GC-102 – TMEM127: Patient presenting with carcinoid tumour and triple-negative breast cancer
BEDARD, Angela C, MINDLIN, Allison M, SHAN, Wen Wen, SCHRADER, Kasmintan A
Affiliations: BC Cancer Agency, Abbotsford
TMEM127 has previously been described as a susceptibility gene for hereditary pheochromocytomas (PCC) and paragangliomas (PGL). A longitudinal study on patients with mutations in TMEM127 found the predominant presentation was adrenal PGL, although carotid, retroperitoneal, and tympanic PGL were also seen. We present the identification of a germline TMEM127 mutation carrier through multiplex sequencing, not selected on the basis of PGL. A 62 year old female presented to the Hereditary Cancer Program (HCP), BC Cancer Agency for genetic assessment of a personal history of metastatic breast cancer and history of carcinoid tumour. She had a known history of multiple sclerosis diagnosed at age 40 prior to her cancer diagnoses. At the age of 51, in 2005, she was diagnosed with node positive carcinoid tumor of the distal ileum, which was resected. In 2011, she was diagnosed with a new primary breast cancer. Pathology revealed a 1.7 cm, node negative, triple negative, grade 3 invasive ductal carcinoma. She was treated with therapeutic left mastectomy, prophylactic right mastectomy, reconstruction, and adjuvant chemotherapy. In 2012 she was seen for genetic counselling, given her history of two primary cancers, along with a family history of cancer. Family history includes two siblings with skin cancer; paternal history significant for 3 cases of breast cancer (one pre-menopausal), 4 cases of colorectal cancer (youngest = 51 yo), and one case of brain cancer. She was declined genetic testing due to not meeting the provincial criteria for funded BRCA1/2 analysis at that time. She expressed disappointment, as she was very concerned about the risk for her daughter, and had hoped to participate in hereditary breast cancer testing to help her family. In 2016, she was diagnosed with a metastatic recurrence of the breast cancer. She was treated with chemotherapy and radiation. In 2017 she was seen again by HCP, at which point she met updated provincial criteria for testing, due to her diagnosis with triple negative breast cancer. Given her history of carcinoid tumor, an expanded 87-gene panel was ordered through the United States. A variant in TMEM127, classified as likely pathogenic, was detected. She expressed satisfaction that the finding would allow for genetic testing and possible early detection of PGL/PCC for her family members and understood the limitations with regard to implicating the variant in the pathogenesis of her multiple primary tumors without further investigation. This is the first report of a carcinoid tumour and a triple negative breast cancer occurring in association with a germline likely pathogenic variant in TMEM127 and suggests that a broader phenotype for the TMEM127 gene may need to be considered. This case illustrates the potential of multiplex testing to expand the phenotypes of known cancer susceptibility syndromes; clinical correlation and proof of causation will remain a challenge.
GC-105 – The impact of parental decision-making styles on the utility of an online decision-making tool for genome wide sequencing
BOYCE Ayanna1, ADAM Shelin1, BANSBACK Nick2, FRIEDMAN Jan1, BIRCH Patricia1
Affiliations: 1Department of Medical Genetics, University of British Columbia, Vancouver
2School of Population and Public Health, University of British Columbia, Vancouver
Introduction: The increasing use of genome-wide sequencing (GWS) to diagnose patients with a suspected genetic disorder creates a need for new approaches to provide decisional support, education and informed consent. DECIDE (Decision aid and E-Counselling for Inherited Disorder Evaluation) was developed as an interactive online decision support tool to help families make choices about GWS. The purpose of this study was to explore the utility of DECIDE in relation to parental decision-making style. The objectives were to determine if decision making style: 1) varies amongst parents making GWS decisions 2) is associated with knowledge gain and 3) is associated with preference regarding how pre-test information is received (ie, genetic counselling vs DECIDE, or both).
Methodology: As part of a study of exome sequencing for children with early-onset epilepsy of unknown cause, parents (N=147) were randomly assigned to receive either DECIDE or genetic counselling first, followed by the other intervention. Knowledge was assessed at baseline, then after the first intervention. Decision-making style was assessed using the Melbourne Decision Making Questionnaire (MDMQ) 4 months post-results. The MDMQ vigilance subscale measures adaptive decision making whereas the hypervigilance, buck-passing, and procrastination subscales measure maladaptive decision-making. Parents were asked about their counselling method preference after completing both genetic counselling and DECIDE. Chi square tests were used to assess the association between decision making styles and preference regarding receipt of information. Spearman’s rho was used to assess the association between knowledge gain and decision making style.
Results: Parents mainly had high adaptive decision making styles and low maladaptive decision making styles. There was no significant association between decision making style and preference regarding receipt of information (all p values >0.05). Decision making style was not associated with knowledge gain (all p values >0.05).
Conclusions: Parents making decisions about GWS decisions were generally adaptive decision makers. Decision making style is not associated with knowledge gained via either conventional genetic counselling or DECIDE. Further, decision making style is not associated with parents’ preference regarding genetic counselling method. Further exploration with a larger sample size may provide insight into whether there are subgroups of patients who are more or less likely to benefit from either in-person genetic counselling or a tool such as DECIDE. Other factors, such as proficiency with English and computer literacy, are important to consider when determining the utility of DECIDE. These additional considerations could improve understanding of its utility and would help inform appropriate implementation into clinical practice.
GC-106 – PhenomeCentral: a portal for phenotypic and genotypic matchmaking of patients with rare genetic diseases
JOHNSTONE, Brittney1, BUSKE, Orion1, GIRDEA, Marta1, DUMITRIU, Sergiu1, ANDJIC, Aleksandra1, MISYURA, Andriy1, KOLTUNOVA, Veronika1, PAVLOVA, Kateryna1, COLLURA, Felicia2, HUM, Courtney3, ROBINSON, Peter4, HARTLEY, Taila5, BOYCOTT, Kym5, BRUDNO, Michael1.
Affiliations: 1Centre for Computational Medicine, Hospital for Sick Children, Toronto, ON, Canada
2Lakeridge Health, Oshawa, ON, Canada
3Prenatal Diagnosis and Medical Genetics, Dept of Obs&Gyn, MSH, Toronto, ON, Canada
4The Jackson Laboratory, Farmington, CT, USA  Children’s Hospital of Eastern Ontario, Ottawa, ON, Canada
The discovery of disease-causing variants typically requires confirmation of the variant or gene in multiple unrelated individuals, and a large number of rare genetic diseases remain unsolved due to difficulty identifying second families.
To enable the secure sharing of case records by clinicians and rare disease scientists, we developed PhenomeCentral (phenomecentral.org), a restricted access portal for sharing de-identified patient phenotype and genotype data to find similar cases around the world. Each record includes a detailed phenotypic description (specified using HPO terms) and relevant genetic information (exome data and/or candidate genes). PhenomeCentral currently incorporates data for 3500 patients with rare genetic diseases (2700 of which are unsolved), along with 50,000 HPO annotations and 700 associated exome sequences. These cases have been contributed by over 950 clinicians and scientists from numerous efforts, including the FORGE and Care4Rare Canada projects, the US NIH Undiagnosed Diseases Program, and the EU Neuromics and AnDDIrare projects.
PhenomeCentral identifies similar patients based on semantic similarity between clinical features, automatically prioritized genes from whole-exome data, and candidate genes entered by the users, enabling both hypothesis-free and hypothesis-driven matchmaking. Additional matches can be found through coordination with the Matchmaker Exchange (MME, matchmakerexchange.org), of which PhenomeCentral is a founding member. Users can opt to include patient records in matchmaking across the MME in order to discover similar patients within other databases, including GeneMatcher, DECIPHER, MyGene2, Broad matchbox, and the Monarch Initiative. This collaboration has already generated over 600 matches involving PhenomeCentral cases and resulted in 16 novel findings that are published or in preparation. With additional sites planning to join the MME, storing deep phenotype and genotype data in PhenomeCentral will facilitate maximum potential for matchmaking for rare disease patient.
GC-109 – Genetic Testing Outcomes from the BC Familial Pancreatic Cancer Program
CREMIN Carol1,2,3, HOWARD Sarah1,2, MACKENZIE Anna1, MUNG SzeWing1, RENOUF Daniel2,3,4, SCHAEFFER David2,4,5, SCHRADER Kasmintan1,2,3
Affiliations: 1Hereditary Cancer Program, BC Cancer Agency, Vancouver, British Columbia
2Pancreas Centre BC, Vancouver, British Columbia
3Department of Medicine, The University of British Columbia, Vancouver, British Columbia
4Division of Medical Oncology, BC Cancer Agency, Vancouver, British Columbia
5Division of Anatomic Pathology and Laboratory Medicine, Vancouver General Hospital, Vancouver, British Columbia
Objectives: The Familial Pancreatic Cancer Program (FPCP) was implemented in 2016 as a research arm of the BC Cancer Agency’s Hereditary Cancer Program (HCP) to offer rapid genetic assessment of pancreatic ductal adenocarcinoma (PDAC) patients with a mission to improve the diagnosis and management of hereditary pancreatic cancer families in BC. Herein we describe the outcome of genetic testing in a prospective unselected PDAC subset seen within the first year of this program.
