A Quarterly Newsletter from GeneInsightIssue 5: March 2015
Winter / Spring 2015
We are pleased to share the Winter/Spring 2015 edition of our newsletter, GeneInsights. In this edition, we feature a Q&A session with Allison Cirino, MS, CGC from Brigham and Women’s Hospital and we highlight the MYO1A gene as part of our ongoing Featured Assessment series.
We hope you enjoy the latest issue of GeneInsights. Happy Spring!
Q and A Session with Alison Cirino, MS, CGC about her use of GeneInsight Clinic at the Brigham and Women’s Hospital Cardiovascular Genetics Center.
Allison Cirino received her M.S. in Genetic Counseling from Northwestern University. She has been a genetic counselor in the Brigham and Women’s Hospital Cardiovascular Genetics Center since 2004.
What was your process for receiving updated variant interpretations or new reports before GeneInsight Clinic? And what were the biggest challenges?
Prior to GeneInsight Clinic we received new results reports via fax to a common fax machine in our office area. Since many ordering providers share the same fax number it sometimes required an additional step to make sure that all ordering providers for a given case received a copy of the results. When it came to variant updates we had to seek out this information from the lab. This was often prompted by a return visit to clinic or a new development in the patient’s medical or family history. We would then need to use our internal database to determine who else in this family or other families was impacted by the variant update. This was a cumbersome and inefficient process before we even got to the hard work of disseminating information to the individuals impacted by the update.
Do you feel the challenges you discuss in question 1 are unique to your clinic or more pervasive throughout the field?
I suspect that most people who order large panel tests would agree that keeping up to date on the current variant classification is a challenging part of genetic medicine. While there may be specific events that prompt an inquiry to the genetic testing lab, this approach is not scalable to every return patient in a busy cardiovascular genetics practice and will not work for deceased patients or those who’ve transferred their care. Variant reclassifications have taught us that we remain tied to patients and families, in some cases long after they stop receiving their care at our institution.
How has the GeneInsight Clinic application addressed these challenges and/or changed this process?
The new results reports are integrated directly into the electronic medical record which then prompts an email alert. We also receive weekly summary emails that tell us what reports and updates are new for the week and what reports/updates are yet to be reviewed. Having the genetic test results and updates centralized in one easily searchable application both improves efficiency and assures us that we have access to information that reflects the current knowledge of the genetic testing lab. The ability to search the GeneInsight Clinic application by clinic, rather than by ordering provider alone for all un-reviewed updates and reports, allows for easier cross-coverage.
How does receiving ongoing variant interpretations/alerts change the way you counsel patients?
Real time high level alerts help us to identify updates that may require more immediate action. One example of this is an individual who previously tested negative for a known familial variant, for which pathogenicity is now in question. We need to re-contact these individuals and advise that they resume the recommended longitudinal screening and cease to use this variant for predictive testing in the family. When it comes to previously untested at-risk relatives, real time alerts may in one case appropriately stop us from ordering familial variant testing when a variant’s pathogenicity is newly under question and in another case allow family members to proceed with predictive genetic testing when a variant’s pathogenicity has become more convincing. It is hard to think of any situation in which real time variant alerts would have anything other than a positive impact on the clinical care of patient and families.
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.
With the advent of next-generation sequencing and the associated dramatic decrease in DNA sequencing cost, it became more feasible and cost-effective to increase the gene content of diagnostic panels albeit at the expense of an unprecedented variant interpretation challenge. Evaluating gene-disease associations is thus becoming the limiting factor for establishing diagnostic panels with the highest clinical validity while reducing the number of clinically irrelevant variants. While efforts for standardization are underway, the clinical genetics community has traditionally been lacking both detailed criteria for defining gene-disease associations and necessary cutoffs for including or excluding genes in sequencing panels. As a result, available clinical panels for the same disease tend to have significantly variable numbers of genes (Rehm 2013), many of which have inadequate evidence supporting disease contribution.
