Poster presentations will take place on Thursday October 11 from 6:00 p.m. to 7:30 p.m.



At the end of this session, participants will be able to:

  • Identify ongoing research around the country.
  • Communicate with colleagues from around the country.
  • Promote research collaboration.
  • Extend opportunities for members to discuss research and clinical work in a supportive, collaborative.


GC-101 Detection rates for hereditary kidney cancer testing in Ontario – One institution’s experience


1UHN Genome Diagnostics, Department of Clinical Laboratory Genetics, University Health Network, Toronto, Canada.

Objectives: Kidney cancer is the 10th most common cancer in Canada with 6,600 new diagnoses each year. Renal cell carcinoma (RCC) comprises approximately 90% of all kidney cancer diagnoses and includes the most common histological subtypes of clear cell RCC, papillary RCC, and chromophobe RCC. Although the majority of cases are sporadic, between 4%-8% of all cases have a hereditary predisposition due to inherited genetic variants. In 2016, the UHN Genome Diagnostics Laboratory began Ontario-wide genetic testing for hereditary renal cancers.

Methodology: Between February 2016 to May 2018, 92 individuals were referred for hereditary kidney cancer testing. DNA was extracted from peripheral blood lymphocytes and analyzed by a custom hybrid capture next-generation sequencing (NGS) Hereditary Cancer Panel (HCP) sequenced on the Illumina NextSeq platform. A custom bioinformatics pipeline was used to perform sequence alignment using BWA-MEM and variant calling based on GATK. Cartagenia NGS Bench software was used to assist with variant annotation. The HCP v1 included the following genes associated with hereditary renal cancer: FH, FLCN, MET, MITF, PTEN, SDHA, SDHC, TP53, TSC1, TSC2 and VHL. In March 2018, the HCP v1 was updated to include the following additional renal cancer genes: BAP1, CDC73, DICER1, SDHAF2, SDHB, SDHD and TMEM127 (now HCP v2).

Results: Of 92 individuals tested to date, disease-causing variants were found in 9 individuals, including pathogenic or likely pathogenic variants in the following genes: FH (3), MITF (3), TSC2 (2) and PTEN (1). Interestingly, the same likely pathogenic MITF variant (MITF c. 952G>A (p.Glu318Lys)) was identified in 3 cases, indicating that this may be a frequently occurring mutation in association with risk for hereditary renal cancer. Variants of uncertain significance (VOUS) were identified in an additional 16 cases, primarily occurring in the FH (3) and FLCN (3) genes. We did not identify variants in the VHL gene in this patient cohort.

Conclusion: Our current detection rate for disease-causing variants in hereditary renal cancer patients tested at our centre is 9.8% (9/92 cases). The detection of the same likely pathogenic MITF variant in 33% (3/9) of variant-positive cases may suggest this is a recurring variant within the Ontario population, while detection of 17% (16/92) cases with VOUS presents challenges for genetic counselling of hereditary renal cancers.


GC-102 Addressing barriers for rapid cancer genetic counselling: triage system for treatment-focused genetic testing

MORGAN Amanda K.1, WONG Nora

1McGill University, Montreal, Canada.

As treatment-focused genetic testing becomes more prevalent so does the need for genetic departments to prioritize patients by both utility of genetic counselling and by the likelihood of identifying a mutation within a given family. A newly implemented hereditary breast and ovarian cancer (HBOC) referral triage system at the Jewish General Hospital (Montreal, QC, Canada) aims to decrease turnaround time (TAT) from referral to result giving for treatment-focused patients by assigning wait-time targets to new referrals. A retrospective chart review was conducted to assess the performance of the new referral triage system. Eligibility for the study included all referrals meeting HBOC referral criteria and patients who were granted special consideration by the triage team between January 2015 and August 2017. Patient demographics, referral information, wait-times, clinical characteristics, and results of genetic testing were summarized for 567 referrals. Analysis with a Chi-Square goodness-of-fit model revealed all referral criteria are enriching carrier frequency to the expected 10% carrier rate. Target wait-times for first appointments are being met for referrals assigned urgent (M = 16.43, Mdn = 9 days) and under 3 months (M = 68.16, Mdn = 48 days). This study provides the first evidence for the effectiveness of the new triage system at the Jewish General Hospital.


GC-103 Novel pathogenic variant in the COL1A1 gene leading to arthrochalasia ehlers danlos syndrome (aEDS)

JOHNSTONE Brittney1, O’CONNOR Constance2, DAMSEH Nadirah3, SCHWARTZ Sarah2, KANNU Peter3, MENDOZA-LONDONO Roberto3

1Department of Genetic Counselling, The Hospital for Sick Children, Toronto, Canada.
2Department of Pediatrics, The Hospital for Sick Children, Toronto, Canada.
3Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, Canada.

Arthrochalasia EDS (aEDS) is a rare subtype of EDS characterized by congenital bilateral hip dislocation, severe generalized joint hypermobility with multiple dislocations/subluxations, and skin hyperextensibility. Other features may include muscle hypotonia, kyphoscoliosis, mild osteopenia, tissue fragility with atrophic scarring, and easy bruising. This condition is inherited in an autosomal dominant manner. The molecular basis for aEDS is heterozygous pathogenic variants in either COL1A1 or COL1A2 that cause entire or partial loss of exon 6 of either gene. We describe a novel pathogenic variant in the COL1A1 gene (c.472-1G>T: IVS5-1G>T), which is expected to interfere with the canonical splice acceptor site in intron 5, resulting in abnormal splicing.