Methodology: Since August 1, 2016 all pancreatic cancer cases referred to the HCP have been offered an appointment with the FPCP Genetic Counsellor within three months from the date of referral. Patients are offered the option of in-person, video, or telephone consultation that are one-on-one or as part of a group information session. Clinical cancer genetic counselling and testing using the 30 gene panel from Color Genomics was offered to all patients with PDAC, regardless of family history. Patient clinical characteristics and cancer family history were reviewed for all patients who completed genetic testing. The study is approved by the BC Cancer Agency Research Ethics Board.
Summary of Results: From August 1, 2016 to June 1, 2017, 42 patients with PDAC completed the 30 gene panel test. Average age was 61.4 (range of 37-82) and 64% of patients were female. Average age at time of cancer diagnosis was 60.2 (range 37-81). Referrals were from oncologists (71%), surgeons (14%) and patient self-referral (12%). 98% of patients were non-Ashkenazi Jewish. Pathogenic or likely pathogenic variants (PV) were detected in 12% (n=5/42) of patients (2 PV in ATM, and one in each of the following genes: CDKN2A, BRIP1 and a monoallelic PV in MUTYH). The average age at diagnosis in the PV group was 54.8 compared to 60.8 in the uninformative/VUS group. Among the 5 individuals with PV, 3 reported a history of an HBOC related cancer in a first degree relative, 4 met the 2017 NCCN criteria for BRCA1/BRCA2 assessment and 3 met the criteria for familial pancreatic cancer.
Conclusions: Germline PV associated with inherited cancer susceptibility were identified in 12% of unselected PDAC patients undergoing genetic testing in the FPCP’s first year of experience. Consistent with prior research, we saw a low PALB2 and CDKN2A mutation prevalence in patients with unselected PDAC. However, the absence of germline BRCA2 and BRCA1 mutations in this cohort was unexpected. It is not known whether germline PV in ATM or BRIP1, which are also associated with the homologous recombination DNA repair pathway, confer similar treatment implications as those in BRCA1 or BRCA2. Outcome data examining treatments stratified by mutation status may provide relevant insights. Due to emerging treatment implications of BRCA1 and BRCA2 mutations, mismatch repair deficiency and potentially other defects in DNA repair, expedited assessment and testing in pancreatic cancer patients is crucial.
GC-111 – BRCA1 and BRCA2 mutations in elderly women
KOBELKA, Christine; SALYER, Chelsea; BARRIE, Allison; LITTELL, Ramey; POWELL, Catherine Bethan
Affiliations:Kaiser Permanente Genetics Department, San Francisco, CA, USA
Objectives: Describe clinical characteristics and risk reducing strategies of women with a known BRCA1 or BRCA2 mutation diagnosis and who have survived to 75 years of age and beyond.
Methods: This is a retrospective cohort study of women in a community based health system identified with a BRCA1 and BRCA2 mutation from January 1st, 1995 to August 15th, 2015. Exclusion criteria included incomplete medical record data and age less than 75 years by August 15th, 2015. A retrospective chart review was performed using an electronic medical record system. Outcomes evaluated included: reason for genetic testing, age at time of identifying a BRCA1 or BRCA2 mutation, personal history of cancer, ethnic background, surgical history and risk-reducing methods.
Results: From January 1st, 1995 through August 15th, 2015, a total of 69 women who were living, or deceased but lived to at least age 75 years, were identified to have a BRCA1 or BRCA2 (“BRCA”) pathogenic or likely pathogenic mutation. Six women lived to 90 years of age or older. The mean age of the cohort at the time of genetic testing was 73.5 years old (range age 57-92). The majority of women were white (81.2%) and 14.5% of women were Ashkenazi Jewish. At the time of genetic testing, 47 women (68%) had a personal history of breast cancer and 27 (39%) had personal history of ovarian cancer. Twenty three (33%) of women were tested for a previously identified familial BRCA mutation.
After learning of their BRCA positive status, fourteen of 30 (46.7%) women who had ovaries in place at time of genetic testing elected risk-reducing salpingo-oophorectomy (RRBSO). Six (43%) of these women had RRBSO after age 70. Two of these women (6.7%) had no prior history of breast cancer. Three out of 19 (15.8%) women who had no prior history of breast cancer elected risk-reducing mastectomies (RRM) after learning their BRCA positive status (at ages 58, 66 and 68). Two of the three women who elected RRM had prior personal history of ovarian cancer. After genetic testing, three women, all with a BRCA2 mutation, developed cancer. One woman developed breast cancer at age 67, and two women developed pancreatic cancer at age 76. Overall, six women (8.7%) had no personal diagnosis of a hereditary breast and ovarian cancer syndrome-related cancer.
Conclusion: The majority of women with BRCA mutations who survived beyond the age of 75 received their positive genetic test result at an older age. Almost half of the women who still had their ovaries in place underwent RRSO after identification of their BRCA mutation. Older women are making medical decisions based on the information from BRCA genetic testing, and it is important that continued attention be paid to the healthcare needs of this cohort.
GC-112 – A Single-Center Experience with Clinician Interpretation of Variants in Cardiovascular Genetics Indicates Clinically Impactful Disagreement with Testing Laboratories
CALESHU Colleen, BLAND Austin, HARRINGTON Elizabeth, DUNN Kyla, PARIANI Mitchel, PLATT Julia, GROVE, Megan
Affiliations: Stanford Center for Inherited Cardiovascular Disease, Stanford
Introduction: Data sharing has revealed that in a subset of cases there is disagreement between genetic testing labs in their classification of variants. However, the frequency of differences in classifications between labs and clinicians has not been investigated.
Aim: We sought to describe the variant interpretation experience of a single cardiovascular genetics center, including frequency and nature of differences in classifications between the clinical team and the genetic testing lab.
Methods: We performed a retrospective review of all variants identified through clinical genetic testing done as part of patient evaluations in the Stanford Center for Inherited Cardiovascular Disease between January 2007 and August 2016. The variant classifications of the clinical team and the testing lab were compared. Where possible, classifications were also compared to ClinVar.
Results: We reviewed 639 variants across 98 genes. Of the 688 lab classifications for these variants, 124 (18%) differed from the clinical team’s classification (eg. likely pathogenic (LP) or pathogenic (P) vs. variant of uncertain significance (VUS); VUS vs. likely benign (LB) or benign (B)). This rate of discordance is similar to that reported between genetic testing laboratories in ClinVar. For the majority of the discordant classifications, the clinical team was more conservative, meaning they were less likely than the lab to consider a variant pathogenic or likely pathogenic (ex. clinical team classification: LP and lab classification: P). The most frequent (66%) disagreement was when the testing lab ruled a variant LP/P and clinicians considered it a VUS. Of the 124 discordant classifications, 103 (83%) were clinically significant, indicating the difference in classification would affect clinical care of the patient and/or family (LP or P vs. VUS, LB, or B). The frequency of discordant classifications differed depending on the testing lab (p<0.0001) and the testing lab’s classification (p< 0.00001). We compared the clinically significant discordant classifications to classifications by other group’s in ClinVar. The clinical team’s classification was discordant with one or more submitter in ClinVar in 49.1% (28/57) of cases, while the testing lab’s classification was discordant with a ClinVar submitter in 82.5% of cases (47/57, p=0.0002). Similarly, more ClinVar submitters agreed with the clinical team than the testing lab (mean 1.4 vs. mean 0.6, p=0.0005).
Conclusions: Variant interpretation by clinicians specialized in cardiovascular genetics are discordant from the testing lab’s interpretation at a rate similar to discordance between genetic testing labs. The majority of these disagreements would affect medical management, with the clinicians being less likely than the lab to consider a variant pathogenic or likely pathogenic.
GC-113 – Mindfulness among genetic counselors is associated with improved empathy, burnout, compassion fatigue, and work engagement
CALESHU Colleen, SILVER Julia, CASSON-PARKIN Sylvie, ORMOND, Kelly
Affiliations: Stanford Center for Inherited Cardiovascular Disease, Stanford
Introduction: Genetic counselors experience high rates of compassion fatigue and an elevated risk for burnout, both of which can negatively impact retention and quality of patient care. In other healthcare professions, mindfulness training has been successfully used to address similar negative psychological sequelae.
Aim: We aimed to assess associations between mindfulness and key professional outcomes, including burnout, compassion fatigue, work engagement and empathy. We hypothesized that mindfulness would be positively associated with work engagement and empathy, and negatively associated with burnout and compassion fatigue.
Methods: Cross-sectional observation study with data collected via a one-time anonymous online survey that included demographic questions and validated measures for mindfulness and each of the key professional outcomes.
Results: The survey was completed by 441 genetic counselors involved in direct patient care. Participant demographics were consistent with demographics of the genetic counseling field. Half of respondents (50.1%) reported engaging in yoga, meditation and/or breathing exercises. We observed no significant correlations between any of these activities and mindfulness, likely due to measurement issues and lack of specificity in self-reported activities. Mindfulness was positively correlated with empathy (as measured through four subscales: perspective taking (r = 0.15, p=0.002), empathic concern (r= 0.11, p=0.03), fantasy (r=-0.11, p=0.03) and personal distress (r=-0.15, p=0.001)). Mindfulness was also positively correlated with work engagement (r=0.24, p<0.001). Mindfulness was negatively correlated with compassion fatigue (r=-0.48, p<0.001) and burnout (r=-0.50, p<0.001). Conclusions: As genomic technologies advance rapidly, pressures on genetic counselors are increasing and retention is becoming more critical. This study identifies beneficial associations between mindfulness and key professional factors relevant to professional satisfaction, retention, and quality of patient care. Given these findings, mindfulness training may be a valuable addition to graduate or continuing education for genetic counselors.
