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Genetics Journal Club: 2010-2011

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

March 2011

Benz, E. J.,Jr. (2011). Newborn screening for alpha-thalassemia--keeping up with globalization. The New England Journal of Medicine, 364(8), 770-771. doi:10.1056/NEJMe1013338

No abstract available.

Lal, A., Goldrich, M. L., Haines, D. A., Azimi, M., Singer, S. T., & Vichinsky, E. P. (2011). Heterogeneity of hemoglobin H disease in childhood. The New England Journal of Medicine, 364(8), 710-718. doi:10.1056/NEJMoa1010174

Abstract:  BACKGROUND: Early diagnosis during newborn screening or infancy has enabled the observation of the natural history of hemoglobin H disease, a subtype of α-thalassemia.
METHODS: We analyzed longitudinal clinical data for patients with hemoglobin H disease arising from the deletion of three of four α-globin genes (HbH) and from hemoglobin H Constant Spring (HCS), caused by the deletion of two α-globin genes and the Constant Spring mutation.
RESULTS: We identified 86 patients with hemoglobin H disease (48 through newborn screening). Of these patients, 60 (70%) had HbH, 23 (27%) had HCS, and 3 (3%) had other, nondeletional forms of hemoglobin H disease. The parental ethnic background was Asian in 81% of patients, Hispanic in 5%, and African American in 3%, whereas mixed ancestry was observed in 10% of patients. Among the patients with deletional hemoglobin H disease, 15% had one or both parents with African-American ancestry. Growth was normal in patients with HbH during the first decade, but growth deficits began during infancy in those with HCS. Anemia was more severe in patients with HCS at all ages (P<0.001). Acute worsening of anemia with infections requiring urgent blood transfusion was observed in patients with HCS but not in those with HbH. The probability of receiving at least one transfusion by the age of 20 years was 3% for patients with HbH and 80% for those with HCS (P<0.001). Among patients with HCS, transfusions occurred in 13% of infants and 50% of children under the age of 6 years; splenectomy was associated with a significant improvement in hemoglobin levels (P=0.01) and a reduction in the number of transfusions.
CONCLUSIONS: HCS should be recognized as a distinct thalassemia syndrome with a high risk of life-threatening anemia during febrile illnesses. HbH was not associated with an increased rate of severe anemia with infections and was managed without blood transfusions. Many patients with these disorders had mixed ethnic backgrounds, which highlights the need for extended newborn screening in populations that are traditionally considered to be at low risk for hemoglobin H disease.

Moretti, A., Bellin, M., Welling, A., Jung, C. B., Lam, J. T., Bott-Flugel, L., . . . Laugwitz, K. L. (2010). Patient-specific induced pluripotent stem-cell models for long-QT syndrome. The New England Journal of Medicine, 363(15), 1397-1409. doi:10.1056/NEJMoa0908679

Abstract: BACKGROUND: Long-QT syndromes are heritable diseases associated with prolongation of the QT interval on an electrocardiogram and a high risk of sudden cardiac death due to ventricular tachyarrhythmia. In long-QT syndrome type 1, mutations occur in the KCNQ1 gene, which encodes the repolarizing potassium channel mediating the delayed rectifier I(Ks) current.
METHODS: We screened a family affected by long-QT syndrome type 1 and identified an autosomal dominant missense mutation (R190Q) in the KCNQ1 gene. We obtained dermal fibroblasts from two family members and two healthy controls and infected them with retroviral vectors encoding the human transcription factors OCT3/4, SOX2, KLF4, and c-MYC to generate pluripotent stem cells. With the use of a specific protocol, these cells were then directed to differentiate into cardiac myocytes.
RESULTS: Induced pluripotent stem cells maintained the disease genotype of long-QT syndrome type 1 and generated functional myocytes. Individual cells showed a “ventricular,” “atrial,” or “nodal” phenotype, as evidenced by the expression of cell-type–specific markers and as seen in recordings of the action potentials in single cells. The duration of the action potential was markedly prolonged in “ventricular” and “atrial” cells derived from patients with long-QT syndrome type 1, as compared with cells from control subjects. Further characterization of the role of the R190Q–KCNQ1 mutation in the pathogenesis of long-QT syndrome type 1 revealed a dominant negative trafficking defect associated with a 70 to 80% reduction in I(Ks) current and altered channel activation and deactivation properties. Moreover, we showed that myocytes derived from patients with long-QT syndrome type 1 had an increased susceptibility to catecholamine-induced tachyarrhythmia and that beta-blockade attenuated this phenotype.
CONCLUSIONS: We generated patient-specific pluripotent stem cells from members of a family affected by long-QT syndrome type 1 and induced them to differentiate into functional cardiac myocytes. The patient-derived cells recapitulated the electrophysiological features of the disorder. (Funded by the European Research Council and others.)

