Karen E. Wain

Towards a Universal Clinical Genomics Database: The 2012 International Standards for Cytogenomic Arrays Consortium Meeting

The 2012 International Standards for Cytogenomic Arrays (ISCA) Consortium Meeting, “Towards a Universal Clinical Genomic Database,” was held in Bethesda, Maryland, May 21–22, 2012, and was attended by over 200 individuals from around the world representing clinical genetic testing laboratories, clinicians, academia, industry, research, and regulatory agencies. The scientific program centered on expanding the current focus of the ISCA Consortium to include the collection and curation of both structural and sequence‐level variation into a unified clinical genomics database, available to the public through resources such as the National Center for Biotechnology Informations ClinVar database. Here, we provide an overview of the conference, with summaries of the topics presented for discussion by over 25 different speakers. Presentations are available online at www.iscaconsortium.org.

The Laboratory-Clinician Team: A Professional Call to Action to Improve Communication and Collaboration for Optimal Patient Care in Chromosomal Microarray Testing

The International Standards for Cytogenomic Arrays (ISCA) Consortium is a worldwide collaborative effort dedicated to optimizing patient care by improving the quality of chromosomal microarray testing. The primary effort of the ISCA Consortium has been the development of a database of copy number variants (CNVs) identified during the course of clinical microarray testing. This database is a powerful resource for clinicians, laboratories, and researchers, and can be utilized for a variety of applications, such as facilitating standardized interpretations of certain CNVs across laboratories or providing phenotypic information for counseling purposes when published data is sparse. A recognized limitation to the clinical utility of this database, however, is the quality of clinical information available for each patient. Clinical genetic counselors are uniquely suited to facilitate the communication of this information to the laboratory by virtue of their existing clinical responsibilities, case management skills, and appreciation of the evolving nature of scientific knowledge. We intend to highlight the critical role that genetic counselors play in ensuring optimal patient care through contributing to the clinical utility of the ISCA Consortium’s database, as well as the quality of individual patient microarray reports provided by contributing laboratories. Current tools, paper and electronic forms, created to maximize this collaboration are shared. In addition to making a professional commitment to providing complete clinical information, genetic counselors are invited to become ISCA members and to become involved in the discussions and initiatives within the Consortium.

Looking Back and Moving Forward: An Historical Perspective from Laboratory Genetic Counselors

Despite a consistent increase in genetic counselors who report working in laboratory positions, there is a relative dearth of literature on laboratory genetic counseling. Semi-structured interviews were completed with nine laboratory genetic counselors to document how positions were created and have changed with time. Interview transcriptions were analyzed for emerging themes. Several common themes were identified, including that early positions were often part-time, laboratory-initiated and had a lack of job definition. Laboratory genetic counselors commented on their evolving roles and responsibilities, with their positions becoming more technical and specialized over time and many taking on managerial and supervisory roles. All genetic counselors surveyed reported using core genetic counseling skills in their positions. The expansion of diagnostic testing and quickly evolving technology were common themes in regards to the future of laboratory genetic counselors, and participants commented on laboratory genetic counselors having expanding roles with data management, result interpretation and reporting, and guidance of other healthcare providers. Other comments included the impact of competition among laboratories and how training programs can better prepare genetic counseling students for a career in the laboratory setting. This study describes the emergence, and subsequent evolution, of laboratory genetic counseling positions as a significant subspecialty of genetic counseling.

The Utilization of Counseling Skills by the Laboratory Genetic Counselor

The number of available genetic testing options and the nuances associated with these options continue to expand. In addition, the scope of genetic testing has broadened to areas and specialties beyond Medical Genetics. In response to these changes, diagnostic laboratories have employed genetic counselors to help navigate the increasing complexity of genetic testing, given their expertise and training in human genetics. However a largely unrecognized aspect of this role involves the use of counseling skills. Counseling skills are used by laboratory genetic counselors in a variety of situations to convey information and facilitate understanding among clinicians and medical staff. This helps to reduce test ordering errors, promote optimal test utilization, and ensure best patient care practices. The specific counseling skills used by laboratory counselors will be explored using three fictional case vignettes, followed by a discussion of the applicability of these skills in other contexts. Exploration of the unique ways in which laboratory genetic counselors apply their counseling skills can be useful for professional development and instructive for graduate training programs.