GC-115 – Clinical cardiovascular genetic counselors take a leading role in team-based variant interpretation
CALESHU Colleen, REUTER Chloe, ORLAND Kate, GROVE Megan, SPOONAMORE Katherine
Affiliations: Stanford Center for Inherited Cardiovascular Disease, Stanford
Introduction: Broader genetic testing and increased recognition of disagreement among labs on variant classification has lead to discussion regarding the role of the clinician in interpretation of clinical genetic test results.
Aim: To describe the genetic test result review and interpretation practices of clinical cardiovascular genetic counselors.
Methods: Data was collected with a one-time anonymous online survey that included questions about genetic counselors’ practices regarding review of clinical genetic test results. Members of the NSGC cardiovascular special interest group were invited to participate and were eligible if they were currently practicing as a clinical cardiovascular genetic counselor.
Results: Forty-six genetic counselors participated (mean years practicing: 9.4; mean years in cardiology: 5.1). Nearly all gather additional data on variants identified through clinical genetic testing, beyond reading the test report (95.7%). The majority also assess the classification of those variants (81%). Variant classification was a more recent addition to practice than gathering additional information (3.3 years and 2 years, respectively; p=0.02). Genetic counselors report multiple reasons for adding assessment of variant classifications to their clinical practices, including prior experiences with disagreements between labs on classifications, incomplete lab reports, and variant reclassifications that impacted patient care. They are also motivated by a desire to maximize their confidence in the genetic test result and a sense of personal professional responsibility for the result. Most genetic counselors reported performing variant interpretation in collaboration with their cardiologist and/or geneticist colleagues (81%). While variant classification was often team-based, in most cases the genetic counselor was the team member primarily responsible for classification (76.7%). Participants reported they more often agreed with the lab’s classification of variants as pathogenic (90.5%), than likely pathogenic (81.9%; p=0.02) or of uncertain significance (73.3%; p=0.001). When the clinical team’s classification disagrees with the lab’s classification, genetic counselors consult with the lab, colleagues, and gene-disease experts and document the reason for the difference in classification. Genetic counselors report that variant interpretation skills were more often gained on the job than in graduate school. Many reported team-based education, noting they learned from physicians and both clinical and laboratory genetic counseling colleagues.
Conclusions: Most cardiovascular genetic counselors perform additional review and classification of clinical genetic test results. Such interpretation is done in a team-based fashion, with the genetic counselor as the team member primarily responsible for review and classification.
GC-118 – Private Pay NIPT uptake in BC: Correlation With Temporal Changes In Consumer Options
GUIMOND, Colleen, BUTLER, Rachel, JING, Chen, TAYLOR, Beth
Affiliations: Olive Fertility Centre, Vancouver, Canada
Background: Prenatal screening for aneuploidy is offered to all pregnant women in British Columbia with the BC Medical services plan (BC MSP) covering the cost for maternal serum screening. BC MSP also pays for nuchal translucency ultrasound and diagnostic testing based on criteria. Non-invasive Prenatal Screening (NIPT) is a safe and accurate screening method for trisomies 21, 18, and 13. NIPT has been available as a private pay screening option for all women in BC from 2012. In November 2015, BC MSP introduced funded NIPT for women deemed to be at high risk for aneuploidy based on either a previous trisomic pregnancy or high-risk prenatal screening results. Consumer options and pricing have changed dramatically in the short time that NIPT has been offered in BC. Here, we report on the uptake of self pay NIPT at one private clinic, overlaid with a comparative timeline indicating changes in pricing, availability and the introduction of provincial criteria for coverage.
Methodology: Clinic data was reviewed for all patients seen at Olive Fertility Centre (OFC) in Vancouver, Canada for an indication of NIPT from September 2013 to May 2017. A historical timeline of NIPT options in BC over this time period including testing companies, pricing, availability, and criteria for funded NIPT was generated through consultation with Perinatal Services BC and review of documents.
Results: Over the 43-month period during which NIPT has been offered at our centre, 1701 tests, representing 1635 distinct patients, have been completed with a monthly average of 38.7 tests (range 1-90). Patients who had completed at least one fertility treatment at OFC represented 25.9% of this group. Average tests per month increased up until May 2015, decreased until April 2016 and has since remained stable. Mean patient age at blood draw was 35.8 years (range 20-50). Mandatory pre-test genetic counselling became optional as of July 2015 and after this time was elected by 381/1096 (34.8%) of patients. NIPT cost at OFC decreased from $1100 to $650, with the most recent decrease occurring in April 2015. Panorama testing, available at Lifelabs, and Harmony testing, both reduced costs to patients in the spring of 2015 and access to Harmony testing was facilitated through an agreement with hospital labs in March 2016. BC MSP-funded NIPT for high-risk pregnancies was introduced in November 2015.
Discussion: The last four years have seen rapid changes to the availability and uptake of self-pay NIPT in BC. Competition between testing companies has driven prices down and the desire for safe, accurate, and early aneuploidy detection has caused a surge in popularity despite the cost. OFC saw a steady increase in NIPT numbers from first availability at our centre up to the months following the reduction of pricing in the community after which there was a decline. The introduction of MSP funded NIPT had a minimum impact. Despite the ease of access and lower pricing of NIPT available elsewhere, OFC NIPT numbers have remained stable which may in part be attributed to past interactions with our clinic and satisfaction with the level of clinical care service provided.
GC-119 – Restrictive testing guidelines miss Canadians at risk of hereditary cancer
HANDFORD Cynthia, SERVAIS Lily, MCFADDEN Will, ZIMMER Anjali, ZHOU
Affiliations: Alicia Color Genomics, Burlingame, California, USA
Objectives: Current hereditary cancer testing guidelines employ strict criteria based on personal and family history of cancer to determine eligibility for genetic testing. In Canada, guidelines are set by individual genetics clinics or provincial health ministries, and therefore may vary by province. These guidelines are typically more restrictive than the NCCN guidelines employed in the United States. However, the decreasing cost of multi-gene panel tests has facilitated a broader testing approach and has revealed that testing individuals excluded by current guidelines may be appropriate. Here, we analyzed mutation carrier rates for Canadian individuals who met or did not meet current testing criteria. We sought to determine the mutational burden that would be missed if testing was only carried out in individuals meeting criteria.
Methods: We analyzed the first 558 people in Canada who received the Color Test, a 30-gene panel for hereditary cancer risk including: APC, ATM, BAP1, BARD1, BMPR1A, BRCA1, BRCA2, BRIP1, CDH1, CDK4, CDKN2A, CHEK2, EPCAM, GREM1, MITF, MLH1, MSH2, MSH6, MUTYH, NBN, PALB2, PMS2, POLD1, POLE, PTEN, RAD51C, RAD51D, SMAD4, STK11, TP53. Variants were classified according to current American College of Medical Genetics and Genomics (ACMG) guidelines. We determined eligibility using combined guidelines and practices from the provinces most represented in the cohort. The most inclusive criteria based off self-reported health history was used (e.g., for APC and MUTYH we considered anyone with a history of colon polyps to be qualified regardless of polyp count).
Results: 49.5% of the cohort qualified and 34.2% did not qualify for testing based on personal/family history, and 16.3% did not provide sufficient information to determine eligibility. Excluding common low penetrance alleles, pathogenic or likely pathogenic mutations were found in 10.8% of individuals: 12.0% among those that qualified, 9.4% among those that did not qualify, and 9.9% amongst those that did not provide enough information. Importantly, 30% of mutation carriers did not meet criteria and would have been missed, and 28% of these missed mutations were in BRCA1/2.
Conclusion: Due to the stringency of current screening guidelines, nearly a third of hereditary cancer mutation carriers would not have qualified for genetic testing. Many of these missed mutation carriers did not qualify because the age of onset of personal or family cancer exceeded current cut-offs. This group had a mutation carrier rate of 9.4%, which is much greater than the often-cited 5% target pickup rate. These data suggest that in order to broadly reveal clinically actionable information, current guidelines should be revisited and broadened, and testing should be considered in individuals who do not strictly meet current criteria.
GC-122 – Spectrum of pathogenic variants identified on a hereditary paraganglioma/pheochromocytoma panel
WILEY, Elizabeth A; SUSSWEIN Lisa R; MARSHALL, Megan L; CARTER, Natalie J; KLEIN, Rachel T; WANG, Ying; HRUSKA, Kathleen S
Affiliations: GeneDx, Gaithersburg, Maryland, USA
Background: Approximately 30% of paragangliomas (PGL) and pheochromocytomas (PCC) have a hereditary basis, and germline variants in the SDHA, SDHB, SDHC, SDHD, SDHAF2, TMEM127, MAX, VHL, FH, RET, MEN1, and NF1 genes have been associated with a predisposition to PGL/PCC. Multi-gene hereditary cancer panel testing for PGL/PCC has become increasingly more common than single-gene testing algorithms.
Purpose: Here we describe the spectrum of pathogenic and likely pathogenic (PV/LPV) variants identified at a clinical laboratory after a year of offering a PGL/PCC panel.
Methods: We performed a retrospective review of clinical and molecular data for all PGL/PCC panels ordered between January 2016 and February 2017.
