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Archive - Oct 2013


October 28th

Awards, Newborn Screening, and Futuristic Presentations Highlight Last Day of ASHG Annual Meeting

The breakthrough-loaded 2013 annual meeting of the American Society of Human Genetics (ASHG) ended its five-day run in Boston with an awards session, followed by concurrent research presentation sessions, and ending with three riveting presentations on the future of genetics and systems biology by three world-leading researchers. The morning started with the presentation of the ASHG Victor A. McKusick Leadership Award presently jointly to Rochelle Hirschorn, M.D., and her husband, Kurt Hirschorn, M.D. The McKusick award honors the legendary Victor McKusick, M.D., who is often referred to as the “Father of Medical Genetics,” and his far-reaching and visionary contributions to genetics. Recipients are chosen for their enduring vision and leadership to ensure that human genetics will flourish and be successfully assimilated into the broader context of science, medicine, and health. In a moving moment, the award recipients were introduced by their son, Joel, M.D., Ph.D., from the Department of Genetics at Harvard Medical School. Dr. Rochelle Hirschorn was the Chief of Medical Genetics at New York University’s Langone Medical Center for 24 years. Her major discoveries include clarifying the sequence of acid alpha glucosidase and most of its defects in Pompe disease, and delineating the genetic structure and pathophysiology of adenosine deaminase (ADA ) deficiency, an autosomal recessive metabolic disorder that causes immunodeficiency. She also described the phenomenon of reverse mutations as a cause of “self-cure” in ADA deficiency patients and predicted the utility of gene therapy for ADA deficiency.

October 26th

Scientists ID Novel Mutation That Causes Aortic Aneurysms and Acute Aortic Dissection

Ascending thoracic aortic aneurysms can lead to life-threatening acute aortic dissections (TAADs). An example of this is the sudden death of popular actor John Ritter, who died from this problem. Subsequent examination of his brother Tommy showed that he had a dangerously large aortic aneurysm that was treated surgically to reduce his risk (see John Ritter’s father, Tex Ritter, known as the “Singing Cowboy,” had died suddenly while clutching his chest and is thus presumed to have died from the same problem as his son John. It is known that gene mutations that lead to decreased contraction of vascular smooth-muscle cells (SMCs) can cause inherited thoracic aortic aneurysms and aortic dissections. Using exome sequencing of distant relatives affected by thoracic aortic disease, followed by Sanger sequencing of additional probands with familial thoracic aortic disease, a research group presenting their results on Friday, October 25, at the American Society of Human Genetics (ASHG) 2013 annual meeting in Boston, reported identifying the same rare variant (c.530G>A) (p.Arg177Gln) in the gene PRKG1 in four families. This mutation segregated with aortic disease in the four families, with the majority (63%) of affected individuals presenting with acute aortic dissections at relatively young ages (mean 31 years, range 17-51 years). The PKRG1 gene encodes a type I cGMP-dependent protein kinase (PKG-1) that is activated upon binding of cGMP and controls SMC relaxation. Although the p.Arg177Gln alteration disrupts binding to the high-affinity cGMP binding site within the regulatory domain, the altered PKG-1 is constitutively activated even in the absence of cGMP.

Multiple, Distinct Y Chromosomes Associated with Significant Excess Risk of Prostate Cancer