The patient was a 6 month old girl with hypotonia, joint hypermobility, and redundant, lax skin. Past medical history was significant for atrial septal defect and patent ductus arteriosus. Her parents were non-consanguineous and of European descent. Family history was non-contributory. The patient was the result of an uncomplicated pregnancy and born at 40 weeks’ gestation. Birth weight was 4.14 kg.

On physical exam, the patient was on the tenth centile for weight and first centile for length. She had generalized joint hypermobility (Beighton score: 8/9); increased range of motion was noted in the hips. There were excessive skin folds over the anterior fontanelle and abnormal scar-like tissue at the left forehead. She had bilateral bitemporal narrowing, frontal bossing, retrognathia, depressed nasal bridge, hypertolerism, short neck, upslanting papebral fissures, and blue sclera. Fingers were short with bilateral camptodactyly at interphalangeal joints. She had bilateral clubfeet. Redundant abdominal skin with umbilical hernia and diastasis recti were present. Ultrasound imaging revealed chronic complete dislocation of both hips with significant pulvinar hypertrophy and displaced labrums. Given our patient’s phenotypic features and the pathogenic variant in COL1A1, a diagnosis of aEDS was confirmed.

Splice site variants result in aberrant gene products that lead to decreased protein production or the production of a protein that lacks an important domain to allow proper functioning. Advances in therapies for genetic disorders have shown that gene editing and gene expression modulation therapies hold promise in the management of these disorders. aEDS may be an ideal subtype of EDS to investigate the effectiveness of splicing modulating therapies.


GC-104 Telephone (early) versus examination (late) disclosure of prognostic uveal melanoma results: Associations with anxiety and depression


1Dynacare, Brampton, Ontario, Canada.
2Wills Eye Hospital, Philadelphia, Pennsylvania, U.S.A.
3University of California Los Angeles (UCLA), Los Angeles, California, U.S.A.

Objective: Molecular prognostic testing of the primary tumor predicts survival in patients with uveal melanoma. Patients are typically informed of the results of their prognostic test by their ocular surgeon at a follow up appointment approximately 4-6 weeks after surgery. Discussing prognostic results can be psychologically challenging, may decrease effectiveness of treatment planning and be both time consuming and difficult for both surgeon and patient. In this report we sought to demonstrate the feasibility of prognostic test result disclosure by telephone from a medical professional, trained in counseling and genetics prior to surgical follow up appointment.

Methodology: A prospective study of anxiety levels, duration of anxiety and duration of follow up appointment were examined in two cohorts of patients. The first cohort (telephone cohort@ 3-4 weeks) included patients who had molecular prognostic test results reviewed by telephone prior to their first follow up appointment after surgery. The second cohort (examination cohort @ 4-6 weeks) included patients who had not yet reviewed results of their molecular prognostic test prior to their first follow up appointment. Anxiety and depression were measured using the Hospital Anxiety & Depression scale in both cohorts before and after each appointment. Duration of each appointment was measured.

Summary: We found improvement in anxiety levels when prognostic results were delivered earlier with medical professionals trained for counseling and genetics compared to anxiety levels when results were given at a clinical follow-up evaluation. Clinical follow up appointments were shorter and could be more focused on post-operative clinical outcomes rather than genetic results.

Conclusion: Delivering prognostic results by telephone and prior to the post-surgical follow up examination may improve anxiety levels in patients and improve patient satisfaction.


GC-105 Cascade Genetic Testing of Relatives for Hereditary Cancer Risk: Results of an Online Initiative

Cynthia Handford, M.S., C.G.C1, Jennifer L. Caswell-Jin, M.D.2, Anjali D. Zimmer, Ph.D.1, Will Stedden, Ph.D.1, Kerry E. Kingham, M.S., C.G.C.2, Alicia Y. Zhou, Ph.D.2, Allison W. Kurian, M.D., M.Sc.2,3

1Color Genomics, Burlingame, CA.
2Department of Medicine, Stanford University School of Medicine, Stanford, CA.
3Department of Health Research & Policy, Stanford University School of Medicine, Stanford, CA.

To achieve the goal of genetically-targeted primary disease prevention, testing for an identified familial mutation must extend to unaffected relatives in a process known as “cascade testing”. However, there are major barriers to effective cascade testing of relatives, including cost, insurance constraints, and confidentiality laws. We evaluated the results of an online initiative in which carriers of one of 30 cancer-associated genes, or their first-degree relatives, could offer low-cost testing to at-risk first-degree relatives. First degree relatives were invited by emails directly from the testing laboratory.

In the first year, 1,101 applicants invited 2,280 first-degree relatives to participate in genetic testing. Of invited relatives, 48% underwent genetic testing, and 12% who tested positive continued the cascade by inviting additional relatives to test. Of first degree relatives who tested, 48% carried the identified familial pathogenic variant (consistent with their stated first-degree genetic relationship to carriers). Interestingly, five percent (5%) of tested relatives had a pathogenic variant in a different gene from the known familial one. Of these unexpected pathogenic variants, 43% were in low-penetrance alleles (specifically MUTYH heterozygotes, APC I1307K, and CHEK2 I157T), 38% were in less well-characterized cancer risk genes (specifically ATM, MITF, BARD1, CHEK2, RAD51C, BRIP1, and NBN), and 19% were in syndromic genes (specifically BRCA1/2, MLH1, MSH2, MSH6, and PMS2). Finally, 17% had a variant of uncertain significance in any gene. These results suggest that an online, low-cost program is an effective approach to implementing cascade testing, and that 5% of the general population may carry a pathogenic variant in one of 30 cancer-associated genes.