Results: Among 160 probands tested for PGL/PCC panels, 34% (n=55) had a PV/LPV. For probands with PGL, the positive test yield was 46% (40/87), with the majority of PV/LPV in SDHB (n=20) and SDHD (13). For probands with PCC, the positive rate was lower (18%; 10/56) with most PV/LPV in SDHB (n=4) and RET (2). Six patients were tested solely due to a family history of PGL/PCC, of whom 3 had a PV/LPV. Ten probands had no personal or family history of PGL/PCC but one had a LPV in SDHB and SDH-deficient renal cancer and another had a MEN1 PV and a pancreatic tumor. Almost one-fifth (18%) of patients with PV/LPV had a sporadic, solitary tumor diagnosed >45y. The average age at tumor diagnosis was lower for probands testing positive than those without PV/LPV for both PGL (39.3y vs 43.4y) and PCC (33.5y vs 42.9y). Overall, the majority of PV/LPV were in SDHB (n=26; 47%), followed by SDHD (15; 27%) and SDHC (5; 9%), with the remaining variants being identified in SDHA (2), VHL (2), RET (2), MEN1 (1), TMEM127 (1), and MAX (1). There were no PV/LPV identified in SDHAF2, NF1, or FH.
Conclusions: Our data are consistent with recent estimations that approximately 30% of PGL/PCC are caused by germline PV/LPV and support previous recommendations that patients with PGL/PCC undergo testing regardless of age at diagnosis or family history. Panel testing is a useful tool for identifying individuals with hereditary PGL/PCC.
GC-123 – An inherited distal 16p11.2 deletion demonstrates variable expressivity and incomplete penetrance for psychiatric illness as well as association with rhizomelic shortening: a case report
MORRIS, Emily, MCGILLIVRAY, Barbara, LEHMAN, Anna, AUSTIN, Jehannine
Affiliations: University of British Columbia, Vancouver, BC
Background: The most commonly reported 16p copy number variant (CNV) – 16p11.2 deletion syndrome
(16pDS) (~600 kb; 29.5 -30.1 Mb) – has been robustly associated with schizophrenia (SZ), as well as intellectual disabilities (ID)/developmental delays (DD), congenital anomalies, dysmorphic features and obesity. Non-overlapping “distal” 16p11.2 deletions (~200 kb; 28.7 -28.9 Mb) are less commonly reported, but have a variable phenotype similar to that of 16pDS, including emerging data suggesting a psychiatric phenotype. We report here on a parent/child dyad who share a distal 16p11.2 deletion. METHODS: Patient 1 (index) was assessed (for indications including seizures, DD, and short limbs) at ages 2, 17, and 36, when she had clinical chromosomal microarray (CMA) (Affymetrix Cytoscan HD array, clinical thresholds: 200 kb (deletions), 400 kb (duplications), Chromosome Analysis suite (v2.0.0 195)). Fluorescence in situ hybridization (FISH) was used to confirm the deletion and determine origin.
Results: Patient 1 was born at term to non-consanguineous parents. A 46XX karyotype was confirmed at age 2 and 17 (testing indications: myoclonic seizures, DD, rhizomelic shortening of upper limbs). At age 17, she was also noted to have small hands (<3rd %ile) and feet (-3.5 SD), large posteriorly rotated ears (+3 SD), brachycephaly, high nasal bridge, and low posterior hairline. She had developed psychosis at 13, and received diagnoses of bipolar disorder type I, ADHD, possible ASD and ID. At 37, she is obese with impaired fasting glucose, and ongoing psychiatric symptoms. CMA revealed a 238Kb deletion at 16p11.2 (28 819 028 – 29 056 973; hg19)) confirmed by FISH as being paternally inherited. Patient 2 is the 69 year-old father of Patient 1. He completed high school despite difficulties, and is not obese but has diabetes mellitus type II. He has rhizomelic shortening of both upper limbs but no history of psychiatric illness.
Discussion: While distal 16p11.2 deletions have been shown to increase risk for schizophrenia, this reports contributes to the emerging evidence that this CNV is also associated with broader psychiatric phenotypes, such as bipolar disorder. The father’s milder cognitive and metabolic phenotype supports variable expressivity of distal 16p11.2 deletions, even when inherited; his negative psychiatric history reinforces the incomplete penetrance of this CNV for psychiatric disorders. This report also contributes to the generation of a more thorough clinical description of the phenotypic range of distal 16p11.2 deletion, which we suggest, includes rhizomelic limb shortening.
GC-125 – Lexigene®: Bridging the Communication Gap through an Online English-French-Spanish Genetic Counselling Lexicon
SILLON Guillaume1, CLOUTIER Mireille2, D. HODGES Priscila3, HATHAWAY Julie4, KRSTIC Nevena5, VANNESTE Rachel6
Affiliations:1 McGill University Health Center, Montreal, QC
2Children’s Hospital of Eastern Ontario, Ottawa, ON
3The University of Texas Health Science Center at Houston, Houston, TX, USA
4St. Paul’s Hospital, Vancouver, BC
5The University of Texas Health Science Center at Houston, Houston, TX, USA
6Prevention Genetics, Marshfield, WI, USA
To facilitate the provision of genetic services in the three most commonly spoken languages in North America and to contribute to the development of the genetic counselling profession, an English-French-Spanish lexicon of terms was created by genetic counsellors for the specific use of genetic counselling. Trainees in bilingual genetic counselling programs, medical interpreters, as well as French and Spanish speakers who have access to the mainly Anglophone scientific literature are in particular need of such a tool. Prior to the creation of Lexigene, no French/English glossaries or lexicons with terms related to genetic counselling were available. Similarly, although a Spanish/English glossary was created in the 1990s, its medical genetics terminology had not been updated in almost twenty years.
The original French-English Lexigene was funded through the Canadian Association of Genetic Counsellors and was published online in 2011. In 2016, the National Society of Genetic Counselors’ Audrey Heimler Special Project Award was given to include Spanish. This trilingual website, www.lexigene.com, allows an individual to search for genetics-related terms in either English, French or Spanish and find the equivalent term in the other language.
Prior to the trilingual online tool’s launch in the Spring of 2017, it was piloted by 18 Spanish-speaking healthcare professionals working in the field of genetics, mainly genetic counsellors. The pilot project consisted of qualitative and quantitative questions. All respondents ranked the tool as “easy” or “very easy” to use and 89% indicated they would use the tool in their practice. Additionally, 80% of the words that respondents searched for were present in Lexigene. Finally, the qualitative feedback provided by those piloting Lexigene was used to improve the website’s functionality.
This online tool boasts ~3600 translated terms, with more being added regularly. This versatile online lexicon will significantly impact not only those who are involved in the field of genetics, but also patients who have limited English proficiency; with the aid of Lexigene, providers and interpreters will be able to enhance their genetics vocabulary and in turn provide better service through accurate communication.
GC-126 ACMG secondary findings reporting preferences in clinical exome sequencing
SROKA Hana, SIEGLER Melisa, KUCERA Cathlin, BAMFORD Abbey, RETTERER Kyle, HENDERSON Lindsay, JUUSOLA Jane
Affiliations: GeneDx, Gaithersburg, MD, USA
In June 2013, the American College of Medical Genetics and Genomics (ACMG) published recommendations for the reporting of secondary findings (SF) in clinical genome and exome sequencing (ES) (Green et al., 2013) and in 2015 amended these recommendation suggesting families should have the option to opt-out of receiving ACMG SF. Our laboratory began offering clinical exome sequencing in June 2013 which included from inception the option of declining reporting of SF. To identify trends in the opt-out rate (OOR), we performed a retrospective review of SF reporting preferences in ES performed at our clinical laboratory. During the study period of June 2013 through March 2017, we observed a steady decline in the proband OOR from 25% in the initial month (35/139) to 8% in the most recent month (63/791). In 2016, the OOR was 3.8% for the top 5% of orderers (n=57, 108/2821) compared to 5.9% for single-test orderers (n=474, 28/474). Whether the difference relates to degree of experience with SF, consenting practices or family characteristics warrants further exploration. Our data suggests parents are more likely to opt-out of SF for themselves than for their children (27.5% vs 9.4%, respectively; p<0.0001). Canadian and international probands were significantly more likely to opt-out (12.5%, 65/519 and 44%, 385/867, respectively) than those from the United States (7.3%, 1166/15,808; p<0.0001). The higher opt-out rate for Canadians in particular may reflect the Position Statement of the Canadian College of Medical Geneticists who do not currently endorse the intentional clinical analysis of disease-associated genes other than those linked to primary indication and may have broader impact to other health jurisdictions internationally (Boycott et al., 2015). In summary, our data indicate that individuals are increasingly consenting to having secondary findings reported as clinical ES has become more widely used. Patient reporting preferences to receive SF may be influenced by multiple factors including region, relationship, age, and provider. An increased awareness of these factors is important as we strive to counsel patients appropriately in the context of evolving genetic testing and clinical recommendations.