An analysis of the genealogical and medical records of males in Utah's multi-generational families strongly supports the case that inherited variations in the Y chromosome, the male sex chromosome, play a role in the development of prostate cancer, according to a study presented on Friday, October 25, at the American Society of Human Genetics (ASHG) 2013 meeting in Boston. The study identified multiple, distinct Y chromosomes associated with a significant excess risk of prostate cancer, said Lisa Cannon-Albright, Ph.D., Professor and Chief of the Division of Genetic Epidemiology at the University of Utah School of Medicine. Dr. Cannon-Albright, who headed the study and presented the results, said that her lab plans to search these Y chromosomes for the genetic mutations that can predispose a man to develop prostate cancer, the second most frequently diagnosed cancer in the U.S. Because most of the Y chromosome does not recombine during cell division, it is passed virtually unchanged from father to son. “As a result, each male resident of Utah shares the Y chromosome of his father and his father’s father and so on,” she said. “This provided the ability to estimate the risk for prostate cancer in independent Y chromosomes represented in Utah.” The study relied upon the Utah Population Data Base (UPDB), which identifies over 6.5 million individuals, including many of the Utah pioneers in the 1800s. The pioneer genealogies in the UPDB are typically large, spanning 15 generations. The Utah population represented in the UPDB is genetically representative of Northern Europe. The database was created in the 1970s to define familial clustering and identify evidence for heritable contribution to cancer.

DNA Variants May Influence Response to Inhaled Bronchodilators by Patients with COPD

Several novel gene variants may help explain the response of patients with chronic obstructive pulmonary disease (COPD) to inhaled bronchodilators, according to a meta-analysis reported on Friday, October 25, at the American Society of Human Genetics (ASHG) 2013 meeting in Boston. The meta-analysis used statistical methods to combine results from four individual studies with a total of 6,500 Caucasian patients with moderate to severe COPD. Over 6.3 million unique single nucleotide polymorphisms (SNPs) were identified in the genotypes of the patients with COPD, which is a progressive breathing disorder that limits airflow in the lungs. The genotypes of over 800 African Americans with COPD were also analyzed. “Identifying single nucleotide polymorphisms associated with bronchodilator responsiveness may reveal genetic pathways associated with the pathogenesis of COPD and may identify novel treatment methods,” said Megan Hardin, M.D., Instructor of Medicine at Harvard Medical School and researcher in the Channing Division of Network Medicine at Brigham and Women's Hospital, Boston. Dr. Hardin, who presented the research, added that multiple genetic determinants likely influence bronchodilator responsiveness. Functional analysis of the SNPs will be conducted, she added. “As we continue to analyze the data, we expect to identify other important SNPs,” said Craig P. Hersh, M.D., who headed the study and is Assistant Professor, Harvard Medical School, and faculty member in the Channing Division of Network Medicine at Brigham and Women’s Hospital. All of the subjects studied had significant histories of smoking, with most (4,561), having smoking histories of over 10 pack-years (i.e., 10 years of smoking a smoking one pack of cigarettes per day.

October 24th

Gene-Diet Interaction Study Identifies Significant Variants Associated with Diet-Related Risk of Colorectal Cancer

A newly discovered potential gene-diet interaction for colorectal cancer was reported today (Thursday, October 24) at the American Society of Human Genetics(ASHG) 2013 meeting in Boston. The interaction may shed light on the statistically significant increased risk of colorectal cancer that is associated with consumption of red and processed meat, the researchers said. “If replicated, our findings have a relevant public health significance because diet is a modifiable risk factor for colorectal cancer,” said Jane Figueiredo, Ph.D., Assistant Professor of Preventive Medicine at the University of Southern California Keck School of Medicine, who presented the study this morning at the ASHG meeting. “It is conceivable that selected individuals at higher risk of colorectal cancer based on genomic profiling could be targeted for screening, diet modification and other prevention strategies,” added Dr. Figueiredo, one of the scientists collaborating in the international NIH-funded Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO). The scientists also determined that the lower colorectal cancer risk associated with vegetable, fruit, and fiber intake also was linked to genetic variants. The possibility that genetic variants may modify an individual’s risk for disease based on diet has not been thoroughly investigated but represents an important new insight into disease development, said Ulrike Peters, Ph.D., M.P.H, who headed the study and is a Member of the Fred Hutchinson Cancer Research Center’s Public Health Sciences Division in Seattle, Washington.