GC-106 Genetic carrier testing for hereditary cancer in British Columbia and Yukon: an overview of the past 20 years

BRALEY, Eryn, BEDARD, Angela, BEARD, Vivienne, ASRAT, Mary-Jill, AUBERTIN, Gudrun, BINNINGTON, Kristin, CREMIN, Carol, COMPTON, Katie, CREIGHTON, Susan, LOHN, Zoe, HEIDARY, Nili, KAURAH, Pardeep, MCCULLUM, Mary, MINDLIN, Allison, NUK, Jennifer, O’LOUGHLIN, Melanie, PETERSEN, Tammy, PORTIGAL-TODD, Cheryl, SCOTT, Jenna, ST-MARTIN, Genevieve, THOMAS, Ruth, THOMPSON, Jennifer, BEDARD, James, SCHRADER, Kasmintan, SUN, Sophie

University of the Fraser Valley, Abbotsford, BC.

Introduction: Genetic carrier testing for hereditary cancer is a highly accurate and cost-effective method for identifying individuals at high risk for cancer, who will significantly benefit from increased screening and/or prevention methods. BC Cancer’s Hereditary Cancer Program has provided the vast majority of the cancer genetic counselling service for the population of British Columbia and the Yukon for the past 22 years. This study is a descriptive analysis of genetic carrier testing facilitated by the program in its first 20 years of operation.

Methods: The HCP’s program database was queried for all carrier tests facilitated between January 1, 1997 and December 31, 2016. The compiled dataset consisted of variables including gender, age, postal code, referral source, genes tested, and cancer diagnoses. Descriptive statistics were computed; mean and standard deviation is reported for continuous variables and proportion is reported for categorical variables.

Results: This analysis revealed that 3605 individuals, from 1709 families, have had carrier testing with our program over the past 20 years; 47 individuals received greater than one carrier test. 55% of test results were positive and 45% of results were negative. Demographic analysis showed 72% of those tested were female and 28% were male; and 84% of tests were for individuals living in urban areas compared to 13% of tests were for those living in a rural area, which is in keeping with BC Census data. The mean age of individuals seeking carrier testing was 46.6 (SD = 17). The majority of carrier tests were for BRCA1 and BRCA2 (68%), followed by 17% for Lynch Syndrome, and 15% for other genes. The proportion of referrals for appointments from family doctors (33%) was close to that from self-referrals (37%). Furthermore, carrier testing has steadily increased over time, with 83% of tests completed in the second decade. Cancer diagnoses for individuals who received carrier testing will be analyzed, including a comparison of the timing of the diagnoses versus the timing of the genetic test results.

Conclusion: Significantly more females than males have received carrier testing for hereditary cancer syndromes, highlighting the need to research what is normative health seeking behavior for males and potential barriers to testing for them. We also found that the average age of testing is 46, which is considerably older than the age by which most hereditary cancer screening protocols begin, demonstrating another area of opportunity. By deepening our understanding of the program’s experience in its first 20 years, we are able to identify potential gaps in service, inspire new avenues for exploration, and serve as a benchmark for new initiatives going forward.


GC-107 Improving timely access to genetic counseling for oncology patients through an integrated telehealth genetic counseling service


GeneMatters, Minneapolis, MN.

In August of 2017, a cancer center in Omaha, Nebraska (Nebraska Methodist Hospital; Methodist Estabrook Cancer Center), added a telehealth genetic counseling service to their existing clinical model. Prior to using telehealth services, the cancer center had one on-site clinical GC to see all oncology patients referred for genetic counseling, with the availability of this genetic counselor being limited to one day per week. It was hypothesized that utilization of telehealth for genetic counseling services would improve access to care for patients in need of genetic counseling in the oncology setting, particularly in this location, where there was limited access to genetic counselors. Quantitative data collected by the cancer center from the six months prior to using telehealth genetic counseling services was compared to data from six months after the implementation of telehealth genetic counseling services. Qualitative data was also collected using open-ended questions. Areas of improvement in the clinical setting and patient care included: 1) An increase in the number of new patient referrals to the cancer center (an approximate 28% increase per month), 2) A 50% increase in number of patients seen per week for genetic counseling 3.) Reduced wait time for returning patients to obtain a second genetic counseling appointment (reduced from approximately two weeks to one week with use of telehealth service, and 4) Increased productivity/decreased work burden for the one on-site clinical GC (turn-around time for completion of GC letters was improved). In conclusion, the addition of a telehealth service, which provided availability for genetic counseling with remote genetic counselors, improved access to care for oncology patients in the clinical/hospital setting. Telehealth genetic counseling could therefore be considered a useful model which can be added in the clinical setting, especially in clinics and hospitals where access to genetic counseling services may be limited.


GC-108 Novel mutations in GOSR2 add to the phenotypic spectrum of progressive myoclonus epilepsy 6

GAMBIN Kristin1,3, MHANNI Aizeddin1,2,3, LEUNG Edward2,4

Departments of Biochemistry and Medical Genetics
1Paediatric and Child Health
2University of Manitoba; Program of Genetics and Metabolism
3Section of Pediatric Neurology
4Children’s Hospital, Winnipeg, Manitoba, Canada.

