A Quarterly Newsletter from GeneInsightIssue 1: November 2013
We are delighted to introduce this first edition of the GeneInsights newsletter. This will be a quarterly publication and our goal is to keep you in touch with news and developments in the field of genomics. This publication is written by and for members of the clinical genomics community.
Q and A Session with Heidi Rehm, Ph.D.,Chief Laboratory Director, LMM, PCPGM, Associate Professor of Pathology, BWH and Harvard Medical School
Heidi Rehm, Ph.D., FACMG, was recruited in 2001 to build the Laboratory for Molecular Medicine (LMM) at Partners HealthCare Center for Personalized Genetic Medicine (PCPGM) and now serves as its Laboratory Director. She is a board-certified clinical molecular geneticist and Associate Professor of Pathology at Harvard Medical School and Brigham & Women’s Hospital with appointments at Massachusetts General Hospital and Children’s Hospital Boston.
We had the pleasure of sitting down with Dr. Rehm to discuss some of the changes that have taken place in the industry and where she sees the field heading.
How has the field of Genetics changed over the past 10 years?
Certainly the technology has changed which has greatly impacted the scope of what we can test for relative to a patient phenotype. Years ago, we performed only single disorder tests for a couple of genes at most. This meant that for certain diseases, patients could only test the most relevant gene or a few genes, and now, because of next gen sequencing, we can in essence test every gene that might be relevant to a broad set of diseases with overlapping phenotypes.
What critical advancements are contributing to the rapid transformation in the industry?
In addition to the major technology advancements, testing is much more reliant on informatics solutions. Laboratories have significant challenges in the interpretation of a much increased number of sequence variants which is, of course, a critical step in providing patients useful test results. As such, labs must have robust bioinformatics and IT systems to support their diagnostic testing and interpretation workflows.
Where do you see the field of Genetics in the next 5 years?
I see continued, rapid adoption of genetics into standard of care. This will include more and more healthy individuals, from newborn babies to adults, getting genetic testing pre-symptomatically to identify risk for diseases. We already see an increase in the use of genetics to determine treatment approaches, as opposed to simply learning the underlying cause of disease, and this area will continue to expand over the next 5 years.
What sort of challenges are your peers facing in the establishment of new clinical labs?
One of the greatest challenges facing a new lab is the high cost to develop and validate tests, particularly very complex genetic tests, as well as the enormous investment required for IT infrastructure to support testing platforms. At the same time, there is unprecedented complexity involved in the interpretation of sequencing test results.
As the Director of the Laboratory for Molecular Medicine (LMM), what decisions do you struggle with the most?
Some of the most challenging decisions I face, with respect to managing the LMM, involve where to focus resources when the industry and technology is evolving at such a fast pace. For example, deciding what testing areas to focus on, or when to continue to launch targeted tests versus focus support for genome and exome testing, requires me to weigh competing priorities and ultimately, make a decision that I believe will best support the laboratory and improve patient care.
What type of innovative programs is the LMM working on?
One major effort we are working on is expanding the number of clinical sites that have access to tools, like GeneInsight Clinic, to deliver electronic reports and receive automated updates of genetic variants as new information is learned. This provides clinicians with the most-up-to-date information that we have available. Another program we are exploring involves sharing our resources and expertise with ordering clinicians who are incorporating genetic testing results into their care protocols. For example, we are sharing our genetic counseling staff with the Pulmonary Genetic Center [at Brigham and Women’s Hospital], a new clinic that focuses on hereditary respiratory disorders, in an effort to help the clinic more seamlessly integrate genetic testing interpretations into patient care. Ultimately, both programs help us better support clinical specialties with genetic-based services.
GeneInsight has been in clinical use since 2005 at the LMM, how has it made a difference?
GeneInsight has allowed us to become more efficient in the way we draft and deliver clinical genetic testing reports and has helped improve the accuracy and consistency of the testing and interpretations that we provide. GeneInsight has also facilitated deeper research into the clinical areas we service. By enabling easy access to, and query of, all of our historical data, we can facilitate new insights into genetic diseases.
How do you think GeneInsight can help address the challenge of providing personalized medicine?
Fundamentally, I believe GeneInsight facilitates a richer connection between the laboratory and clinics by enabling updated information to reach the hands of patients and their physicians at the time the information is needed. GeneInsight helps support patient care through delivery of structured genetic results directly to electronic health records that can be leveraged for clinical decision-making. It allows for delivery of real-time information and relevant updates to reach the hands of clinicians who can help make a difference in the life of that patient.
Our Featured Assessment is intended to highlight the assessment of a specific gene or variant as part of an ongoing series included in the GeneInsights newsletter. This segment will review the process of assigning significance to a variant or gene in the clinical and/or research setting.