GC-127 Enhancing service delivery: Review of the first five years of a new General Genetic Counselling Team
PERRAS, Hélène and SAWYER, Sarah
Affiliations: Children’s Hospital of Eastern Ontario, Ottawa
As expanded chromosomal and molecular genetic testing has become available, the volume of referrals to Genetics has increased for new diagnoses and for interpretation of genetic test results, with little or no increase in funding or staffing. As a result, in 2012, a new team was formed within the Regional Genetics Clinic at CHEO: the General Genetic Counselling (GGC) team. Originally, its main goal was to address the management of referrals that did not fit in any of the existing specialty clinics (prenatal, neurogenetics, cardiogenetics, cancer), but the team has evolved to have a key role in the triaging of referrals for the clinic and in enhancing services for all patients. The team consists of a Lead Medical Geneticist, a Lead Genetic Counsellor, the booking clerk, and geneticists and genetic counsellors involved in providing services to this patient population. Referrals directed to the GGC clinic have increased 2.5-fold since 2012. To accommodate these referrals and manage wait times, some common and/or low risk referrals are no longer accepted by the Genetics clinic, and are declined with a faxback providing information to the referring provider. These include: MTHFR, Factor V Leiden, recurrent miscarriages, consanguinity, pseudo-cholinesterase deficiency, family history of a translocation, hemoglobinopathy carriers, alpha-1-antitrypsin deficiency, hereditary hemochromatosis, glucose-6-phosphate deficiency, and director-to-consumer test results. Overall, 34% of GGC referrals were declined in 2016. To further enhance service delivery, the GGC team has implemented group counselling for cystic fibrosis carrier testing, has expanded to include ocular genetics, and has developed template letters for some of the most common indications. As wait times to see a medical geneticist have increased, a new type of patient appointment was created, where the genetic counsellor takes the primary responsibility for the appointment and the geneticist provides medical expertise and performs a clinical exam when necessary, thus allowing the geneticists to focus on more complex patient referrals. Future endeavours will focus on the addition of other types of referrals to streamline other teams, such as non-complex cancer referrals, in order to help the overall clinic wait times and efficiency. Benefits of having a GGC team include more consistent triaging of referrals, decreased wait times for patients, and increased satisfaction for genetic counsellors and geneticists. Service delivery has been enhanced by focussing our available resources to better serve our referred population.
GC-128 A pilot study to implement psychiatric genetic counseling at the Depressive Disorders Program, Douglas Mental Health University Institute
EL HELOU Janine, AUSTIN Jehannine, TURECKI Gustavo
Affiliations: McGill University Health Centre, Montreal
Background: Previous studies have demonstrated that individuals with psychiatric conditions are interested in and benefit from specialized psychiatric genetic counseling (PGC). However, there are currently very few established PGC clinics, and most of the research done so far comes from one main group. Objective: This pilot study aimed to independently evaluate PGC for individuals with depressive disorders in the context of the predominantly French-speaking city of Montreal, Quebec. Methodology: English and French speaking adults were recruited from the Depressive Disorders Program at a mental health institution in Montreal. Consenting participants completed the genetic counseling outcome scale (GCOS, measuring empowerment), and a self-efficacy questionnaire both in their primary language. Previous publications had used the self-efficacy scale in French, and for the GCOS, we translated it into French and had it back translated to check for fidelity. Participants were then randomly assigned to either an intervention (PGC) or control group, each of n=10. Four weeks later, participants completed the same questionnaires again. We conducted a descriptive analysis for patient demographics and compared mean scores evaluating the levels of empowerment and self-efficacy before and after the PGC session. Summary of results: Of 70 individuals approached, 29 agreed to participate (response rate = 41%), 9 of whom were lost to follow-up. For the group that received PGC, there was an increase of mean scores in empowerment after the PGC session (M=112.82) compared to before the session (M= 96.03), whereas participants in the control group reported no such increase (baseline M=114.89, one month later M=114.43). There was no increase in the mean self-efficacy scale scores after the PGC session as compared to before the session. Conclusion: This study suggests that individuals with depression have improvements in empowerment after receiving specialized PGC. This is the first study of PGC to include French speakers, and further supports provision of PGC for people with psychiatric disorders.
GC-129 A non-coding mutation in DONSON underlies microcephaly-micromelia syndrome
PARTLOW Jennifer N1, EVRONY Gilad D1, CORDERO Dwight R2 , SHEN Jun2, YU Timothy W1, RODIN Rachel E1, HILL R Sean1, COULTER Michael E1, MARTEL M Jocelyne3, SPOONER Betty3, ROBINSON Christopher A4, CHIBBAR Rajni4, DIUDEA Dana4, FOLKERTH Rebecca2, WIEBE Sheldon4, BARKOVICH A James5, MOCHIDA Ganeshwaran H1, IRVINE James4,6, LEMIRE Edmond G4, BLAKLEY Patricia4, WALSH Christopher A1.
Affiliations: 1Division of Genetics and Genomics, Howard Hughes Medical Institute, Boston Children’s Hospital; Departments of Neurology and Pediatrics, Harvard Medical School, Boston, MA, USA.
2Departments of Pathology and Obstetrics, Gynecology and Reproductive Biology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA.
3Department of Obstetrics and Gynecology and Northern Medical Services, University of Saskatchewan College of Medicine, Saskatoon, SK, Canada.
4Departments of Pathology, Medical Imaging and Pediatrics, Royal University Hospital, University of Saskatchewan, Saskatoon, SK, Canada.
5Department of Radiology, University of California San Francisco, San Francisco, CA, USA.
6Population Health Unit, Mamawetan Churchill River and Keewatin-Yatthé Health Regions, and Athabasca Health Authority, LaRonge, SK, Canada.
Objectives Microcephaly-micromelia syndrome (MMS), first described in a Saskatchewan First Nations population in 1980, is characterized by growth restriction, severe microcephaly with distinct craniofacial features, limb malformations, and nearly uniform perinatal lethality. Together with the community and local clinicians, we aimed to uncover the genetic cause of this recessive condition that has impacted an isolated population for decades.
Methodology Homozygosity and haplotype analysis using SNP-microarray genotypes in families affected by MMS identified significant linkage of disease to a small region on chromosome 21. Targeted-capture in the linkage region, as well as whole exome and genome sequencing, did not identify a causal coding, canonical splicing, copy number or structural variant. RNA sequencing was applied to affected and control tissues to investigate functional impacts of non-coding variants.
Results RNA sequencing analyses detected only one abnormality in the identified linkage region: significantly increased retention of intron 6 of DONSON due to a rare, homozygous, non-coding variant in MMS samples. Investigation revealed that DONSON is expressed in progenitor cells of embryonic human brain and other proliferating tissues, and is co-expressed with components of the DNA replication machinery, and that Donson is required for early embryonic mouse development. This evidence points to an essential conserved role for DONSON in the cell cycle.
Conclusion The integration of RNA sequencing with genome sequencing enabled our discovery of a hypomorphic splicing mutation in DONSON as the cause of MMS in a First Nations population. Recently, additional hypomorphic DONSON mutations leading to a spectrum of microcephaly syndromes were reported in a series of cases world-wide. Together, our studies implicate an essential role for DONSON in genome replication and link MMS clinically and mechanistically to other microcephalic primordial dwarfisms.
GC-131 Canadian experience with hereditary cancer panel testing: LHSC perspective.
PANABAKER Karen, DIRAIMO Jennifer, MACCANNELL Amanda, AINSWORTH Peter
Affiliations: London Health Sciences Centre, London, Ontario, Canada.
Background: Hereditary cancer panel testing by NGS was approved as a clinical test at London Health Sciences Centre in February 2016, replacing the routine BRCA1/2 screen for all new patients as per the Ontario MOH guidelines. Eligibility criteria for a panel, in the context of a new patient or a negative BRCA1/2 patient/family, however, have not yet been established.
Objectives: The purpose of this retrospective review is to describe our first years’ experience with ordering a hereditary cancer panel in-house, including an overview of all results and clinical outcomes. Case examples will be shared regarding incidental findings, as well as the clinical and management implications of finding a pathogenic variant in a moderate risk gene in a high risk family.
Methods: 192 charts were reviewed on patients who consented to have a multi-gene panel test at LHSC between February 29, 2016 and May 31, 2017. Patients included those who previously tested negative on a BRCA1/2 screen, as well as new referrals for a variety of cancer family histories. Results were analyzed for frequency of pathogenic variants and variants of unknown significance (VUS), and were stratified by gene and clinical history.
Results: Overall, 24 (12.5%) patients were found to have a pathogenic or likely pathogenic mutation, whereas 13 (6.7%) of these variants involved non-BRCA genes. The VUS detection rate was 29% overall, and correlated with the increased number of genes included on the panel. Incidental findings, including germline mosaicism, were identified in at least 5% of patients tested, and have proven to be the most challenging regarding post-test counselling and the provision of appropriate clinical risk management.
Conclusion: This overview will describe how panel testing has changed our pre- and post-test counselling for hereditary cancer referrals. Despite the fact that there are currently no established provincial criteria for when to offer panel testing vs. syndrome-specific testing, our experience will propose that offering a panel to patients/families who meet criteria for at least one syndrome is appropriate. Incidental findings create significant challenges in our ability to provide informative post-test genetic counselling, which ultimately may result in more ongoing follow-up with cancer patients than previously encountered with targeted testing.
GC-133 SMARCA4 Variants in Families with Small Cell Carcinoma of the Ovary, Hypercalcemic Type (SCCOHT)
DOONANCO Kurston, MARSHALL Megan, HIRAKI Susan, SUSSWEIN Lisa R., MURPHY Patricia D., KLEIN Rachel T., HRUSKA Kathleen S.