Individuals with homozygous or compound heterozygous mutations in GOSR2 are related to progressive myoclonus epilepsy (PME) 6 (OMIM#614018). We describe a 15 year-old female who was identified to be a compound heterozygote for two novel variants of uncertain significance in GOSR2. To our knowledge, less than 20 individuals have been described in the literature, with the majority of them being homozygous for the c.430G>T mutation.

Our patient underwent an epileptic encephalopathy panel molecular testing and was identified to have two GOSR2 (NM_004287.3) variants, c.557_584del (p.Ala186Valfs*5) and c.364G>A (p.Glu122Lys). Parental testing confirmed the two variants to be in trans configuration. In silico prediction programs SIFT, PolyPhen2, MutationTaster predict the c.364G>A variant to be “tolerated”, “benign”, and “disease causing”, respectively. While in silico prediction programs were not completed for the c.557_584del variant, it is suspected that there would be a deleterious effect due to a frame shift.

The current literature describes a limited phenotypic spectrum, one of which paints a picture of a severe and progressive phenotype. In contrast our patient at the age of 15 years presents with some of the classical features of PME6, but is more mildly affected. We provide this clinical summary and review of the published patients to summarize the reported phenotype of this disorder to date to allow for appropriate genetic counselling for other patients and their families.


GC-109 Implementing PP4 in CHEO-Specific FBN1 Variant Interpretation

LITTLE Leichelle; EDIAE Grace; NFONSAM Landry; BRONICKI Lucas

CHEO, Ottawa

Background: The American College of Medical Genetics and Genomics (ACMG) created guidelines for classifying variants based on criteria using typical types of variant evidence. A patient’s phenotype, for example, can be considered supporting evidence for pathogenicity (known as category “PP4”) if the patient has a well-defined syndrome with little overlap with other clinical presentations.

Marfan syndrome (MFS) is a well-defined monogenic disorder with a widely accepted systematic phenotypical scoring criteria described in the Ghent II nosology (Dietz et al., 1991; De Paepe et al., 1996; Loeys et al., 2010). Unfortunately, however, variant-databases often contain inaccurate and incomplete phenotype data for MFS, and laboratories seldom report results referring to the Ghent II variant criteria. This is problematic as laboratories use these variant databases as a diagnostic tool when assessing variants for evidence of pathogenicity.

In an effort to provide a comprehensive quality evaluation of variant-databases, Groth et al., (2017) introduced a new tool known as “The Marfan-score” (MFS-score). This phenotype scoring system is a method for scoring FBN1 variants associated to MFS. Points are assigned based on how much phenotypic information is available regarding the variant of interest. A new, well-curated, variant database (known as the “Marfan-score Database”) was created, focusing on genotype–phenotype correlation.

Aim or Purpose of Research: We hope to implement the MFS-score as a measure of variant genotype-phenotype association, allowing us to apply PP4 criteria in our variant interpretation process. This will potentially reduce the number of variants of uncertain clinical significance (VUS) and improve the quality of our FBN1 variant interpretation.

Methods: This project has four major stages:

  1. Calculating CHEO-specific MFS-scores for all variants in the MFS-score database,
  2. Comparing the MFS-score database variants to FBN1 CHEO-variants,
  3. Validating MFS-score-based PP4 application to FBN1 variant interpretation, and
  4. Providing recommendations for applying MFS-score-based PP4 to FBN1 variant interpretation.


Dietz, Harry C., et al. “Marfan syndrome caused by a recurrent de novo missense mutation in the fibrillin gene.” Nature352.6333 (1991): 337.
De Paepe, Anne, et al. “Revised diagnostic criteria for the Marfan syndrome.” American Journal of Medical Genetics Part A 62.4 (1996): 417-426.
Loeys, Bart L., et al. “The revised Ghent nosology for the Marfan syndrome.” Journal of medical genetics 47.7 (2010): 476-485.


GC-110 Defining functional domains based on pathogenicity of known missense variants to assist with novel variant assessments

WATKINS Nicholas Arthur, ZHU Yun Amber, SERRAO Natasha, WONG Andrew, LERNER-ELLIS Jordan, CHARAMES George

Sinai Health System, Mount Sinai Hospital, Toronto.

Introduction: In 2015 the American College of Medical Genetics (ACMG) and the Association of Molecular Pathology (AMP) developed guidelines in order to address ongoing issues with the interpretation and reporting of genetic test results. These guidelines provided standards in detail on how to weigh specific types of evidence and to combine these evidences to arrive at a classification for variants identified in Mendelian disease genes. However not all categories of evidence are accessible to a laboratory without additional analysis. The category PM1 is such a piece of evidence stating that well-established protein functional domains can be leveraged as evidence of pathogenicity if a missense variant is known to reside within such a domain. Naturally it was not within the scope of the guidelines to define these domains for each known disease gene. We present here a method to establish functional domains given the definition presented in the ACMG-AMP guidelines.

Objective: In this study, we set out to identify criteria that assist in defining regions that fulfill the AMCG-AMP criteria for well-established functional domains. Once these regions are established we can incorporate PM1 in variant assessments.