Variant: Gly137Ala in the ARSE gene
The recently launched clinical genome sequencing service at the Partners HealthCare Laboratory for Molecular Medicine (LMM) enables patients to receive a General Genome Report containing incidental findings. This report has been generated in conjunction with the MedSeq project, a randomized clinical trial aimed at determining the impact of integrating genome sequencing into clinical care. The genome analysis and interpretation approach developed over the last year and a half is fairly exhaustive, and similar to what is being done at other institutions (Dorschner et al, 2013), though in a more expansive manner.
Clinical interpretation of an incidental finding:
In one healthy male individual, a hemizygous variant was identified in the ARSE gene (NM_000047.2:c.410G>C, p.Gly137Ala). The arylsulfatase E gene (ARSE) is important for bone and cartilage formation and pathogenic ARSE variants are strongly associated with X-linked recessive chrondodysplasia punctata type 1 (CDPX1, Braverman et al 2008). The phenotype for CDPX1 is variable, even within families, and most affected males tend to have limited morbidity that improves by adulthood. The disease is characterized by stippling of the epiphyses in all individuals, along with nasal hypoplasia and brachytelephalangy in greater than 2/3 of individuals (Nino et al 2008). However, a subset of individuals will present with more severe features, including respiratory disease, cervical spine stenosis, and cognitive delay.
The Gly 137Ala variant has been previously reported in 2 males with CDPX1 (Nino 2008, Sheffield 1998), however, it was identified in one unaffected male relative. In addition, this variant has been identified in 1 European American female (1/6728 chromosomes) by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/). There is also some functional data that suggests this variant may affect ARSE activity levels (Matos-Miranda 2013). While the functional data is compelling, it was generated using transfected cell lines, so it is unclear how this would translate into an in vivo system. Computational analyses of the variant (conservation, PolyPhen2, etc) all indicate a change at this position may not be tolerated, and changes at the same position in a paralogous gene (ARSB) lead to a disease with skeletal anomalies (Maroteux-Lamy syndrome).
After distilling all the data and gathering consensus from the larger group, the team settled on a classification of Variant of Uncertain Significance – Favor Pathogenic. Although there is evidence for pathogenicity, identifying this variant in two seemingly unaffected males (including this individual) raises some doubts. The team agreed to include this variant on the incidental findings report. There is an easy, unobtrusive diagnostic assay to help determine the clinical interpretation, and there is potential for grandsons of this individual (and other family members) to receive early diagnosis and treatment for phenotypes with a high morbidity.
Current Clinical Interpretation:
The Gly137Ala variant in ARSE has been previously identified in 2 males with chondrodysplasia punctata; however, this variant was also identified in one unaffected male family member (Sheffield 1998, Nino 2008). Variants in a paralogous gene (ARSB) at the same position have also been identified in an individual with Maroteux-Lamy syndrome, which also features skeletal abnormalities (Franco 1995). Functional studies indicate that the Gly137Ala variant leads to reduced ARSE activity (Matos-Miranda 2013). In summary, although some data support a disease-causing role, there is currently insufficient evidence for pathogenicity leading to a current classification of uncertain significance.
Contributed by Partners HealthCare Laboratory for Molecular Medicine and The MedSeq Project.
Michael O. Dorschner, Laura M. Amendola, Emily H. Turner, et al. Actionable, Pathogenic Incidental Findings in 1,000 Participants’ Exomes. Am J Hum Genet. 2013. Oct;Vol. 93, Issue 4, pp. 631-640.
Braverman NE, Bober M, Brunetti-Pierri N, et al. Chondrodysplasia Punctata 1, X-Linked. 2008 Apr 22 [Updated 2011 Nov 3]. In: Pagon RA, Adam MP, Bird TD, et al., editors. GeneReviews™ [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2013.Available from: http://www.ncbi.nlm.nih.gov/books/NBK1544/
Nino, M., Matos-Miranda, C., Maeda, M., et al. Clinical and molecular analysis of arylsulfatase E in patients with brachytelephalangic chondrodysplasia punctata. Am J Med Genet. 2008. 146A: 997–1008.
Sheffield LJ, Osborn AH, Hutchison WM et al. Segregation of mutations in arylsulphatase E and correlation with the clinical presentation of chondrodysplasia punctata. J Med Genet. 1998. Dec;35(12):1004-8.
A prospective study of brachytelephalangic chondrodysplasia punctata: identification of arylsulfatase E mutations, functional analysis of novel missense alleles, and determination of potential phenocopies. Genet Med. 2013 Aug;15(8):650-7.
GeneInsight in the News
GeneInsight will be exhibiting at several conferences in 2013 and 2014. If you are interested in meeting with a team member, please stop by our booth or contact firstname.lastname@example.org to schedule a demo.
Association for Molecular Pathology (AMP) Conference
November 14-16, 2013, Phoenix, AZ
GeneInsight booth # 222
American College of Medical Genetics and Genomics (ACMG) Annual Clinical Genetics Meeting
March 25-29, 2014, Nashville, TN