Affiliations: GeneDx, Gaithersburg, Maryland, USA
Objectives: Inactivating SMARCA4 variants have been reported in association with small cell carcinoma of the ovary, hypercalcemic type (SCCOHT), also referred to as malignant rhabdoid tumor of the ovary (MRTO), and rhabdoid tumor predisposition syndrome-2 (RTPS2). Loss of SMARCA4 expression has been suggested to be specific to SCCOHT, distinguishing it from other ovarian tumors. We sought to describe the findings from the first twelve months of SMARCA4 testing at a clinical diagnostic laboratory.
Methods: Beginning October 2015, next-generation sequencing and deletion/duplication analysis of SMARCA4 was offered as a single-gene test or as part of a custom multi-gene hereditary cancer panel of up to 61 cancer susceptibility genes through our clinical diagnostic laboratory. Within a twelve-month period, 335 individuals underwent germline molecular diagnostic testing including the SMARCA4 gene. We retrospectively reviewed the molecular and clinical details of individuals who underwent SMARCA4 testing.
Results: Eight distinct variants, two likely pathogenic (LPV) and six of uncertain significance (VUS), were identified in 21 individuals (6.3%). One LPV, a previously published canonical splice variant, was identified in the unaffected sister of an individual who developed SCCOHT in childhood, and was paternally inherited. The second LPV was a novel substitution at another canonical splice site, identified in an individual with SCCOHT in her 20s. While one VUS was observed in an individual with a family history of a malignant rhabdoid tumor, the other five VUS were not observed in association with a personal or family history of SCCOHT or malignant rhabdoid tumor.
Review of clinical test indications of the 335 individuals whose testing included SMARCA4 revealed three individuals with childhood malignant rhabdoid tumors, all of whom tested negative for variants in SMARCA4. Of five individuals with SCCOHT, one was found to carry a LPV, as discussed above, and the four others, who developed SCCOHT in their 30s and 40s, were negative. Additionally, of the 41 individuals with a personal history of ovarian cancer of non-SCCOHT or unspecified type, two carried a SMARCA4 VUS.
Conclusions: In our testing cohort, pathogenic or likely pathogenic variants in SMARCA4 were not common. Two likely pathogenic variants were detected in association with SCCOHT, and none in individuals with a personal history of other ovarian tumors, consistent with published reports. Further data are needed to fully characterize the clinical presentations associated with SMARCA4.
GC-135 Australian Genomics Health Alliance: Integrating Genomics into Clinical Practice
O’LOUGHLIN, Melanie, BOUGHTWOOD Tiffany, CHRISTODOULOU John, HAAS Matilda, PEREIRA Keri, PHILLIPS Peta
Affiliations: Victorian Clinical Genetics Services, Murdoch Children’s Research Institute, Melbourne Australia
The Australian Genomics Health Alliance is made up of over 75 partner organisations aligned in the aim of integrating genomic medicine into standard healthcare. The barriers to integrating genomic medicine into clinical practice in Australia include: lack of cohesive funding models, inequity of access across geographical regions, gaps in workforce genomic literacy and lack of coordinated policy with respect to privacy and ethics. The initiatives of Australian Genomics are many and aimed at addressing these barriers. This presentation will focus on the Rare Disease Flagships and the genetic counselling issues that have arisen in this setting. The Rare Disease program is offering genomic testing (WES, WGS or large capture panels) to groups of patients with rare diseases at paediatric and adult centres around Australia with the aim of informing health funding decisions and policy development. In the first phase of Australian Genomics genomic testing is being offered to patients with Epileptic Encephalopathies, Brain Malformations, Mitochondrial conditions, Renal Genetic disorders, Genetic Immunology conditions, Intellectual disabilities and Neuromuscular disorders. Eligible patients are referred to the study and consented by a study genetic counsellor.
Participants in the rare disease flagships consent to undergoing clinical grade genomic testing, completing surveys (patient experience and health economics), allowing access to health data and are directly linked to further flow-on research following their initial clinical genomic test. The aim of this approach is to add to the body of evidence around efficacy of genomic testing for specific rare disease phenotypes. The direct link to research is aimed to increase diagnoses for patients by building robust networks between clinicians and functional genomics researchers. The health economic analysis is aimed to determine the impact of molecular diagnosis on patient management and health spending. It is envisaged that a primary outcome of the Australian Genomics will be to inform policy and guide government funding decisions.
The rare disease flagships are in the early stages of patient recruitment. It is anticipated that ~1850 patients will be recruited through these flagships nationally over two years. This presentation will focus on the early findings and genetic counselling issues arising in this setting with illustrative case examples. The Australian Genomics Health Alliance is funded by NHMRC GNT1113531 and is led by Professor Kathryn North.
GC-136 Patient attitudes and behaviors towards sharing information with at-risk relatives in inherited arrhythmia syndromes
RUINSKY, Melissa1,2, SPEARS, Danna6, SHUMAN, Cheryl1,2,3, WASIM, Syed2,4, CHITAYAT, David1,2,5, HAMILTON, Robert7, and CARE, Melanie1,4,6
Affiliations: 1Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada
2Division of Clinical and Metabolic Genetics, Department of Pediatrics, The Hospital for Sick Children, Toronto, ON, Canada
3Department of Genetic Counselling, The Hospital for Sick Children, Toronto, ON, Canada
4Fred A. Litwin Family Centre in Genetic Medicine, University Health Network, Toronto, ON, Canada
5Prenatal Diagnosis and Medical Genetics Program, Department of Obstetrics and Gynecology, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada
6Peter Munk Cardiac Centre, Department of Electrophysiology, Toronto General Hospital, Toronto, ON, Canada
7Labatt family Heart Centre, Department of Paediatrics, The Hospital for Sick Children, Toronto, ON, Canada
Inherited arrhythmia syndromes are known to be associated with sudden cardiac death (SCD), a major cause of mortality in Western and European countries. Genetic testing can provide molecular confirmation of a clinically suspected inherited arrhythmia syndrome, allowing for cascade screening for all at-risk first-degree relatives. Disclosure of diagnostic or genetic information has been well studied in other areas of genetics, but is currently limited in the field of inherited arrhythmia syndromes. Our study aimed to gain insight regarding the self-reported rate of disclosure as well as to investigate patient attitudes and behaviors towards sharing this information with at-risk family members. A questionnaire consisting of multiple-choice questions, likert scales, and qualitative questions was mailed to eligible participants. Descriptive statistical analysis as well as thematic content analysis was used to analyze the data. A total of 112/313 participants completed the survey representing a 36% response rate. Of the 112 respondents, 104 reported having genetic testing, 7 reported not having genetic testing, and 1 was unsure. For participants who underwent genetic testing, 101/104 (97%) reported disclosing their results to at least 1 at-risk family member. Additionally, 87/112 (78%) reported that at least 1 at-risk family member had been clinically evaluated for an inherited arrhythmia syndrome. In total, 280 first degree relatives and 117 second degree relatives were evaluated by way of cascade screening. Common motivations for sharing genetic information included: 1) Wanting to help relatives make medical decisions; 2) Wanting to provide relatives with information about their risk; and 3) Feeling obligated to share. Common barriers included: 1) Information was emotionally difficult to share; 2) Information was complex/patients did not know what to say; and 3) Family estrangement. Our data provide baseline knowledge on the self-reported rate of disclosure as well as several new themes in regards to motivations and barriers surrounding sharing this information in patients with inherited arrhythmia syndromes.
GC-137 Exome sequencing for Adults in Toronto, Canada
WATKINS Nicholas, GU Jessica, ZAKOOR Kathleen, CARE Melanie, FAGHFOURY Hanna, HORSBURGH Sheri, MORAR Oana, MOREL Chantal, MURPHY Jillian, SILVER Josh, SO Joyce, SZYBOWSKA Marta, LERNER-ELLIS Jordan
Affiliations: Sinai Health System, Toronto
Advances in genomic research and DNA sequencing technologies have revolutionized our understanding of human genetic variation associated with disease, as well as our ability to provide a molecular diagnosis for individuals with complex medical issues. For such individuals, whole exome sequencing (WES) allows clinicians to circumvent the step-wise targeted single-gene or gene panel tests in favour of a more cost- and time-effective diagnostic tool. Currently, WES is not yet clinically available in Canadian diagnostic laboratories, but individuals may receive approval for testing outside of Canada. In Ontario, the Ministry of Health and Long-Term Care determines eligibility for out-of-country clinical WES. However, adults with suspected genetic conditions rarely meet eligibility criteria and are often denied coverage for this test. This lack of access has significant clinical implications. The Fred A. Litwin Family Centre in Genetic Medicine, Toronto’s primary adult genetics clinic, services over 1,600 patients annually, with fewer than 30% reaching a diagnosis despite extensive diagnostic investigations. As a result, providing guidance for prognosis, appropriate clinical management and treatment, and recurrence risk for these individuals and their family members is an enormous challenge. The Advanced Molecular Diagnostics Laboratory of Mount Sinai Hospital has undertaken a research initiative to provide WES to adults with suspected genetic etiologies for their clinical features, but for whom standard genetic testing results were unrevealing. Individuals for this study were enrolled from one of three genetics clinics associated with Mount Sinai Hospital in Toronto, Ontario: 1) the Fred A. Litwin Family Centre in Genetic Medicine, 2) the Marvelle Koffler Breast Centre, and 3) the Familial Gastrointestinal Cancer Registry. Informed consent was obtained for individuals and, if available, families for the study, and exome data were analyzed for variants related to the reason for referral. Only clinically significant variants and variants of uncertain significance relevant to the reason for referral were reported; incidental findings were reported at the request of the referring clinician. As of November 2016, 39 families comprising of 81 individuals have been enrolled in the study. Here, we report on our results and experience with WES to date, including our diagnostic yield with case examples, challenges, implications, and recommendations for future studies and eligibility for whole exome sequencing in Ontario.