Methods: We identified well annotated missense variants through our clinical genetic testing laboratory’s variant database or through ClinVar relying only on entries that underwent expert review. By mapping these variants back onto the gene, we identify regions with no benign variants and an abundance of pathogenic variants. We next identified functional protein studies in order to better examine the known functional importance of the identified regions. In order to differentiate the ACMG-AMP defined domains from functional domains already established in the literature we refer to the AMCG-AMP functional domains as motifs.

Result: We utilized MLH1 and BRCA1 well annotated missense variants to develop criteria to identify functional motifs. We identified 300 variants in MLH1 and 236 variant in BRCA1. In MLH1 we defined 7 motifs, all of which are encompassed by larger previously established functional domains including an ATPase domain, a Transducer domain, and an Interaction domain. In BRCA1 we defined 4 motifs, all of which are found within the RING finger domain and the C-terminal BRCT domain. In addition, variants of uncertain significance within these motifs were reclassified to likely pathogenic when evidence PM1 was incorporated as such variants already had some evidence of pathogenicity.

Conclusion: Well-defined functional motifs as described by ACMG-AMP guidelines for interpretation of sequence variants can be identified using known and well established missense variants. We identify such regions in the proteins MLH1 and BRCA1 and establish a set of criteria to easily identify these regions for any gene with well annotated missense variants. When compared to the functional domains established through various protein studies these functional motifs are all smaller and reside within the functional domains. Therefore functional domains are found to have benign variation within their regions and should not be used to establish PM1 regions when utilizing ACMG-AMP sequence variant interpretation guidelines.


GC-111 Microduplication 17p13.3 syndrome in a father and his two fetuses

MARTIN Nicole1,2, MALINOWSKI Annie2,3, WEIND MATTHEWS Kirsten2,4, SHANNON Patrick2,5, KOLOMIETZ Elena2,5, CHITAYAT David1,2,3,6

1The Prenatal Diagnosis and Medical Genetics Program, Mount Sinai Hospital, Toronto, Ontario.
2University of Toronto, Toronto, Ontario.
3Dept. of Obstetrics and Gynecology, Mount Sinai Hospital, Toronto, Ontario.
4Dept.of Medical Imaging, Mount Sinai Hospital, Toronto, Ontario.
5Dept. of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Ontario.
6Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, Ontario.

17p13.3 microduplication syndrome can be categorized into two classes based on the size of chromosome duplication: class I microduplications contain the gene YWHAE and do not include the PAFAH1B1 gene. Patients with class I microduplications typically display autistic and other behavioral symptoms, delay in speech and motor abilities. Class II microduplications always contain the gene PAFAH1B1. Phenotypes associated with class II microduplications include intellectual disability, hypotonia and mild brain malformations. We report two fetuses with brain abnormalities with microduplication 17p13.3 including three genes VPS53, BHLHA9 and YWHAE, which is inherited from a father with major brain abnormalities and mild delay. The mother of East Indian descent presented initially in her first pregnancy at age 36 with fetal ultrasound findings of posterior fossa cyst, which communicated with the forth ventricle, vermian agenesis and splaying of the cerebellar hemispheres consistent with Dandy Walker Malformation. The couple elected to terminate the pregnancy and the autopsy confirmed the prenatal findings. Their second pregnancy was complicated with fetal ultrasound findings of intracranial avascular cyst at the level of the falx, inferior vermian hypoplasia and a cystic component in the cisterna magna at 16 weeks gestation. A detailed fetal ultrasound at 19 weeks gestation showed posteriorly rotated dysplastic vermis and segmental multicystic dysplastic right kidney. The couple elected to terminate the pregnancy and the autopsy confirmed a multiloculated cyst in the right renal lower pole and hypoplastic cerebellar vermis. Whole Exome Sequencing identified paternally inherited 815 kb duplication within cytogenetic band 17p13.3 in both fetuses. Further discussion with the couple revealed that the father did not complete his education and had difficulties in school. His brain MRI showed marked hypoplasia of the inferior vermis, mild hypoplasia of the superior vermis, generalized volume loss of the cerebellar hemispheres, mild focal atrophy within the body of the corpus callosum, mild generalized volume loss of the cerebral hemispheres, bilateral small subdural hygromas, and symmetrical cortical thinning in the perirolandic regions bilaterally. Phenotypes associated with microduplication 17p13.3 syndrome are diverse and show inter and intrafamilial variability. Microduplications involving PAFAH1B1 gene are typically associated with brain malformations although there are 2 case reports with smaller duplications not involving PAFAH1B1 gene with reported mild brain malformations. Our cases help clarify the clinical manifestations and brain findings associated with this microduplication syndrome and help in defining the growing information on this rare condition.


GC-112 Exploring prevalence of ASD among children of adults with ASD


The Hospital for Sick Children, Department of Genetic Counselling, Toronto.

Autism spectrum disorder (ASD) is the most prevalent neurodevelopmental disorder in the world. The increasing rate of ASD is due in part to a change in the diagnostic criteria, which captures a wider range of clinical presentations. Severely affected individuals, historically classified as having “autism” and higher-functioning individuals, previously classified as having “Asperger’s” are now recognized under the same umbrella diagnostic term of “ASD”. This shift in classification has impacted family’s access to evidence-based interventions and therapies, which have shown positive outcomes across multiple domains. As a result, the outlook for some individuals with ASD has dramatically changed.