Scientists Identify First Gene for Most Common Form of Mitral Valve Prolapse

Research on the DNA of a large multi-generational family has provided a genetic clue that enabled scientists to pinpoint a gene that plays a role in mitral valve prolapse (MVP), a common cardiac disease that is the leading cause of heart valve surgery, according to a study presented today (Thursday, October 24) at the American Society of Human Genetics (ASHG) 2013 meeting in Boston. MVP affects 2.5% of the population and typically presents symptoms in adulthood, often leading to heart failure. 15% of the patients inherit the disease, but the remaining 85% of MVP incidence is sporadic. The scientists who located the gene, named DCSH1 (from the dachsous1 gene in Drosophila), also determined how mutations in this gene disrupt the normal embryonic development of the mitral valve, one of the valves that controls blood flow in the heart. “This work provides insights into the pathways regulating valve growth and development,” said Susan Slaugenhaupt, Ph.D., Professor of Neurology in the Center for Human Genetic Research at Massachusetts General Hospital (MGH) and Harvard Medical School and one of the lead scientists in the collaborative group that conducted the research. “The results implicate a previously unrecognized paradigm in the development of long-term structural integrity in the mitral valve,” said Ronen Y. Durst, M.D., former member of Dr. Slaugenhaupt’s lab and now a senior cardiologist at Hebrew University and Hadassah Medical Center in Jerusalem. Dr. Durst presented the study this afternoon at ASHG 2013. The researchers’ first step was to link MVP to a region on human chromosome 11 in the DNA of the group of relatives with the heart disorder. By sequencing that DNA region in family members, the scientists were able to link mutations in DCSH1 to MVP.

BROCA Panel Provides Comprehensive Testing of All Known Breast Cancer Genes

Since 1994, many thousands of women with breast cancer from families severely affected with the disease have been tested for inherited mutations in BRCA1 and BRCA2 by the Myriad Genetics test. The vast majority of those patients were told that their gene sequences were normal. With the development of modern genomics sequencing tools, the discovery of additional genes implicated in breast cancer, and the change in the legal status of genetic testing for BRCA1 and BRCA2 due to the June 13, 2013 U.S. Supreme Court decision to bar the patenting of naturally occurring genes that ended Myriad’s monopoly on the testing for BRCA1 and BRCA2 mutations, it is now possible to determine how often families in these circumstances actually do carry cancer-predisposing mutations in BRCA1, BRCA2, or any of a number of breast cancer-associated genes, despite the results of their previous genetic tests. This was the challenge addressed by Mary-Claire King (photo), Ph.D., American Cancer Society Professor of Medicine and Genome Sciences at the University of Washington, Seattle, past President of the ASHG, and renowned breast cancer genetic researcher; and Tomas Walsh, Ph.D., Associate Research Professor of Medical Genetics, also at the University of Washington, Seattle. The researchers conducted complete genomic sequencing of all genes known to be implicated in breast cancer on DNA samples from breast cancer patients who had normal BRCA1 and BRCA2 commercial test results (Myriad testing). The commercial testing occurred because the patients had a severe family history of breast cancer, defined as a family with three or more relatives affected by breast or ovarian cancer. The results were presented today by Dr. Walsh at the American Society of Human Genetics 2013 annual meeting in Boston.

Rare Mutations in RINT1 Tumor Suppressor Gene Associated with Early-Onset Breast Cancer and Possibly Other Cancers

