Dr. Peter Byers, Director of the UW Medicine Center for Precision Diagnostics, will be presenting at the upcoming ACMG Annual Clinical Genetics Meeting in Phoenix, Arizona.
Topic: What Every Clinical Geneticist Should Know About Testing for Osteogenesis Imperfecta in Suspected Child Abuse Cases
Date: Friday, March 24, 2017
Time: 1:40 PM – 2:00 PM
Location: Phoenix Convention Center
Room: North Ballroom BC
For more information, please visit the conference page HERE
Each year in the UW some 25,000 children between the ages of birth and 3years are abused in ways that result in fractures. In that same age group are about 1200 infants and children with osteogenesis imperfecta (OI) and a smaller number with other genetic predispositions to bone fragility and fracture. The presentation of fracture in children with OI may mimic that of children who have been abused in that multiple unexplained fractures can be present and baffle both the parents and the clinicians as to their origin. More than 90% of individuals with OI have mutations in the type I collagen genes (COL1A1 and COL1A2) and all but a handful of the rest have mutations in any of an additional 15 genes. Mutations in all these genes can now be reliably identified by genetic sequence analysis, which has completely supplanted analysis of proteins produced by cultured fibroblasts for diagnosis. The decision of which children to study in the context of concerns about abuse is difficult and even the most stringent procedures to screen out children with OI still leaves questions in a small number among whom about 5% have genetic and biochemical evidence of OI upon testing. In that context the failure to find a causative genetic alteration, .however, dramatically lowers the likelihood that a child has OI and facilitates further assessment of the family.
The Center for Precision Diagnostics, Collagen Diagnostic Laboratory is pleased to announce that genetic testing for Ehlers-Danlos syndrome (EDS) periodontal type is now available individually and through our new Comprehensive EDS Panel. The testing for EDS periodontal type (also known as EDS type VIII) includes genomic sequence analysis of C1S and C1R. Researchers in our group recently described pathogenic variants in these two genes as the underlying cause of EDS VIII. This autosomal dominant disorder is characterized by early-onset periodontitis and tooth loss.
The Center for Precision Diagnostics researchers, in collaboration with Austrian, Swedish and UK geneticists, recently identified that the cause of the periodontal form of Ehlers-Danlos syndrome (EDS type VIII) results from a mutation in one of an unexpected pair of genes, C1S or C1R. Both genes dictate the synthesis of complement, a protein that plays a role in fighting infection and moving foreign cells out the cell. Most other forms of EDS are caused by sequence variants in collagen proteins. A C1S or C1R gene sequence abnormality leads to a dominant form of EDS type VIII , causing aggressive periodontitis and tooth loss at a young age. The surprising discovery accomplished by exome sequencing research is opening the door to learn how the disease progresses, a necessary step for considering treatment. Read the details of the research in the American Journal of Human Genetics.
The UW Medicine Center For Precision Diagnostics is pleased to announce that it has recently received a Medical Laboratory Permit from the State of Maryland. All CPDx tests and services may be ordered by Maryland health care providers. For more information, please contact us at 206-685-1176.
The CPDx recognizes that obtaining insurance pre-authorization for genetic testing may be challenging and time consuming. We are happy to assist clients in obtaining prior authorizations to determine whether genetic testing will be a covered service under the patient’s plan.
Center for Precision Diagnostics laboratory director, Dr. Peter Byers and genetic counselor, Melanie Pepin recently attended the Ehlers-Danlos Society (EDS) International Symposium 2016 in New York City (May 3-6, 2016). Invited members of the EDS medical community and interested affected individuals and family members from around the world gathered to update and expand present clinical diagnostic categories and nomenclature for the many forms of EDS. Both Dr. Byers and Melanie presented clinical data gathered from research participants in the Collagen Diagnostic Research Repository.
We welcome Dr. Jennifer Schleit to the CPDx team! Dr. Schleit has over 15 years research experience in a variety of fields including cancer biology, aging, and genetics. She received her undergraduate degree from Dalhousie University in Biochemistry, Microbiology, and Immunology and her PhD from the University of Washington, Department of Pathology. Her graduate research focused on how genetic variation influences the response to dietary restriction and environmental pollutants.
Following her passion for genetics, Dr. Schleit continued at the University of Washington as post-doctoral fellow with Dr. Peter Byers and the Collagen Diagnostic Laboratory, studying how genetic variants influence mRNA splicing. During this time, she also completed a clinical fellowship in clinical molecular genetics and became certified by the American Board of Medical Genetics and Genomics (ABMGG) in 2015.
Currently, Dr. Schleit’s research focuses on the inherited aneurysm syndrome Ehlers-Danlos Syndrome Type IV, examining why specific regions of the vasculature appear to be prone to aneurysm and identifying potential targets for therapy development. We are excited to have Dr. Schleit as a member of the Center for Precision Diagnostics team.
Brad Rolf is a clinical genetic counselor who is working with Dr. Dorschner and the NCGL team on a research project aimed at identifying genetic contributions to risk for dementia and cognitive impairment. He earned his masters of genetic counseling at the University of Texas Health Science Center in Houston. His interest in adult-onset genetic conditions brought him to the Adult Genetic Medicine Clinic at the University of Washington where he worked with adult patients affected by a wide array of genetic conditions.