The idea that individuals with ASD could live independently, get married, and have children was long thought to be nearly impossible. People believed that impairments in communication, lack of reciprocal social interaction, and tendencies towards restricted and repetitive behaviours were hardly conducive to maintaining romantic relationships and becoming capable parents. The fact that individuals with ASD are becoming parents is evident in the growing number of online blogs, message boards and support groups for affected parents and prospective parents. Questions posed, both on these community forums and in clinical settings, about the risk of having a child with ASD when one or both parents have ASD are common. Despite increased recognition that adults with ASD are having children and worried about recurrence risk, there is currently no research data to guide families and clinicians.

The primary objective of the study is to quantify the prevalence of ASD among children of adults with ASD. Utilizing a cross-sectional cohort design we will survey (i) parents of adults with ASD and (ii) adults with ASD; from two sample populations: families enrolled in the research study currently entitled “Molecular and Genomic Analysis of Autism Spectrum Disorders and Related Conditions” at SickKids and individuals in the general population who voluntarily opt to participate. We anticipate ~400 participants will be enrolled in the study utilizing this convenience/ volunteer and snowball sampling methods.

We hypothesize the prevalence of ASD among children of adults with ASD will be higher than the general population. Additionally, recurrence risk estimates for parents with ASD will be higher than estimates for siblings (i.e. 10-20%). Analyses using frequency and association calculations will be presented at CAGC AEC. As the increasing number of children with ASD become adults, the need for empirical recurrence risk data is crucial. The current lack of research not only offers little support for these individuals, but leaves geneticists and genetic counsellors unprepared for the influx of individuals diagnosed with ASD, considering having children and worried about their risk.


GC-113 Clinical Outcomes of Whole Exome Sequencing in a Large Community Hospital


North York General Hospital, Toronto, ON.

The North York General Hospital Genetics Program is a large community-based genetics service providing approximately 5000 new patient visits annually. The clinic provides care and counselling to a wide range of populations including prenatal, pediatrics, adult and cancer. Currently in Ontario the Ministry of Health and Long Term Care is funding clinical whole exome sequencing (WES). Clinic resources in the community hospitals are limited and the challenges that WES technology brings with respect to consenting, managing and interpreting large amounts of data has not been efficiently addressed.

In January 2017, we established a WES clinic at North York General Hospital with four geneticists and one genetic counsellor. Over 18 months (January 2017 – June 2018), WES was offered and funded by the Ministry of Health and Long Term Care for 37 cases: 18 adults, 15 children and 4 fetuses. Thirty one cases were trios, which included both parents and the proband. Of the 37 cases, two families declined research and secondary findings; one family consented to research but declined secondary findings; and three families declined secondary findings. To date, results have been received for 34/37 cases. Four cases came back normal with no variants found in disease genes or possible genes associated with the reported phenotype. Seven cases had two or more variants identified. Of the WES cases where variants were identified, 53% were identified as causative variants in disease genes associated with the reported phenotype, and 47% were identified as variants in genes possibly associated with reported phenotype. One case had a variant in a gene possibly associated with the reported phenotype that was re-classified to a causative variant.

As the number of WES tests requested in the community clinic increases, one of the main concerns is how to maintain and manage patients who have had WES, especially for those for whom a causative variant has not been identified. Currently we are in the process of developing a database for the WES data at North York General Hospital. The database will filter WES data received from clinical exome testing into a simple reporting system highlighting the most relevant clinical information for clinician and the referring physician in the community. In addition, the database will help monitor when re-assessment of the WES data is needed and to help with research and publications. Since the resources available to genetic clinics in community hospitals are unlikely to increase, an internal database capturing all of our WES patients will help to manage the WES data more efficiently and ensure patients are being followed in a timely manner.


GC-114 Fetal Sex Discordance by Non-Invasive Prenatal Testing: current practices and possible explanations

LEVY Tess, HODSON Katherine, POUCHET Carly, FITZPATRICK Jennifer

McGill University Health Center, Dynacare, Montreal QC.

Objective: The objective of this study was to analyze cases of discordant fetal sex results using Non Invasive Prenatal Testing (NIPT) to determine whether these cases represent underlying fetal abnormalities. If these cases do often represent a fetal abnormality, we aim to assemble the data into a usable resource for genetics professionals to use if faced with a similar situation.

Method: Cases were obtained through an online survey sent out to genetics professionals. The survey included 42 questions aimed to gather as much information as possible about the case in question.

Results: A total of 49 cases were used in the data analysis. Out of these 49 cases, 23 (46.9%) had a fetal abnormality with clinical significance, 18 of those with a confirmed diagnosis. The most common diagnosis was one of a sex reversal disorder (n=8). Out of the 49 cases, 24 (49%) did not have a fetal abnormality. The most common explanations of phenotypically normal newborns were vanishing twin (n=4) and human error (n=4). The remaining two cases did not report a phenotypic outcome though one of these resulted in miscarriage.

Conclusion: The finding of discordant fetal sex results while using NIPT is worth investigating due to the increased probability of clinically relevant findings.


