Myra I. Roche

Incidental Findings with Genomic Testing: Implications for Genetic Counseling Practice.

This paper summarizes the current controversies surrounding the identification and disclosure of “incidental” or “secondary” findings from genomic sequencing and the implications for genetic counseling practice. The rapid expansion of clinical sequencing has influenced the ascertainment and return of incidental findings, while empiric data to inform best practices are still being generated. Using the North Carolina Clinical Genomic Evaluation by Next Generation Exome Sequencing (NCGENES) research project as an example, we discuss the implications of different models of consent and their impact on patient decisions.

How parents search, interpret, and evaluate genetic information obtained from the internet

This study describes how parents of a child referred for genetic services searched the Internet for information, summarizes how they interpreted and evaluated the information they obtained, and identifies barriers that they encountered. Audio-taped interviews were conducted with 100 ethnically diverse families referred to a pediatric genetics clinic. After transcription, coded text was entered into a software program (QSR N6) for searching and data retrieval. Matrices were created to systematically categorize and compare families’ Internet use. Eighty-three percent of families obtained Internet information about the diagnosis, the clinic visit, and/or treatment and services. Those not conducting searches lacked access, Internet experience, or a diagnostic term and had lower incomes and less education, regardless of ethnicity. Families sought information in preparation for the clinic visit but barriers to obtaining and interpreting relevant information were common. Parents’ Internet searching experiences illustrate common barriers to obtaining and understanding genetic information. Identifying them can help genetic counselors facilitate parents’ searches for relevant information.

Newborn Sequencing in Genomic Medicine and Public Health.

The rapid development of genomic sequencing technologies has decreased the cost of genetic analysis to the extent that it seems plausible that genome-scale sequencing could have widespread availability in pediatric care. Genomic sequencing provides a powerful diagnostic modality for patients who manifest symptoms of monogenic disease and an opportunity to detect health conditions before their development. However, many technical, clinical, ethical, and societal challenges should be addressed before such technology is widely deployed in pediatric practice. This article provides an overview of the Newborn Sequencing in Genomic Medicine and Public Health Consortium, which is investigating the application of genome-scale sequencing in newborns for both diagnosis and screening.

A semiquantitative metric for evaluating clinical actionability of incidental or secondary findings from genome-scale sequencing.

Purpose:As genome-scale sequencing is increasingly applied in clinical scenarios, a wide variety of genomic findings will be discovered as secondary or incidental findings, and there is debate about how they should be handled. The clinical actionability of such findings varies, necessitating standardized frameworks for a priori decision making about their analysis.Methods:We established a semiquantitative metric to assess five elements of actionability: severity and likelihood of the disease outcome, efficacy and burden of intervention, and knowledge base, with a total score from 0 to 15.Results:The semiquantitative metric was applied to a list of putative actionable conditions, the list of genes recommended by the American College of Medical Genetics and Genomics (ACMG) for return when deleterious variants are discovered as secondary/incidental findings, and a random sample of 1,000 genes. Scores from the list of putative actionable conditions (median = 12) and the ACMG list (median = 11) were both statistically different than the randomly selected genes (median = 7) (P < 0.0001, two-tailed Mann-Whitney test).Conclusion:Gene–disease pairs having a score of 11 or higher represent the top quintile of actionability. The semiquantitative metric effectively assesses clinical actionability, promotes transparency, and may facilitate assessments of clinical actionability by various groups and in diverse contexts.Genet Med 18 5, 467–475.

Is "incidental finding" the best term?: A study of patients' preferences

Purpose:There is debate within the genetics community about the optimal term to describe genetic variants unrelated to the test indication but potentially important for health. Given the lack of consensus and the importance of adopting terminology that promotes effective clinical communication, we sought the opinion of clinical genetics patients.Methods:Surveys and focus groups with two patient populations were conducted. Eighty-eight survey participants were asked to rank four terms according to how well each describes results unrelated to the test indication: incidental findings, secondary findings, additional findings, and ancillary findings. Participants in six focus groups were guided through a free-thought exercise to describe the desired attributes of such a term and then asked to formulate the best term to represent this concept.Results:The term additional findings had the most first-choice rankings by survey participants, followed by secondary findings, incidental findings, and ancillary findings. Most focus group participants preferred the term additional findings; they also gave reasons why other terms were not optimal.Conclusion:Additional findings was preferred because it was more neutral and accessible than other terms currently in use. Patient perceptions and comprehension will be framed by the terminology used by healthcare providers. Thus, patient opinions should be considered by medical genetics professionals.Genet Med 19 2, 176–181.