Hereditary Hemorrhagic Telangiectasia and Risks for Adverse Pregnancy Outcomes

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant vascular dysplasia characterized by epistaxis, mucocutaneous telangiectasias, and arteriovenous malformations (AVM) in the brain, lung, liver, gastrointestinal tract, or spine. While pregnant women with HHT are known to have increased risks due to pulmonary AVMs, little is known about any increased risk for fetal birth defects or other adverse pregnancy outcomes. To investigate potential increased risk, individuals with a clinical diagnosis of HHT were asked to complete a survey composed of four sections: demographics, personal history of HHT, personal history of birth defects (modeled after state registries), and reproductive history. A total of 226 participants reported outcomes of 560 pregnancies, as well as self‐reported personal history of birth defects. Of the 560 pregnancies, 450 (80.4%) resulted in 457 live births and 63 (13.8%) were pre‐term. Of the 110 pregnancy losses, 80 (72.7%) were first trimester and five were stillborn. Anomalies considered to be medically or cosmetically significant were reported in 17 babies (3.7%). The presence of significant anomalies was not significantly associated with whether the baby had an HHT diagnosis (P = 0.55) or the gender of the parent with HHT (P = 0.32). Four liveborn babies and one stillborn had a cerebral AVM or hemorrhage in the perinatal period. Prevalence of uterine hemorrhage, pre‐eclampsia, placental abnormalities, low‐birth weight, and infertility did not appear increased over the general population. These data provide some reassurance that HHT does not lead to an appreciable increased risk for birth defects or other adverse pregnancy outcomes.

A Commentary on Opportunities for the Genetic Counseling Profession through Genomic Variant Interpretation: Reflections from an Ex-Lab Rat

The genetic counseling profession continues to expand and respond to the changing landscape of genomic medicine. “Non-traditional” genetic counseling roles have become more commonplace and the transferability of the genetic counselor skill set has been widely acknowledged, particularly in genetic laboratory settings. As these expanding roles continue to mature, all genetic counselors can benefit by learning and adopting clinically relevant skills, such as genomic variant interpretation, which can be applied to direct patient care. These skills can enrich our patients’ understanding of their test results, help ensure quality patient care, and could be useful in positioning genetic counselors as critical members in the medical team as we continue to fully transition into the genomic medicine era.

The value of genomic variant ClinVar submissions from clinical providers: Beyond the addition of novel variants

With the increasing use of clinical genomic testing across broad medical disciplines, the need for data sharing and curation efforts to improve variant interpretation is paramount. The National Center for Biotechnology Information (NCBI) ClinVar database facilitates these efforts by serving as a repository for clinical assertions about genomic variants and associations with disease. Most variant submissions are from clinical laboratories, which may lack clinical details. Laboratories may also choose not to submit all variants. Clinical providers can contribute to variant interpretation improvements by submitting variants to ClinVar with their own assertions and supporting evidence. The medical genetics team at Geisingers Autism & Developmental Medicine Institute routinely reviews the clinical significance of all variants obtained through clinical genomic testing, using published ACMG/AMP guidelines, clinical correlation, and post‐test clinical data. We describe the submission of 148 sequence and 155 copy number variants to ClinVar as “provider interpretations.” Of these, 192 (63.4%) were novel to ClinVar. Detailed clinical data were provided for 298 (98.3%), and when available, segregation data and follow‐up clinical correlation or testing was included. This contribution marks the first large‐scale submission from a neurodevelopmental clinical setting and illustrates the importance of clinical providers in collaborative efforts to improve variant interpretation.

ClinGen's GenomeConnect registry enables patient-centered data sharing

GenomeConnect, the NIH‐funded Clinical Genome Resource (ClinGen) patient registry, engages patients in data sharing to support the goal of creating a genomic knowledge base to inform clinical care and research. Participant self‐reported health information and genomic variants from genetic testing reports are curated and shared with public databases, such as ClinVar. There are four primary benefits of GenomeConnect: (1) sharing novel genomic data—47.9% of variants were new to ClinVar, highlighting patients as a genomic data source; (2) contributing additional phenotypic information—of the 52.1% of variants already in ClinVar, GenomeConnect provided enhanced case‐level data; (3) providing a way for patients to receive variant classification updates if the reporting laboratory submits to ClinVar—97.3% of responding participants opted to receive such information and 13 updates have been identified; and (4) supporting connections with others, including other participants, clinicians, and researchers to enable the exchange of information and support—60.4% of participants have opted to partake in participant matching. Moving forward, ClinGen plans to increase patient‐centric data sharing by partnering with other existing patient groups. By engaging patients, more information is contributed to the public knowledge base, benefiting both patients and the genomics community.