GC-138 Assessing the impact of universal Lynch syndrome screening in British Columbia
LEE, Petra WC, SAMIMI, Setareh, BEDARD, Angela C, BEDARD, James EJ, GILKS, C Blake, SCHAEFFER, David F., WOLBER, Robert, KWON, Janice, LIM, Howard J, SUN, Sophie, SCHRADER, Kasmintan A
Affiliations: University of the Fraser Valley, Abbotsford
Referral for assessment of Lynch syndrome (LS) has traditionally required patients to meet a combination of personal and family medical history criteria, such as the Amsterdam criteria. A recent large critique of the Amsterdam II criteria indicated that up to 70% of people with LS do not meet referral criteria for assessment. Some jurisdictions are performing universal screening for LS on colorectal and endometrial tumour samples; universal screening uses immunohistochemistry to screen the tumour samples for the presence of two to four mismatch repair proteins that are associated with LS. At present, the Vancouver Coastal Health Authority of BC performs universal screening for LS on all cases of colorectal (CRC) and endometrial cancer (EC). An analysis of all patients with resected CRC who had reflex IHC MMR testing from January 2012 to July 2013 was previously performed. Out of 1500 cases, 198 had an abnormal screen; of the 198, 98 were BRAF wild type or showed the MSH2, MSH6, or PMS2 protein absent, and 46 of the 98 were referred to the provincial hereditary cancer program for further testing. The present study aims to characterize the effect of universal screening in British Columbia, with comparison to patients referred by traditional criteria from January 2012 to present. These data will include analysis of patients referred since the introduction of a next-generation sequencing multi-gene panel in 2014 by the provincial hereditary cancer program. We will present aggregate results from our experience for those who have received universal screening versus referral by traditional criteria. We will present referral rates, mutation detection rates, and PREMM scores for hereditary cancer risk for both the patients referred through universal screening and patients referred by other medical/family history criteria. We will determine if patients referred by universal screening would have met other criteria for referral. Results from this ascertainment will help provide important insights into the performance of universal LS screening in a population-based Canadian setting and may provide evidence to expand the utilization of universal screening to more jurisdictions across the country. In addition these data will help inform the impact of the anticipated widespread tumour testing following demonstration of tumour mismatch-repair status in predicting clinical benefit of immune checkpoint blockade and a recent FDA approval for this indication.
GC-139 Short interpregnancy intervals, maternal folate levels, and infants born small for gestational age: preliminary data to guide genetic counselling practice
CARRION, Prescilla1*, CHEN, Buffy1*, GREWAL, Ravneet1,2, INGLIS, Angela1,2, HIPPMAN, Catriona1,3, MORRIS, Emily1,2, ANDRIGHETTI, Heather1, ALBERT, Arianne3, and AUSTIN, Jehannine1,2
* these two authors contributed equally to this work
Affiliations: 1Department of Psychiatry, University of British Columbia, Vancouver, British Columbia, Canada
2Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada
3Women’s Health Research Institute, BC Women’s Hospital and Health Centre, Vancouver, Canada
Background: Short interpregnancy intervals (SIPI) have been associated with increased risks for adverse neonatal outcomes including preterm delivery and infants small for gestational age (SGA). It has been suggested that mechanistically, adverse neonatal outcomes after SIPI arise due to insufficient recovery of depleted maternal folate levels prior to the second pregnancy. However, empirical data are lacking regarding physiological folate levels in pregnant women with SIPI, and relationships between quantified physiological folate levels and outcomes like SGA.
Purpose: Therefore, we sought to test two hypotheses, specifically that compared to controls, women with SIPI would: a) have lower red blood cell folate (RBCF) levels and b) be more likely to have SGA infants (defined as <10th percentile).
Methods: Using data collected in BC, Canada for a larger study on perinatal psychopathology, we documented supplementation use and compared prenatal RBCF levels and proportion of SGA infants between women with SIPI (second child conceived ≤24 months after previous birth, n=26) and matched controls (no previous pregnancies, or >24 months between pregnancies, n=52).
Results: There were no significant differences in either mean RBCF levels (Welch’s t-test, p = 0.7) or proportion of SGA infants (Fisher’s exact test, p = 0.7) between women with SIPI and matched controls.
Conclusion: We report the first data about RBCF levels in the context of SIPI. If confirmed, our finding of no relationship between these variables in this population suggests that continued folic acid (FA) supplementation following an initial pregnancy mitigates folate depletion; furthermore, if validated, these data could inform genetic counsellors’ discussions of FA supplementation in SIPI pregnancies and potentially support recommending FA supplementation in the postpartum to reduce the risk for adverse outcomes following SIPI. We found no relationship between SIPI and SGA.
GC-143 Keep in touch: Recontacting breast cancer patients for updated genetic testing
NEIL Sarah1,2, MCCUAIG Jeanna1,3, KIM Raymond H4,5, CHITAYAT David1,2,6, SHUMAN Cheryl1,2, RANDALL ARMEL Susan1,3
Affiliations: 1Department of Molecular Genetics, University of Toronto, Toronto, ON.
2Division of Clinical and Metabolic Genetics, Department of Pediatrics, The Hospital for Sick Children, Toronto, ON.
3Familial Breast and Ovarian Cancer Clinic, Department of Gynecologic Oncology, Princess Margaret Cancer Centre, Toronto, ON.
4Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, ON.
5Department of Medicine, University of Toronto, Toronto, ON.
6Prenatal Diagnosis and Medical Genetics Program, Department of Obstetrics and Gynecology, Mount Sinai Hospital, University of Toronto, Toronto, ON.
Background: In an era of rapidly-advancing and increasingly cost-effective genetic testing technologies, discussion has arisen regarding the duty of the clinician to recontact patients for updated testing. Currently, no formal guidelines exist, nor is there a clear consensus on the legal versus ethical implications of a ‘duty’ to recontact. Studies suggest that clinicians agree that recontacting patients is ethically appropriate, but feel that it may be prohibitively challenging in practice. However, there is limited research exploring the responses when patients are indeed recontacted. A study in our clinic, reviewing genetic test results in male and young female breast cancer patients, offered a unique opportunity to examine the outcome of recontacting patients for multi-gene panel testing in a breast cancer setting.
Methods: The clinic database was queried to identify female breast cancer patients diagnosed ≤35 years of age and all male breast cancer patients. Those individuals who had a negative BRCA1/BRCA2 test result, but had not yet completed multi-gene panel testing, were mailed a letter inviting them to return to the clinic. A total of 92 females and 23 males meeting these criteria were identified, 6 of whom were excluded because they were deceased, palliative at last contact, or had moved to an unknown address. The remaining 86 females and 23 males were mailed a letter explaining that they were eligible for further genetic testing, and that they could contact the clinic to arrange an appointment if interested.
Results: Of the 109 letters mailed, 3 (2 females and 1 male) were returned and 15 (14 females and 1 male) contacted the clinic to book appointments for testing. Excluding the returned letters, an overall response rate of 14.2% was observed, with 4.5% of males and 16.3% of females responding. Overall, 11 female patients chose to proceed with testing, one declined, and two did not attend their appointment. The single male that responded to the invitation has a pending clinic visit.
Conclusions: Given that past research demonstrates that most patients are amenable to being recontacted by their clinicians, the observed response rate in our study was considerably lower than expected. To our knowledge, however, this is the first study to examine the response rate of patients offered multi-gene panel testing, and research regarding patient perspectives of panel testing is currently limited. Our results suggest that additional research is warranted to determine what motivates patients to respond to recontact invitations, and subsequently, what barriers might exist.
GC-144 Prenatal genetic testing for Huntington disease: ethical considerations
ASHTIANI, Setareh1, DOONANCO Jasmine, SUCHOWERSKY Oksana
Affiliations: 1Department of Medicine (Neurology), University of Alberta, Edmonton
The predictive genetic testing protocol for Huntington disease (HD) is well-established and is offered to individuals at 50% or 25% risk for the condition. The international guidelines for predictive testing are followed. Direct prenatal testing is offered to couples when the fetus is at 50% risk, after extensive counseling and with the intention of termination of an affected pregnancy. We present the case of a woman of child-bearing age who asked for testing her fetus for the HD-causing expansion, shortly after completing the predictive testing process where she learned she carried the mutation. Extensive counseling identified that the patient’s desire to know the information was solely for planning future pregnancies, and that the pregnancy would be continued regardless of the gene-status of the fetus. As this was contrary to our current guidelines, opinions were obtained from the hospital ethicist and other HD clinicians/geneticists. Ethical considerations included that a mutation-positive result can harm more than help a child, through potential impacts such as alteration of self-image and psychological distress. Other considerations include the right of their future child to decide whether or not to undergo pre-symptomatic test in adulthood. The principle of respect for autonomy dictates that individuals make these decisions for themselves. Thus, some at-risk asymptomatic adults may decide to have predictive testing for HD, while research and our team’s clinical experience suggest that most at-risk individuals decide against predictive genetic testing. Following significant discussions and ethical considerations, the decision was that in spite of the patient’s wishes, prenatal testing could not be offered as it would be the same as testing an asymptomatic child for HD.
