by using next-generation or dideoxy sequencing. We evaluated deleterious variants for cosegregation in families and assessed clinical characteristics.
RESULTS:  We identified 72 unique mutations (25 nonsense, 23 frameshift, 23 splicing, and 1 large tandem insertion) that altered full-length titin. Among subjects studied by means of next-generation sequencing, the frequency of TTN mutations was significantly higher among subjects with dilated cardiomyopathy (54 of 203 [27%]) than among subjects with hypertrophic cardiomyopathy (3 of 231 [1%], P=3×10(-16)) or controls (7 of 249 [3%], P=9×10(-14)). TTN mutations cosegregated with dilated cardiomyopathy in families (combined lod score, 11.1) with high (>95%) observed penetrance after the age of 40 years. Mutations associated with dilated cardiomyopathy were overrepresented in the titin A-band but were absent from the Z-disk and M-band regions of titin (P≤0.01 for all comparisons). Overall, the rates of cardiac outcomes were similar in subjects with and those without TTN mutations, but adverse events occurred earlier in male mutation carriers than in female carriers (P=4×10(-5)).
CONCLUSIONS:  TTN truncating mutations are a common cause of dilated cardiomyopathy, occurring in approximately 25% of familial cases of idiopathic dilated cardiomyopathy and in 18% of sporadic cases. Incorporation of sequencing approaches that detect TTN truncations into genetic testing for dilated cardiomyopathy should substantially increase test sensitivity, thereby allowing earlier diagnosis and therapeutic intervention for many patients with dilated cardiomyopathy. Defining the functional effects of TTN truncating mutations should improve our understanding of the pathophysiology of dilated cardiomyopathy. (Funded by the Howard Hughes Medical Institute and others.).

January 2012

Bochukova, E., Schoenmakers, N., Agostini, M., Schoenmakers, E., Rajanayagam, O., Keogh, J. M., . . . Chatterjee, K. (2012). A mutation in the thyroid hormone receptor alpha gene. N Engl J Med, 366(3), 243-249.

Thyroid hormones exert their effects through alpha (TRα1) and beta (TRβ1 and TRβ2) receptors. Here we describe a child with classic features of hypothyroidism (growth retardation, developmental retardation, skeletal dysplasia, and severe constipation) but only borderline-abnormal thyroid hormone levels. Using whole-exome sequencing, we identified a de novo heterozygous nonsense mutation in a gene encoding thyroid hormone receptor alpha (THRA) and generating a mutant protein that inhibits wild-type receptor action in a dominant negative manner. Our observations are consistent with defective human TRα-mediated thyroid hormone resistance and substantiate the concept of hormone action through distinct receptor subtypes in different target tissues.

Heravi-Moussavi, A., Anglesio, M. S., Cheng, S. -. G., Senz, J., Yang, W., Prentice, L., . . . Huntsman, D. G. (2012). Recurrent somatic DICER1 mutations in nonepithelial ovarian cancers. N Engl J Med, 366(3), 234-242. doi:10.1056/NEJMoa1102903

Germline truncating mutations in DICER1, an endoribonuclease in the RNase III family that is essential for processing microRNAs, have been observed in families with the pleuropulmonary blastoma–family tumor and dysplasia syndrome. Mutation carriers are at risk for nonepithelial ovarian tumors, notably sex cord–stromal tumors.

December 2011

Nathwani, A. C., Tuddenham, E. G., Rangarajan, S., Rosales, C., McIntosh, J., Linch, D. C., . . . Davidoff, A. M. (2011). Adenovirus-associated virus vector-mediated gene transfer in hemophilia B. The New England Journal of Medicine, doi:10.1056/NEJMoa1108046