Developing a conceptual, reproducible, rubric-based approach to consent and result disclosure for genetic testing by clinicians with minimal genetics background

PurposeIn response to genetic testing being widely ordered by nongenetics clinicians, the Consent and Disclosure Recommendations (CADRe) Workgroup of the Clinical Genome Resource (ClinGen; clinicalgenome.org) developed guidance to facilitate communication about genetic testing and efficiently improve the patient experience. Considering ethical, legal, and social implications, and medical factors, CADRe developed and pilot tested two rubrics addressing consent for genetic testing and results disclosure. The CADRe rubrics allow for adjusting the communication approach based on circumstances specific to patients and ordering clinicians.MethodsWe present results of a formative survey of 66 genetics clinicians to assess the consent rubric for nine genes (MLH1, CDH1, TP53, GJB2, OTC; DMD, HTT, and CYP2C9/VKORC1). We also conducted interviews and focus groups with family and patient stakeholders (N = 18), nongenetics specialists (N = 27), and genetics clinicians (N = 32) on both rubrics.ResultsFormative evaluation of the CADRe rubrics suggests key factors on which to make decisions about consent and disclosure discussions for a “typical” patient.ConclusionWe propose that the CADRe rubrics include the primary issues necessary to guide communication recommendations, and are ready for pilot testing by nongenetics clinicians. Consultation with genetics clinicians can be targeted toward more complex or intensive consent and disclosure counseling.

First report of an interstitial deletion, del(5)(q33.1q35.1) in a girl with primary amenorrhea, seizures, and severe behavioral and developmental deficiencies†

Constitutional interstitial deletions of the long arm of chromosome 5 are extremely rare with only 36 cases reported [Courtens et al., 1998]. Deletions distal to 5q33 have been reported only in 10 patients [Joseph et al., 1990; Kleczkowska et al., 1993; Stratton et al., 1994; Giltay et al., 1997; Gibbons et al., 1999; Krammer et al., 1999; Pauli et al., 1999; Spranger et al., 2000; Schafer et al., 2001; Schiffer et al., 2003]. To our knowledge, there are no reports of constitutional interstitial deletion, del(5)(q33q35) in adolescents. Here, we report on a 17-year-old Caucasian female with del(5)(q33.1q35.1) presenting with primary amenorrhea, seizures, and severe behavioral and mental deficiencies. A 17-year-old, Caucasian girl was referred to genetics clinic because of failure to thrive and primary amenorrhea. She had a history of mental retardation, cerebral palsy and seizures. On physical examination, her weight was 34.7 kg (<5th centile), height was 150 cm (<5th centile), and head circumference was 52 cm (<5th centile). She had minor dysmorphic features including narrow face, deepset eyes, low-set ears, deviated nasal bridge, higharched palate, triangular face, and poor dentition. She also had clinodactyly of the 5th digit and flexion contractures of digits on the hands. She had Tanner III stage breast development. There were no other major organ malformations. However, she displayed very unusual behaviors, such as aggressive sexual behavior towards males and acting like a dog or cat by barking at people and licking her hands repeatedly. She could walk, but was very wobbly, and was not able to talk, write, or distinguish colors. She had a history of chronic diarrhea and constipation. Despite an enormous appetite, she had lost 9.1 kg within a span of 3 months secondary to diarrhea. Laboratory investigations included chromosome analysis, FISHstudies, serumaminoacidsandhormone levels. Serum amino acid screen showed high serum levels of threonine (24.8; normal 9.0–18.8 mmol/dl), glutamine (104.4; normal 21.5–82.5 mmol/dl), glycine (85.1; normal 17.2–41.0 mmol/dl), alanine (84.0; normal 22.7–53.7 mmol/dl), citrulline (4.5; normal 1.9–4.3 mmol/dl), alpha-amino-N-butyric acid (2.3; normal 1.0–2.2 mmol/dl); cystine (14.8; normal 3.4– 12.0mmol/dl), cystathionine (0.2mmol/dl), lysine (22.5; normal9.7–18.7mmol/dl), 1-CH3-histidine (2.2;normal 0–0.9 mmol/dl) and low serum levels of aspartic acid (1.2; normal 1.4–7.2 mmol/dl), and tyrosine (4.3; normal 4.4–10.6 mmol/dl). These results are suggestive of hepatic dysfunction although liver function tests were normal. Serum FSH and LH levels were normal while the estradiol was very low (8 pg/ml). Chromosome analysis from cultured peripheral blood lymphocytes showed an unbalanced structural rearrangement in all 20 cells analyzed. Based on