With the recent rise in available genetic testing has come the challenge of interpreting human genetic variation. One of Brad’s primary clinical interests lies in genetic variant interpretation and classification. Brad is using his knowledge of genetics as well as a number of other resources to classify genetic variants identified by the NCGL.
The Collagen Diagnostic Laboratory has moved! Please note the new room number for sample delivery is now Room H-561 Health Science Building, 1959 NE Pacific Street, University of Washington, Seattle WA 98195-7655.
Positive predictive value of non-invasive prenatal screening for fetal chromosome disorders using cell-free DNA in maternal serum: independent clinical experience of a tertiary referral center.
Published in BMC Medicine June 2015
Non-invasive prenatal screening (NIPS) for fetal chromosome abnormalities using cell-free deoxyribonucleic acid (cfDNA) in maternal serum has significantly influenced prenatal diagnosis of fetal aneuploidies since becoming clinically available in the fall of 2011. High sensitivity and specificity have been reported in multiple publications, nearly all of which have been sponsored by the commercial performing laboratories. Once results are returned, positive and negative predictive values (PPVs, NPVs) are the performance metrics most relevant to clinical management. The purpose of this report is to present independent data on the PPVs of NIPS in actual clinical practice.
Charts were retrospectively reviewed for patients who had NIPS and were seen March 2012 to December 2013 in a tertiary academic referral center. NIPS results were compared to diagnostic genetic test results, fetal ultrasound results, and clinical phenotype/outcomes. The PPV was calculated using standard epidemiological methods. Correlation between screen results and both maternal age at delivery and gestational age at time of screening was assessed using Wilcoxon’s rank sum test.
Of 632 patients undergoing NIPS, 92 % of tests were performed in one of the four major commercial laboratories offering testing. However, all four laboratories are represented in both the normal and abnormal results groups. There were 55 abnormal NIPS results. Forty-one of 55 abnormal NIPS results were concordant with abnormal fetal outcomes, 12 were discordant, and 2 were undetermined. The PPV for all conditions included in the screen was 77.4 % (95 % CI, 63.4 – 87.3). Of 578 patients with normal NIPS results, normal pregnancy outcome was confirmed for 156 (27 %) patients. This incomplete follow-up of normal NIPS results does not affect PPV calculations, but it did preclude calculations of sensitivity, specificity, and NPV. Maternal age at delivery was significantly lower for patients with abnormal discordant results, compared to patients with abnormal concordant results (P = 0.034). Gestational age at time of screening was not associated with concordance of screen results (P = 0.722).
The experience of using NIPS in clinical practice confirms that abnormal results cannot be considered diagnostic. Pre-test counseling should emphasize this. Diagnostic genetic testing should always be offered following abnormal NIPS results.
Diagnosing a genetic abnormality as the cause of miscarriage allows for recurrence risk counseling, reduces parental feelings of guilt, and eliminates the need for further workup. Unfortunately, maternal cell contamination and culture failure both complicate testing done by traditional chromosome analysis.
Based on a review of the medical literature, existing professional society practice guidelines, chromosome abnormality detection rates using different test methods, and the cost and insurance provider landscapes, the Clinical Cytogenomics Laboratory has developed new recommendations for genetic testing of fetal tissue and products of conception. This tiered testing approach takes advantage of cytogenomic microarray analysis (CMA) and interphase fluorescence in situ hybridization (IFISH), methods which have advantages over karyotyping. Neither requires living cells, producing a higher success rate of obtaining results. Neither requires culturing, allowing detection of monosomies and multiple aneuploidies that aren’t viable in culture. And results are thus less susceptible to maternal cell contamination and culturing artifacts. CMA has a further advantage in that it detects subchromosomal alterations not visible with karyotyping.
Collagen Diagnostic Laboratory Next Generation Sequencing Panels include evidence-based gene lists for comprehensive testing for connective tissue disorders. These tests offer improved turnaround times and reduced pricing, all while maintaining the molecular and clinical expertise of the CDL. See the CDL test menu for more details.
One Center: Four Labs – An Array of Testing Possibilities. The Center for Precision Diagnostics (CPDx) has launched a comprehensive approach to genetic testing and research. The aim of the CPDx is to provide rapid genetic diagnostic testing with a commitment to understand mechanism and outcome. Clinicians and scientists will work together as a team to solve the unknowns in inherited disease.
September 9-11, 2015 Chicago IL: UW Collagen Diagnostic Laboratory directors, genetics counselors and staff, assisted by generous contributions from vEDS families, met with 20 clinical investigators from the USA and Europe to discuss recent research and to carve a path for future treatment and improved research in vEDS. vEDS is an inherited disorder caused by dominantly inherited mutations in COL3A1 that lead to very fragile blood vessels, bowel wall, and uterine wall during pregnancy, and risk of early death. This was the first session of its kind, the brainchild of the UW Collagen Diagnostic Laboratory testing and research team. Read a summary of the presented papers.
In the event a family is not able to afford testing (or insurance is billed and denies coverage) the Center for Precision Diagnostics offers several options through University of Washington Physicians (UWP) including a monthly payment plan, full pay discounts, and charity care options. Please see Billing for more information.