Example: MYO1A gene
The MYO1A gene was originally implicated in autosomal dominant nonsyndromic hearing loss based on a multigenerational Italian family that showed linkage to the DFNA38 locus which encompasses the MYO1A gene (D’Adamo 2003, Donaudy 2003). This gene is also linked to autosomal dominant hearing loss in expert-authored, peer-reviewed human genetic reference databases such as GeneReviews and the Online Mendelian Inheritance in Man (OMIM). As a result, the MYO1A gene is available on most nonsyndromic hearing loss diagnostic panels offered by clinical laboratories including the OtoGenome V2 panel by the Laboratory for Molecular Medicine (LMM).
In reviewing the evidence associating this gene with disease, we noticed that a subsequent study failed to identify a causative variant after sequencing the MYO1A gene in the Italian family originally reported by D’Adamo et al (Donaudy 2003). Furthermore, Donaudy and colleagues proceeded to sequence this gene in other families with dominant sensorineural hearing loss and reported eight candidate variants in MYO1A (Donaudy 2003). This study, however, lacked segregation or functional data to support pathogenicity of any of the identified variants. In addition, four of these variants had allele frequencies ranging between 0.5% and 3.8% in Caucasian individuals (by the NHLBI Exome Sequencing Project) contradicting the assumption of a causal role for these variants in dominant nonsyndromic hearing loss. Interestingly, two more recent reports showed that MYO1A is dispensable for normal hearing in both human and mice (Eisenberger 2014, Shearer 2014) consistent with the refutation of causality of the previously reported MYO1A variants to hearing loss.
Solution and Clinical Implications
In response to the urgent need for defining the clinical validity of genes on diagnostic sequencing panels, we developed a systematic approach for evaluating disease associations of candidate genes at the LMM. We devised a scoring system to quantify the strength of evidence presented in the literature and in public databases, and a threshold for including genes on clinical panels. Our preliminary review showed that many other MYO1A-like genes have made it into testing panels exacerbating the variant interpretation bottleneck. Recognizing the challenge, the Gene Curation Working Group of Clinical Genome (ClinGen) Resource more recently released a classification system to organize gene-disease associations into seven tiers (http://www.clinicalgenome.org/site/assets/files/1995/clinical_validity_classifications_7_8_14_clean.pdf).
In conclusion, systematic evaluation of genes’ causality will help not only to limit interpretation to the most clinically relevant genes but also to avoid a large number of unknown clinical significance variants in genes with weak or no contribution to disease. This will consequently reduce unnecessary cost, effort, and anxiety associated with the cumbersome variant interpretation in the laboratory and the lengthy communications in the clinic between patients and providers.
D’Adamo P, Pinna M, Capobianco S, Cesarani S, D’Eustacchio A, Fogu P, Carella M, Seri M, Gasparini P. A novel autosomal dominant non-syndromic deafness locus (DFNA48) maps to 12q13–q14 in a large Italian family. Hum Genet. 2003 Mar;112(3):319–320.
Donaudy F, Ferrara A, Esposito L, Hertzano R, Ben-David O, Bell RE, Melchionda S, Zelante L, Avraham KB, Gasparini P. Multiple mutations of MYO1A, a cochlear-expressed gene, in sensorineural hearing loss. Am J Hum Genet. 2003 Jun;72(6):1571-7.
Eisenberger T, Di Donato N, Baig SM, Neuhaus C, Beyer A, Decker E, Mürbe D, Decker C, Bergmann C, Bolz HJ. Targeted and genomewide NGS data disqualify mutations in MYO1A>, the “DFNA48 gene”, as a cause of deafness. Hum Mutat. 2014 May;35(5):565-70.
Rehm, HL. Disease-targeted sequencing: a cornerstone in the clinic. Nat Rev Genet. 2013 Apr;14(4):295-300.
Shearer AE, Eppsteiner RW, Booth KT, Ephraim SS, Gurrola J 2nd, Simpson A, Black-Ziegelbein EA, et al. Utilizing ethnic-specific differences in minor allele frequency to recategorize reported pathogenic deafness variants. Am J Hum Genet. 2014 Oct 2;95(4):445-53.
GeneInsight in the News
March 25th-March 27th, Salt Lake City, UT
Please attend our VariantWire reception on March 26th, at 7pm, at the Salt Lake Marriott Downtown at City Creek. Heidi Rehm, PhD, FACMG, and Jordan Lerner-Ellis, PhD, FACMG will be speaking about their experiences with data sharing. Food and drink will be provided. Please RSVP via email.