February 2011

D'Andrea, A. D. (2010). Susceptibility pathways in fanconi's anemia and breast cancer. The New England Journal of Medicine, 362(20), 1909-1919. doi:10.1056/NEJMra0809889

No abstract available.

Gandotra, S., Le Dour, C., Bottomley, W., Cervera, P., Giral, P., Reznik, Y., . . . Vigouroux, C. (2011). Perilipin deficiency and autosomal dominant partial lipodystrophy. The New England Journal of Medicine, 364(8), 740-748. doi:10.1056/NEJMoa1007487

Abstract: Perilipin is the most abundant adipocyte-specific protein that coats lipid droplets, and it is required for optimal lipid incorporation and release from the droplet. We identified two heterozygous frameshift mutations in the perilipin gene (PLIN1) in three families with partial lipodystrophy, severe dyslipidemia, and insulin-resistant diabetes. Subcutaneous fat from the patients was characterized by smaller-than-normal adipocytes, macrophage infiltration, and fibrosis. In contrast to wild-type perilipin, mutant forms of the protein failed to increase triglyceride accumulation when expressed heterologously in preadipocytes. These findings define a novel dominant form of inherited lipodystrophy and highlight the serious metabolic consequences of a primary defect in the formation of lipid droplets in adipose tissue.

January 6, 2011

Please read these articles and then add your comments:

Scully, R. (2010). The spindle-assembly checkpoint, aneuploidy, and gastrointestinal cancer. The New England Journal of Medicine, 363(27), 2665-2666. doi:10.1056/NEJMe1008017

No abstract available.

Rio Frio, T., Lavoie, J., Hamel, N., Geyer, F. C., Kushner, Y. B., Novak, D. J., . . . Foulkes, W. D. (2010). Homozygous BUB1B mutation and susceptibility to gastrointestinal neoplasia. The New England Journal of Medicine, 363(27), 2628-2637. doi:10.1056/NEJMoa100656

Abstract: A patient received a diagnosis of adenocarcinoma of the ampulla of Vater at 34 years of age. Two decades later, adenomatous polyps were found, followed by multiple primary invasive adenocarcinomas of both the colon and the stomach. Premature chromatid separation and mosaic variegated aneuploidy, combined with structural chromosomal abnormalities, were detected in his cells. We identified a germline homozygous intronic mutation, c.2386-11A→G, in the spindle-assembly checkpoint gene BUB1B, which creates a de novo splice site that is favored over the authentic (i.e., preferentially used) site. Our findings expand the phenotype associated with BUB1B mutations and the mosaic variegated aneuploidy syndrome to include common adult-onset cancers and provide evidence for the interdependency of the APC protein (encoded by the adenomatous polyposis coli gene) and the BUBR1 protein (encoded by BUB1B) in humans. (Funded by the Turner Family Cancer Research Fund and others.).

December 6, 2010

Please read these articles and then add your comments:

Van Raamsdonk, C. D., Griewank, K. G., Crosby, M. B., Garrido, M. C., Vemula, S., Wiesner, T., Obenauf, A. C., Wackernagel, W., Green, G., Bouvier, N., Sozen, M. M., Baimukanova, G., Roy, R., Heguy, A., Dolgalev, I., Khanin, R., Busam, K., Speicher, M. R., O'Brien, J., & Bastian, B. C. (2010). Mutations in GNA11 in uveal melanoma. New England Journal of Medicine, 363(23), 2191-2199.

BACKGROUND: Uveal melanoma is the most common intraocular cancer. There are no effective therapies for metastatic disease. Mutations in GNAQ, the gene encoding an alpha subunit of heterotrimeric G proteins, are found in 40% of uveal melanomas.

METHODS: We sequenced exon 5 of GNAQ and GNA11, a paralogue of GNAQ, in 713 melanocytic neoplasms of different types (186 uveal melanomas, 139 blue nevi, 106 other nevi, and 282 other melanomas). We sequenced exon 4 of GNAQ and GNA11 in 453 of these samples and in all coding exons of GNAQ and GNA11 in 97 uveal melanomas and 45 blue nevi.

RESULTS: We found somatic mutations in exon 5 (affecting Q209) and in exon 4 (affecting R183) in both GNA11 and GNAQ, in a mutually exclusive pattern. Mutations affecting Q209 in GNA11 were present in 7% of blue nevi, 32% of primary uveal melanomas, and 57% of uveal melanoma metastases. In contrast, we observed Q209 mutations in GNAQ in 55% of blue nevi, 45% of uveal melanomas, and 22% of uveal melanoma metastases. Mutations affecting R183 in either GNAQ or GNA11 were less prevalent (2% of blue nevi and 6% of uveal melanomas) than the Q209 mutations. Mutations in GNA11 induced spontaneously metastasizing tumors in a mouse model and activated the mitogen-activated protein kinase pathway.