GC-115 Oncology Clinic Based Genetic Testing in British Columbia: Review of the First Two Years

LOHN Zoe1, RICHARDSON Matthew2, MIN Hae Jung1, MUNG Sze Wing1, NUK Jennifer1, MCCULLUM Mary1, COMPTON Katie1, MITCHELL Gillian1, KARSAN Aly3, REGIER Dean4, BROTTO Lori5, SUN Sophie1,6, SCHRADER Kasmintan1,7

1Hereditary Cancer Program, BC Cancer Agency, Vancouver, B.C., Canada.
2Department of Interdisciplinary Oncology, The University of British Columbia, Vancouver, B.C., Canada.
3Department of Pathology and Laboratory Medicine, The University of British Columbia, Vancouver, B.C., Canada.
4Department of School of Population and Public Health, The University of British Columbia, Vancouver, B.C., Canada.
5Department of Obstetrics and Gynaecology, The University of British Columbia, Vancouver, B.C., Canada.
6Department of Medical Oncology, The University of British Columbia, Vancouver, B.C., Canada.
7Department of Molecular Oncology, The University of British Columbia, Vancouver, B.C., Canada.

Due to increased demands for hereditary cancer genetic testing, the Hereditary Cancer Program (HCP) introduced a novel service delivery model to improve efficiency of genetic counselling services in British Columbia (BC). The traditional model within BC has been for HCP genetic counsellors to provide both pre-test and post-test genetic counselling. The oncology clinic based model presented here was adapted from one that was developed at the Royal Marsden Hospital (George et al 2016). Eligible HCP patients were women referred for index BRCA1/BRCA2 testing due to a personal history of: non-mucinous epithelial ovarian cancer, invasive breast cancer diagnosed at or before age 35, or ‘triple negative’ breast cancer diagnosed at or before age 60. The oncology clinic based model is as follows: 1) interested oncologists complete an orientation with the HCP Medical Director; 2) pre-test counselling for index multiplex hereditary cancer panel testing is provided by oncologists; 3) post-test counselling is provided by HCP genetic counsellors. Patients referred from June 2015 to August 2017 were invited to participate in the study with the following measures utilized: Genetic Counselling Outcome Scale (GCOS)-24, Decisional Conflict Scale, Genetic Knowledge Questionnaire, Multidimensional Impact of Cancer Risk Assessment (MICRA) Questionnaire, and Patient Acceptability Scale. Patients who presented for index HBOC testing through the traditional HCP model within the same timeframe were invited for comparison. Completed questionnaires were received from 236 patients, including 57 patients who underwent the oncology clinic based model, and 179 women patients who underwent the traditional model. There were no significant differences between the two groups with respect to empowerment, satisfaction, knowledge, or distress measures. Wait time until the pre-test appointment was significantly shorter for the oncology clinic based model than the traditional model (300 days versus 108 days respectively). Emerging data presented here suggests that an oncology clinic based model is both acceptable to patients and feasible to implement.


GC-116 Validating and optimizing NGS-based diagnostics to improve diagnostic yield and clinical utility

Miko Valori2, Julie Hathaway1, Tero-Pekka Alastalo1, Ville Kytölä2, Pertteli Salmenperä2, Matias Rantanen2, Massimiliano Gentile2, Samuel Myllykangas2

1Blueprint Genetics; 1268 Missouri Street, San Francisco, CA, 94107: US.
2Blueprint Genetics; Biomedicum 2U, Tukholmankatu 8, 00290 Helsinki; Finland.

Utility of Whole Exome Sequencing (WES) in clinical diagnostics has been limited by the non-uniform sequencing coverage across exons, leaving a substantial proportion of the regions with shallow coverage that prevents accurate variant detection. We evaluated a WES assay that is specifically designed for clinical use, enables wide breadth of coverage resembling high-coverage gene-panel based assays, and provides high sensitivity in variant detection. We performed WES capture experiments using an assay with boosted clinical content, namely xGen Exome Research Panel (IDT) assay that was spiked-in with custom designed clinical content. Sequencing was performed using an Illumina NovaSeq sequencing system and data was down-sampled to 100M reads. Performance of the WES assay was demonstrated by using reference samples with high-quality variant calls (The Genome In a Bottle Consortium and Platinum Genome samples for SNVs and INDELs and Coriell samples for assessing Del/Dups and complex genetic variants). In clinically associated CCDS genes, the assay achieved high average sequencing depth (183x) and coverage (99.7% of regions covered >20x). Sensitivity to detect SNVs was 0.998, and for INDELs 0.97. Sensitivity to detect 1 exon deletions and duplications was 0.93 and 0.99 for 5 exon deletions and duplications. The assay was observed to provide a uniform coverage over difficult-to-sequence regions (e.g. the RPGR gene) and GC-rich 1st exons. Our results demonstrate that WES assay with boosted clinical content provide high sequencing coverage and allows high variant calling sensitivity for different genetic variations, which makes it well-suited for clinical diagnostics of inherited disorders.


GC-117 Germline Pathogenic RAD51C Variants in Breast Cancer Families


1Sunnybrook Odette Cancer Centre, Toronto, ON, Canada.

RAD51C is a key player in the homologous recombination pathway that repairs DNA double-strand breaks.1 It was first suggested as a cancer susceptibility gene in 2010, after biallelic RAD51C mutations were identified in a family with a Fanconi anemia-like phenotype.2 Subsequent studies have established RAD51C as a rare, moderate-to-high risk gene for breast and ovarian cancer.1,3-10 Although several studies have demonstrated a statistically significant association between RAD51C mutations and ovarian cancer risk, their association with breast cancer risk remains uncertain. Thus, no useful clinical guidelines exist for the genetic screening of RAD51C in individuals and families with breast cancer. The following is a retrospective study of 1282 women with a personal and/or family history of breast and/or ovarian cancer that underwent hereditary breast and ovarian cancer panel testing between the years 2015 and 2018. We have identified RAD51C pathogenic or likely pathogenic variants in four women from breast cancer only families. Two of the women have breast cancer, as well as at least one close blood relative with breast cancer. One woman has breast cancer, but no known family history of cancer. The fourth woman is unaffected, with her mother diagnosed with breast cancer at age of 37. Current NCCN guidelines state there is unknown or insufficient evidence for breast cancer risk. These findings support the need to further explore breast cancer risk in RAD51C carriers. This is important to guide decision making on for RAD51C testing in individuals with a personal and/or family history breast cancer, as well as guide breast cancer screening recommendations for individuals with RAD51C mutations.