Abstract: Background Hemophilia B, an X-linked disorder, is ideally suited for gene therapy. We investigated the use of a new gene therapy in patients with the disorder. Methods We infused a single dose of a serotype-8-pseudotyped, self-complementary adenovirus-associated virus (AAV) vector expressing a codon-optimized human factor IX (FIX) transgene (scAAV2/8-LP1-hFIXco) in a peripheral vein in six patients with severe hemophilia B (FIX activity, <1% of normal values). Study participants were enrolled sequentially in one of three cohorts (given a high, intermediate, or low dose of vector), with two participants in each group. Vector was administered without immunosuppressive therapy, and participants were followed for 6 to 16 months. Results AAV-mediated expression of FIX at 2 to 11% of normal levels was observed in all participants. Four of the six discontinued FIX prophylaxis and remained free of spontaneous hemorrhage; in the other two, the interval between prophylactic injections was increased. Of the two participants who received the high dose of vector, one had a transient, asymptomatic elevation of serum aminotransferase levels, which was associated with the detection of AAV8-capsid-specific T cells in the peripheral blood; the other had a slight increase in liver-enzyme levels, the cause of which was less clear. Each of these two participants received a short course of glucocorticoid therapy, which rapidly normalized aminotransferase levels and maintained FIX levels in the range of 3 to 11% of normal values. Conclusions Peripheral-vein infusion of scAAV2/8-LP1-hFIXco resulted in FIX transgene expression at levels sufficient to improve the bleeding phenotype, with few side effects. Although immune-mediated clearance of AAV-transduced hepatocytes remains a concern, this process may be controlled with a short course of glucocorticoids without loss of transgene expression. (Funded by the Medical Research Council and others; number, NCT00979238 .).

Boyer O.  et. al.  INF2 Mutations in Charcot-Marie-Tooth Disease with Glomerulopathy.  New England Journal of Medicine (NEJM).  December 22, 2011:  365; 25: 2377-2388.

No abstract available.  Article begins:  Charcot–Marie–Tooth disease refers to a heterogeneous group of inherited chronic peripheral motor and sensory neuropathies.1 Affected persons typically present with progressive distal-muscle weakness and atrophy, reduced tendon reflexes, and foot and hand deformities.

O'Donnell, C. J., & Nabel, E. G. (2011). Genomics of cardiovascular disease. The New England Journal of Medicine, 365(22), 2098-2109. doi:10.1056/NEJMra1105239

No abstract available.  Article begins: Cardiovascular disease is the leading cause of death in the United States. Considerable progress has been made in the past 50 years to define, identify, and modify risk factors for cardiovascular disease (e.g., hypertension, dyslipidemia, obesity, type 2 diabetes, cigarette smoking, and physical inactivity) and to develop treatments, such as coronary care units, percutaneous coronary interventions, and beta-blockers.

November 2011

Hafner, C., Toll, A., & Real, F. X. (2011). HRAS mutation mosaicism causing urothelial cancer and epidermal nevus. New England Journal of Medicine, 365(20), 1940-1942.

No abstract available.  Article begins:  Mosaicism of an oncogenic AKT1 mutation causes Proteus syndrome, which is associated with epidermal nevi and an increased risk of cancer.  The occurrence of oncogenic mutations in mosaicism may increase a person's risk for malignant conditions. Somatic RAS mutations occur in 30% of tumors; germline mutations have been identified in rare developmental disorders, such as HRAS mutations in the Costello syndrome.  Here we report on a patient with multiple urothelial tumors reflecting mosaicism of an oncogenic HRAS mutation.

Ramsey, B. W., Davies, J., McElvaney, N. G., Tullis, E., Bell, S. C., Dřevínek, P., et al. (2011). A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. New England Journal of Medicine, 365(18), 1663-1672.

Abstract: Increasing the activity of defective cystic fibrosis transmembrane conductance regulator (CFTR) protein is a potential treatment for cystic fibrosis.