CONCLUSIONS: Of the uveal melanomas we analyzed, 83% had somatic mutations in GNAQ or GNA11. Constitutive activation of the pathway involving these two genes appears to be a major contributor to the development of uveal melanoma. (Funded by the National Institutes of Health and others.).


Herlyn, M., & Nathanson, K. L. (2010). Taking the guesswork out of uveal melanoma. New England Journal of Medicine, 363(23), 2256-2257.

No abstract available.

October 25, 2010

Please read this article and then add your comments:

Visel, A., Zhu, Y., May, D., Afzal, V., Gong, E., Attanasio, C., et al. (2010). Targeted deletion of the 9p21 non-coding coronary artery disease risk interval in mice. Nature, 464(7287), 409-412.

Sequence polymorphisms in a 58-kilobase (kb) interval on chromosome 9p21 confer a markedly increased risk of coronary artery disease (CAD), the leading cause of death worldwide. The variants have a substantial effect on the epidemiology of CAD and other life-threatening vascular conditions because nearly one-quarter of Caucasians are homozygous for risk alleles. However, the risk interval is devoid of protein-coding genes and the mechanism linking the region to CAD risk has remained enigmatic. Here we show that deletion of the orthologous 70-kb non-coding interval on mouse chromosome 4 affects cardiac expression of neighbouring genes, as well as proliferation properties of vascular cells. Chr4(Delta70kb/Delta70kb) mice are viable, but show increased mortality both during development and as adults. Cardiac expression of two genes near the non-coding interval, Cdkn2a and Cdkn2b, is severely reduced in chr4(Delta70kb/Delta70kb) mice, indicating that distant-acting gene regulatory functions are located in the non-coding CAD risk interval. Allele-specific expression of Cdkn2b transcripts in heterozygous mice showed that the deletion affects expression through a cis-acting mechanism. Primary cultures of chr4(Delta70kb/Delta70kb) aortic smooth muscle cells exhibited excessive proliferation and diminished senescence, a cellular phenotype consistent with accelerated CAD pathogenesis. Taken together, our results provide direct evidence that the CAD risk interval has a pivotal role in regulation of cardiac Cdkn2a/b expression, and suggest that this region affects CAD progression by altering the dynamics of vascular cell proliferation.

October 25, 2010

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McPherson, R. (2010). Chromosome 9p21 and coronary artery disease. New England Journal of Medicine, 362(18), 1736-1737.

Cardiovascular medicine is increasingly focused on understanding the molecular basis of disease in an ongoing search for new markers of risk and potential therapeutic targets. A recent study by Visel and colleagues1 is a step toward these goals in that it uncovers a mechanistic link between a common, previously implicated haplotype on chromosome 9p21 and coronary artery disease...

October 25, 2010

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Dietz, H. C. (2010). Genomic medicine: New therapeutic approaches to Mendelian disorders. New England Journal of Medicine, 363(9), 852-863.
Progress in the treatment of genetic disorders has derived from insight into their causes and has focused on nutritional limitation of a substrate, the purging of a toxic metabolite, or compensatory expression of a protein whose deficiency causes disease, through gene delivery. In this review, I focus on therapeutic strategies that exploit a precise understanding of the pathogenesis of a mendelian disease, giving examples that illustrate the strengths and limitations of each approach, as well as the potential for broadening its application to the treatment of more common disorders.

September 3, 2010

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Esserman, L. & Kaklamani V. (2010). Lessons Learned from Genetic Testing.  JAMA, 304(9), 1011-1012.

No abstract available.

September 2, 2010

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Domchek, S. M., Friebel, T. M., Singer, C. et al.  (2010). Association of Risk-Reducing Surgery in BRCA1 or BRCA2 Mutation Carriers With Cancer Risk and Mortality.  JAMA, 304(9), 967-975.