1Meindl A, Hellebrand H, Wiek C, Erven V, Wappenschmidt B, Niederacher D, Freund M, Lichtner P, Hartmann L, Schaal H, et al. Germline mutations in breast and ovarian cancer pedigrees establish RAD51C as a human cancer susceptibility gene. Nature Genet. 2010;42(5):410-414.
2Vaz F, Hanenberg H, Schuster B, Barker K, Wiek C, Erven V, Neveling K, Endt D, Kesterton I, Autore F, et al. Mutation of the RAD51C gene in a Fanconi anemia-like disorder. Nature Genet. 2010;42(5):406-409.
3Clague J, Wilhoite G, Adamson A, Bailis A, Weitzel JN, Neuhausen SL. RAD51C germline mutations in breast and ovarian cancer cases from high-risk families. PLoS One. 2011;6(9):e25632.
4Romero A, Perez-Segura P, Tosar A, Garcia-Saenz JA, Diaz-Rubio E, Caldes T, de la Hoya M. A HRM-based screening method detects RAD51C germline deleterious mutations in Spanish breast and ovarian cancer families. Breast Cancer Res Treat. 2011;129(3):939-946.
5Thompson ER, Boyle SE, Johnson J, Ryland GL, Sawyer S, Choong DY, kConFab, Chenevix-Trench G, Trainer AH, Lindeman GJ, et al. Analysis of RAD51C germline mutations in high-risk breast and ovarian cancer families and ovarian cancer patients. Hum Mutat. 2012;33(1):95-99.
6Vuorela M, Pylkas K, Hartikainen JM, Sundfeldt K, Lindblom A, von Wachenfeldt Wappling A, Haanpaa M, Puistola U, Rosengren A, Anttila M, et al. Further evidence for the contribution of the RAD51C gene in hereditary breast and ovarian cancer susceptibility. Breast Cancer Res Treat. 2011;130(3):1003-1010.
7Osorio A, Endt D, Fernandez F, Eirich K, de la Hoya M, Schmutzler R, Caldes T, Meindl A, Schindler D, Benitez J. Predominance of pathogenic missense variants in the RAD51C gene occurring in breast and ovarian cancer patients. Hum Mol Genet. 2012;21(13):2889-2898.
8Blanco A, Gutierrez-Enriquez S, Santamarina M, Montalban G, Bonache S, Balmana J, Carracedo A, Diez O, Vega A. RAD51C germline mutations found in Spanish site-specific breast cancer and breast-ovarian cancer families. Breast Cancer Res Treat. 2014;147(1):133-143.
9Rashid MU, Muhammad N, Faisal S, Amin A, Hamann U. Deleterious RAD51C germline mutations rarely predispose to breast and ovarian cancer in Pakistan. Breast Cancer Res Treat. 2014;145(3):775-784.
10Sanchez-Bermudez AI, Sarabia-Mesequer MD, Garcia-Aliaga A, Marin-Vera M, Macias-Cerrolaza JA, Henarejos PS, Guardiola-Castillo V, Pena FA, Alonso-Romero JL, Noguera-Velasco JA, et al. Mutational analysis of RAD51C and RAD51D genes in hereditary breast and ovarian cancer families from Murcia (southeastern Spain). Eur J Med Genet. 2018;61(6):355-361.


GC-118 A family with atypical Purine Nucleoside Phosphorylase (PNP) deficiency

GOSSE Géraldine1, CAMPBELL Nicholas2, WEISSER Caroline3, GRUNEBAUM Eyal3, CHAPDELAINE Hugo1,2

1Montreal Clinical Research Institute, Université de Montréal
2Centre Hospitalier de l’Université de Montréal, Université de Montréal
3The Hospital for Sick Children, University of Toronto Faculty of Medicine.

Introduction: PNP deficiency is a rare form of autosomal recessive inborn error of metabolism causing severe combined immunodeficiency (SCID). It typically presents in infancy with recurrent infections, often accompanied by failure to thrive, autoimmune symptoms and neurological manifestations such as spasticity and intellectual disability. Prognosis is poor without successful hematopoietic stem cell transplantation in childhood, which is the only curative treatment.

Case presentation: We present a case for which genetic counselling was complicated by a milder phenotype and later onset than classically documented. The index case was referred to our adult immunodeficiency clinic at 20 years old for a severe lymphopenia, incidentally found in the context of chronic sinusitis with polyposis. Genetic testing revealed a homozygous likely pathogenic variant in the PNP gene in this individual. Two additional siblings were diagnosed in this consanguineous family through familial screening.

Conclusions: Clinical manifestations of PNP deficiency can present later in life and less severely than initially described. As genetic testing expands in the field of primary immunodeficiency, more of these milder cases will be uncovered, bringing challenges for the diagnosis, genetic counselling and treatment.