October 2011

Cho, J. H., & Gregersen, P. K. (2011). Genomics and the multifactorial nature of human autoimmune disease. The New England Journal of Medicine, 365(17), 1612-1623. doi:10.1056/NEJMra1100030

No abstract available.  Article begins: The major autoimmune diseases, including rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, type 1 diabetes mellitus, psoriasis, and inflammatory bowel disease, share epidemiologic, clinical, and therapeutic features. In each of these diseases, chronic and often intermittent inflammation contributes over time to the destruction of target organs that house inciting antigens or are the sites of immune-complex deposition. For some of these disorders, such as inflammatory bowel disease, the contribution of autoimmune mechanisms is questioned, but the overlap of genetic associations that have been identified during the past 5 years suggests a shared immune pathogenesis...

September 2011

Feero, W. G., & Green, E. D. (2011). Genomics education for health care professionals in the 21st century. JAMA : The Journal of the American Medical Association, 306(9), 989-990. doi:10.1001/jama.2011.1245

No abstract available.  Article begins: Recent genomic discoveries have brought about far-reaching advances in understanding the molecular basis of human health and disease. The vision for the future of genomics research developed by the National Human Genome Research Institute suggests more discoveries are likely to occur over the next few decades...

August 2011

Rasko, D. A., Webster, D. R., Sahl, J. W., Bashir, A., Boisen, N., Scheutz, F., . . . Waldor, M. K. (2011). Origins of the E. coli strain causing an outbreak of hemolytic-uremic syndrome in Germany. The New England Journal of Medicine, 365(8), 709-717. doi:10.1056/NEJMoa1106920

BACKGROUND: A large outbreak of diarrhea and the hemolytic-uremic syndrome caused by an unusual serotype of Shiga-toxin-producing Escherichia coli (O104:H4) began  in Germany in May 2011. As of July 22, a large number of cases of diarrhea caused by Shiga-toxin-producing E. coli have been reported--3167 without the hemolytic-uremic syndrome (16 deaths) and 908 with the hemolytic-uremic syndrome  (34 deaths)--indicating that this strain is notably more virulent than most of the Shiga-toxin-producing E. coli strains. Preliminary genetic characterization of the outbreak strain suggested that, unlike most of these strains, it should be classified within the enteroaggregative pathotype of E. coli. METHODS: We used third-generation, single-molecule, real-time DNA sequencing to determine the complete genome sequence of the German outbreak strain, as well as  the genome sequences of seven diarrhea-associated enteroaggregative E. coli serotype O104:H4 strains from Africa and four enteroaggregative E. coli reference strains belonging to other serotypes. Genomewide comparisons were performed with  the use of these enteroaggregative E. coli genomes, as well as those of 40 previously sequenced E. coli isolates. RESULTS: The enteroaggregative E. coli O104:H4 strains are closely related and form a distinct clade among E. coli and enteroaggregative E. coli strains. However, the genome of the German outbreak strain can be distinguished from those of other O104:H4 strains because it contains a prophage encoding Shiga toxin 2 and a distinct set of additional virulence and antibiotic-resistance factors. CONCLUSIONS: Our findings suggest that horizontal genetic exchange allowed for the emergence of the highly virulent Shiga-toxin-producing enteroaggregative E. coli O104:H4 strain that caused the German outbreak. More broadly, these findings highlight the way in which the plasticity of bacterial genomes facilitates the emergence of new pathogens.

Rohde, H., Qin, J., Cui, Y., Li, D., Loman, N. J., Hentschke, M., . . . E. coli O104:H4 Genome Analysis Crowd-Sourcing Consortium. (2011). Open-source genomic analysis of shiga-toxin-producing E. coli O104:H4. The New England Journal of Medicine, 365(8), 718-724. doi:10.1056/NEJMoa1107643

An outbreak caused by Shiga-toxin–producing Escherichia coli O104:H4 occurred in  Germany in May and June of 2011, with more than 3000 persons infected. Here, we report a cluster of cases associated with a single family and describe an open-source genomic analysis of an isolate from one member of the family. This analysis involved the use of rapid, bench-top DNA sequencing technology, open-source data release, and prompt crowd-sourced analyses. In less than a week, these studies revealed that the outbreak strain belonged to an enteroaggregative  E. coli lineage that had acquired genes for Shiga toxin 2 and for antibiotic resistance.