GC-145 Genetic counsellors’ perspectives on the telegenetics service delivery model: why, when, how?
MACDONALD Shelley1,2, MURPHY Jillian3, WASIM Syed2,3, SHUMAN Cheryl1,2, ROBART Sarah4, CHITAYAT David1,2,5, BABINEAU STURK Tina6
Affiliations: 1Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada
2Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, ON, Canada
3Fred A. Litwin Family Centre in Genetic Medicine, University Health Network, Toronto, ON, Canada
4Clinical Research Network: Genetics, Great Ormond Street Hospital for Children, London, UK
5Prenatal Diagnosis and Medical Genetics Program, Department of Obstetrics and Gynecology, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada
6LifeLabs Genetics, Toronto, ON, Canada
Alternatives to in-person genetic counselling help reduce barriers to equitable patient care,
particularly for patients living in remote locations. One option is the use of videoconferencing or web-based audiovisual technologies (“telegenetics”). Overall, favourable opinions and outcomes have been reported for patients who have used telegenetics; however, there is less information available regarding the perception of genetic counsellors, particularly from those who have yet to use this service delivery model. A total of 254 genetic counsellors responded to our online survey and provided information on the perceived benefits and limitations of telegenetics, barriers to its implementation and use, appropriateness and efficacy of this model, and needs for training and support specific to using this model. In general, respondents reported confidence in using telegenetics and felt it was appropriate to offer for a variety of indications, but considered it significantly less effective than in-person appointments for many of the tasks routinely performed by genetic counsellors. Specifically, telegenetics was rated as less effective and least appropriate for positive results, uncertain results, and psychosocial counselling. We also identified several significant differences in responses based on genetic counselling specialties, attitude toward telegenetics, and previous use of telegenetics. Our results suggest that direct experience with telegenetics is likely to play a role in gaining confidence using this model, and show that most genetic counsellors value training and educational opportunities specific to using telegenetics. These insights into the perspectives of current and potential users of telegenetics contribute to its implementation as a strategy to increase access to genetic counselling services while maintaining high standards of care.
GC-146 Group Counselling for the Familial Colon Cancer Clinic (FCCC)
GREWAL Sonya, NOREAU-HEISZ Danielle, KIDD Meridith, AMBUS Ingrid
Affiliations: North York General Hospital, Toronto, ON
Objectives: North York General Hospital Genetics Program is a large community-based genetics service providing approximately 5500 new patient visits annually. Over the years, there has been an increase in the number of patients being referred for a personal or family history of colon cancer or colon polyps. Originally patients referred to the FCCC were given appointments within 2-3 months during various times of the week. Given the increased number of patients being referred and no increase in resources, we decided to introduce a group counselling session for our FCCC patients to ensure patients were seen in a timely manner. The objective of the group counselling approach for the FCCC is to maintain a 2 month patient appointment turnaround time; use genetic counsellor resources more efficiently, while still providing the best care to the patient and to simplify patient information provided to the patient and referring physician.
Methodology: We collected data to estimate the number of patients referred for a personal or family history of colon cancer over the course of a year. The data was collected to identify the number of group counselling clinics needed yearly, the number of patients to be booked in each clinic and the number of genetic counsellors involved. The group counselling approach is a two part appointment done over the course of a morning. The first part is a group information / presentation session. The second part is a one on one meeting with a genetic counsellor. The clinic was evaluated over 9 months and a patient advisor was recruited to review our group presentation and the information sheets that are provided to each patient who goes through our group counselling sessions.
Summary of results: Our group counselling model for the FCCC was initiated in November 2015. Patients referred for a personal and / or family history of colon cancer or colon polyps were included. Patients who were recently diagnosed with colon cancer and undergoing chemotherapy or were referred for predictive testing were excluded from the group. The clinic was done on the fourth Wednesday of each month. Six patients were booked and three genetic counsellors were involved in each clinic. Following the 9 month evaluation it was estimated that the group presentation took approximately 30 minutes and the one on one meeting with a genetic counsellor took approximately 18 minutes. The patient advisor feedback included suggestion regarding clarity of colon polyposis syndromes and reducing technical terms.
Conclusions: By using a group counselling model with standardized clinic times, we have maintained a 2 month patient appointment turnaround time while also ensuring patients are booked more efficiently and cancellation spots are filled more easily. Standardized information sheets and letters have also contributed to greater efficiency in the clinic.
GC-147 Unique Syndactyly in a case of Smith-Lemli-Opitz Syndrome
CLARKE Stephanie, MARLES Sandra, PHILLIPS Susan, MENTICOGLOU Savas, BERNIER Mark
Affiliations: WRHA Genetics & Metabolism Program, University of Manitoba, Winnipeg, MB
Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive condition caused by a defect in the cholesterol synthesis pathway. Previous literature describing the features of SLOS report mainly 2-3 Y-shaped syndactyly of the toes. We present a confirmed case of SLOS with a presentation of syndactyly that differs from the previously reported literature.
A 36-year-old woman presented at 17 weeks and 5 days gestation with a positive maternal serum screen for SLOS. Family history was unremarkable and consanguinity was denied. An earlier ultrasound had confirmed the gestational age with a normal nuchal translucency measurement. An ultrasound was performed which reported multiple anomalies including oligohydramnios, absent bladder, a likely cardiac defect and polydactyly. An amniocentesis was attempted however only 0.5cc of amniotic fluid was obtained. QF-PCR analysis reported a normal complement of chromosomes 13, 18 and 21 in a male fetus. Induction of labor was requested and samples of cardiac blood and fibroblasts were collected after birth.
The autopsy reported multiple anomalies including: prominent maxillary alveolar processes, cleft palate, low set and posteriorly-rotated ears, limb contractures, coarctation of the aorta, atrial and ventricular septal defects, pulmonary hypoplasia, absent kidneys and ureters with a hypoplastic bladder, ambiguous genitalia, bilateral post-axial polydactyly of the hands, hypospadias, and left clubfoot.
The feet had partial 2-3 syndactyly and full syndactyly of digits 3-4 on examination. X-rays of the fetal feet showed soft tissue syndactyly between the third to fifth toes with bilateral post-axial polydactyly with two small ossified phalanges in each extra toe.
This fetus had features that were suspicious for SLOS, however the full 3-4 syndactyly of the feet was uncharacteristic based on previously described features and expert opinion. The diagnosis was confirmed by elevated 7-dehydrocholesterol in the fetal cardiac blood sample and subsequent molecular testing of the DHCR7 gene which revealed two previously described pathogenic variants in the DHCR7 gene: c.964-1G>C and c.452G>A (appropriate parental segregation was confirmed).
To our knowledge, there have been no other reported cases of SLOS with this type of syndactyly. This example should prompt clinicians to keep SLOS in the differential diagnosis for fetuses or children with other forms of syndactyly.
GC-151 Strategies to Maximize Clinic Efficiency: Our experience to enhance patient care in a cancer genetics setting
BRYKSA Veronica, JUNG Jack
Affiliations: Erie St. Clair Regional Cancer Program, Windsor, ON.
Objectives: Cancer genetics clinics across Canada are bursting at the seams with patient referrals, which has resulted in long appointment wait times. To mitigate wait times, we implemented two strategies to directly impact genetic counsellor work-load and decrease patient wait times. The first strategy was the implementation of an online family history questionnaire (FHQ). The second strategy was to enforce stricter rules for the return of the family history questionnaire in two formats – paper-based or online. Our study objectives were to evaluate the effect of the aforementioned strategies on various wait times.
Method: The implementation of an online family history tool included obtaining verbal consent from patients at first point of contact after physician referral. Patients verbalizing a preference for the online FHQ tool were emailed a questionnaire link through a third-party website inviting them to complete the questionnaire within one month. We compared the average wait time for an appointment between people who completed the online tool between vs. those who completed the paper-based family history questionnaire, throughout a one-year period.
Our second clinic efficiency strategy was to implement a new FHQ return process. Patients (intervention group) were given four weeks (compared to previous three months) to complete the FHQ (paper-based or online). If the FHQ was not returned within four weeks, the patient received a reminder call at week four and then again at week five. After six weeks, their chart was closed. To evaluate the effect of this change in process, we compared the average appointment wait times for patients referred between April 2016 to September 2016 (pre-intervention group) to our intervention group (November 2016 to April 2017).
Summary of Results: At this time only preliminary data analysis is available, which indicates patients given a four-week deadline are returning their FHQ within an average of 12 days, whereas those given a deadline of twelve-weeks are returning their FHQ within an average of 47 days. Patients completing the FHQ tool online had a faster response time and resultantly decreased wait-time to genetic counselling. Complete data will be presented if accepted, including overall wait time reduction measures and response rate comparisons for both strategies. Discussion of results will include actionable strategies to enhance clinic efficiency.
Conclusion: The implementation of an online family history tool and adding firmer deadlines for return of FHQ has improved response-rates and decreased the length of time from referral to appointment in a cancer genetics setting. Using an online family history tool enhances patient care by decreasing wait times to genetic counselling.