Context: Mastectomy and salpingo-oophorectomy are widely used by carriers of BRCA1 or BRCA2 mutations to reduce their risks of breast and ovarian cancer. Objective: To estimate risk and mortality reduction stratified by mutation and prior cancer status. Design, Setting, and Participants:  Prospective, multicenter cohort study of 2482 women with BRCA1 or BRCA2 mutations ascertained between 1974 and 2008. The study was conducted at 22 clinical and research genetics centers in Europe and North America to assess the relationship of risk-reducing mastectomy or salpingo-oophorectomy with cancer outcomes. The women were followed up until the end of 2009.  Main Outcomes Measures:  Breast and ovarian cancer risk, cancer-specific mortality, and overall mortality. Results:  No breast cancers were diagnosed in the 247 women with risk-reducing mastectomy compared with 98 women of 1372 diagnosed with breast cancer who did not have risk-reducing mastectomy. Compared with women who did not undergo risk-reducing salpingo-oophorectomy, women who underwent salpingo-oophorectomy had a lower risk of ovarian cancer, including those with prior breast cancer (6% vs 1%, respectively; hazard ratio [HR], 0.14; 95% confidence interval [CI], 0.04-0.59) and those without prior breast cancer (6% vs 2%; HR, 0.28 [95% CI, 0.12-0.69]), and a lower risk of first diagnosis of breast cancer in BRCA1 mutation carriers (20% vs 14%; HR, 0.63 [95% CI, 0.41-0.96]) and BRCA2 mutation carriers (23% vs 7%; HR, 0.36 [95% CI, 0.16-0.82]). Compared with women who did not undergo risk-reducing salpingo-oophorectomy, undergoing salpingo-oophorectomy was associated with lower all-cause mortality (10% vs 3%; HR, 0.40 [95% CI, 0.26-0.61]), breast cancer–specific mortality (6% vs 2%; HR, 0.44 [95% CI, 0.26-0.76]), and ovarian cancer–specific mortality (3% vs 0.4%; HR, 0.21 [95% CI, 0.06-0.80]).  Conclusions:  Among a cohort of women with BRCA1 and BRCA2 mutations, the use of risk-reducing mastectomy was associated with a lower risk of breast cancer; risk-reducing salpingo-oophorectomy was associated with a lower risk of ovarian cancer, first diagnosis of breast cancer, all-cause mortality, breast cancer–specific mortality, and ovarian cancer–specific mortality.


July 26, 2010

Please read this article and then add your comments:

Feero, W. G., Guttmacher, A. E., & Collins, F. S. (2010). Genomic medicine - an updated primer. New England Journal of Medicine, 362(21), 2001-2011.

Cathy, a 40-year-old mother of three, arrives in your office for her annual physical. She has purchased a commercial genomewide scan (see the Glossary), which she believes measures the clinically meaningful risk that common diseases will develop, and has completed her family history online using My Family Health Portrait (, a tool developed for this purpose by the U.S. Surgeon General. Her genomewide scan suggests a slightly elevated risk of breast cancer, but you correctly recognize that this information is of unproven value in routine clinical care. On importing Cathy's family-history file, your office's electronic health record system alerts you to the fact that Cathy is of Ashkenazi Jewish heritage and has several relatives with breast cancer, putting her at heightened risk for the hereditary breast and ovarian cancer syndrome. The system prompts you to discuss Cathy's risk of breast and ovarian cancer during the visit. Considering both her family history and ancestry, you refer Cathy to a health care professional with advanced genetics training for consultation. In the coming months Cathy elects to have her DNA tested for mutations in BRCA1 and BRCA2, the genes associated with hereditary breast and ovarian cancer syndrome, and to undergo a mammographic examination. Although the results of her genetic tests are negative, her mammogram reveals a suspicious abnormality. A biopsy is performed, and breast cancer is detected. Surgery is successful. Pathological examination of tissue from the excised tumor reveals that it is positive for estrogen-receptor protein and negative for human epidermal growth factor receptor type 2 (HER2); the lymph glands are free of cancer cells. Genetic-expression profiling of the tumor indicates a relatively high risk of recurrent cancer, and Cathy elects to receive adjuvant chemotherapy followed by treatment with tamoxifen. Five years later, the cancer has not recurred.

July 2010

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Hamburg, M. A., & Collins, F. S. (2010). The path to personalized medicine. New England Journal of Medicine, 363(4), 301-304. 

No abstract available. 

Magen, D., Berger, L., Coady, M. J., Ilivitzki, A., Militianu, D., Tieder, M., et al. (2010). A loss-of-function mutation in NaPi-IIa and renal fanconi's syndrome. New England Journal of Medicine, 362(12), 1102-1109.

We describe two siblings from a consanguineous family with autosomal recessive Fanconi's syndrome and hypophosphatemic rickets. Genetic analysis revealed a homozygous in-frame duplication of 21 bp in SLC34A1, which encodes the renal sodium-inorganic phosphate cotransporter NaPi-IIa, as the causative mutation. Functional studies in Xenopus laevis oocytes and in opossum kidney cells indicated complete loss of function of the mutant NaPi-IIa, resulting from failure of the transporter to reach the plasma membrane. These findings show that disruption of the human NaPi-IIa profoundly impairs overall renal phosphate reabsorption and proximal-tubule function and provide evidence of the critical role of NaPi-IIa in human renal phosphate handling. 2010 Massachusetts Medical Society

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