An international team of scientists has identified an association between heritable, rare mutations in the RINT1 gene and increased risk of early-onset breast cancer, according to research reported today (October 24) at the American Society of Human Genetics (ASHG) 2013 Annual Meeting in Boston. The rare mutations in RINT1, a tumor suppressor gene, were detected in 3 of 49 families participating in a study that sequenced the whole exome, the protein-coding DNA, of families with multiple individuals affected by breast cancer. “Although mutations in RINT1 are rare, it is most likely that the remaining unknown breast cancer susceptibility genes will account for similar small proportions of the disease,” said Daniel J. Park, Ph.D., who presented the study at ASHG 2013 and is Senior Research Fellow in genetic epidemiology at the University of Melbourne, Australia. Only approximately 35 percent of the familial risk for breast cancer has been explained so far, according to Dr. Park and his collaborators, who added that the discovery of the RINT1 variants’ association with the disease could help members of families with multiple cases of breast cancer to identify their individual risk for developing the cancer. Dr. Park’s collaborators in the search for unidentified breast cancer susceptibility genes are scientists at the Institute Curie in Paris, the International Agency for Research on Cancer in Lyon, France, the Huntsman Cancer Institute in Salt Lake City, Utah, as well as the University of Melbourne.

October 23rd

“The Play’s the Thing” at American Society of Human Genetics Annual Meeting in Boston

A provocative new interactive play, “The Drama of DNA: Anticipating the Future with WGS,” was performed by a cast of distinguished genomics professionals on the first evening, Tuesday, October 22, of the 2013 American Society of Human Genetics (ASHG) annual meeting in Boston. The play was hugely popular. It was sold out two weeks after the availability of tickets was announced and at the end of the play many in the audience were asking how they could implement such an innovative approach at their own institution or organization. In the play, fictionalized characters explored a hypothetical research protocol in which the entire DNA codes of children diagnosed with autism spectrum disorder (ASD), their “unaffected” siblings and parents, including their pregnant mothers, would be deciphered. The play brought to life the challenges and potential implications of using whole genome sequencing (WGS) in research and medicine, said the co- authors, Lynn W. Bush, Ph.D., M.S., M.A., and Karen Rothenberg, J.D., M.P.A. Dr. Bush, a psychologist and bioethicist, is on the faculty of pediatric clinical genetics at Columbia University. Rothenberg, the founding director of the Law and Health Care program and Professor at the University of Maryland School of Law, is Senior Advisor on Genomics and Society to the National Human Genome Research Institute (NHGRI) Director Eric D. Green, M.D., Ph.D., one of the play’s 13 “actors” who performed in the play. Among the other genomics professionals who participated in the play were: Carlos Bustamante, Ph.D., Professor of Genetics, Stanford School of Medicine; Vence Bonham, J.D., Chief of the Education and Involvement Branch of the NHGRI; Jeff Botkin, M.D., M.P.H.., Chief of Medical Ethics, University of Utah Health Care; Malia Fullerton, D.

Gone Today, Hair Tomorrow

Researchers at Columbia University Medical Center (CUMC) and collaborators at Durham University in the UK have devised a hair restoration method that can generate new human hair growth, rather than simply redistribute hair from one part of the scalp to another. The approach could significantly expand the use of hair transplantation to women with hair loss, who tend to have insufficient donor hair, as well as to men in the early stages of baldness. The study was published on October 21, 2013 in the online edition of PNAS. “About 90 percent of women with hair loss are not strong candidates for hair transplantation surgery because of insufficient donor hair,” said co-study leader Angela M. Christiano, Ph.D., the Richard and Mildred Rhodebeck Professor of Dermatology and professor of genetics & development at CUMC. “This method offers the possibility of inducing large numbers of hair follicles or rejuvenating existing hair follicles, starting with cells grown from just a few hundred donor hairs. It could make hair transplantation available to individuals with a limited number of follicles, including those with female-pattern hair loss, scarring alopecia, and hair loss due to burns.” According to Dr. Christiano, such patients gain little benefit from existing hair-loss medications, which tend to slow the rate of hair loss but usually do not stimulate robust new hair growth. “Dermal papilla cells give rise to hair follicles, and the notion of cloning hair follicles using inductive dermal papilla cells has been around for 40 years or so,” said co-study leader Colin Jahoda, Ph.D., professor of stem cell sciences at Durham University, England, and co-director of North East England Stem Cell Institute, who is one of the early founders of the field.