Supporting Parental Decisions About Genomic Sequencing for Newborn Screening: The NC NEXUS Decision Aid

Advances in genomic sequencing technology have raised fundamental challenges to the traditional ways genomic information is communicated. These challenges will become increasingly complex and will affect a much larger population in the future if genomics is incorporated into standard newborn screening practice. Clinicians, public health officials, and other stakeholders will need to agree on the types of information that they should seek and communicate to parents. Currently, few evidence-based and validated tools are available to support parental informed decision-making. These tools will be necessary as genomics is integrated into clinical practice and public health systems. In this article we describe how the North Carolina Newborn Exome Sequencing for Universal Screening study is addressing the need to support parents in making informed decisions about the use of genomic testing in newborn screening. We outline the context for newborn screening and justify the need for parental decision support. We also describe the process of decision aid development and the data sources, processes, and best practices being used in development. By the end of the study, we will have an evidenced-based process and validated tools to support parental informed decision-making about the use of genomic sequencing in newborn screening. Data from the study will help answer important questions about which genomic information ought to be sought and communicated when testing newborns.

“Not Tied Up Neatly with a Bow”: Professionals’ Challenging Cases in Informed Consent for Genomic Sequencing

As the use of genomic technology has expanded in research and clinical settings, issues surrounding informed consent for genome and exome sequencing have surfaced. Despite the importance of informed consent, little is known about the specific challenges that professionals encounter when consenting patients or research participants for genomic sequencing. We interviewed 29 genetic counselors and research coordinators with considerable experience obtaining informed consent for genomic sequencing to understand their experiences and perspectives. As part of this interview, 24 interviewees discussed an informed consent case they found particularly memorable or challenging. We analyzed these case examples to determine the primary issue or challenge represented by each case. Challenges fell into two domains: participant understanding, and facilitating decisions about testing or research participation. Challenges related to participant understanding included varying levels of general and genomic literacy, difficulty managing participant expectations, and contextual factors that impeded participant understanding. Challenges related to facilitating decision-making included complicated family dynamics such as disagreement or coercion, situations in which it was unclear whether sequencing research would be a good use of participant time or resources, and situations in which the professional experienced disagreement or discomfort with participant decisions. The issues highlighted in these case examples are instructive in preparing genetics professionals to obtain informed consent for genomic sequencing.

The phenotype of multiple congenital anomalies-hypotonia-seizures syndrome 1: Report and review

The Multiple Congenital Anomalies‐Hypotonia‐Seizures Syndrome 1 (MCAHS1) has been described in two families to date. We describe a 2‐year‐old Mexican American boy with the syndrome and additional manifestations not yet reported as part of the phenotype. The patient presented with severe hypotonia, microphallus and left cryptorchidism, and was later diagnosed with epilepsy and severe cortical visual impairment. He also had supernumerary nipples, pectus excavatum, a short upturned nose, fleshy ear lobes, and a right auricular pit. Massively parallel exome sequencing and analysis revealed two novel compound heterozygous missense (Trp136Gly and Ser859Thr) variants in the PIGN gene. This report extends and further defines the phenotype of this syndrome.

How Can Psychological Science Inform Research About Genetic Counseling for Clinical Genomic Sequencing

Next generation genomic sequencing technologies (including whole genome or whole exome sequencing) are being increasingly applied to clinical care. Yet, the breadth and complexity of sequencing information raise questions about how best to communicate and return sequencing information to patients and families in ways that facilitate comprehension and optimal health decisions. Obtaining answers to such questions will require multidisciplinary research. In this paper, we focus on how psychological science research can address questions related to clinical genomic sequencing by explaining emotional, cognitive, and behavioral processes in response to different types of genomic sequencing information (e.g., diagnostic results and incidental findings). We highlight examples of psychological science that can be applied to genetic counseling research to inform the following questions: (1) What factors influence patients’ and providers’ informational needs for developing an accurate understanding of what genomic sequencing results do and do not mean?; (2) How and by whom should genomic sequencing results be communicated to patients and their family members?; and (3) How do patients and their families respond to uncertainties related to genomic information?

GCH1 heterozygous mutation identified by whole-exome sequencing as a treatable condition in a patient presenting with progressive spastic paraplegia

Objective: Whole-exome-sequencing can be a powerful tool for diagnosing complex neurogenetic conditions and identifying treatable conditions. Background: Confirming a genetic basis for a complex neurological condition can be challenging, particularly for conditions such as hereditary spastic paraplegia with which more than 40 genes have been associated. However another challenge is the difficulty of precisely defining a clinical phenotype, in this case, the difficulty distinguishing distal dystonia/spasticity from spasticity due to hereditary spastic paraplegia. Method: A 36 year-old female presented with a progressive spastic gait that at times painful. She was completely healthy until 6-year when she first noted to be toe-walking. She was initially diagnosed with “cerebral palsy” and later with hereditary spastic paraplegia. She had many orthopedic surgeries and became dependent on crutches at 18-year. She also developed mild arm impairment, dysarthria and shortness of breath. On examination, she walked with a spastic gait and had significant hyper-reflexia. She had undergone numerous medical evaluations and tests in search of an etiology including panels for spastic paraplegia. She was recently enrolled in a research study of whole-exome-sequencing. Results: Initial analysis focused on variants associated with spastic paraplegia was negative. However upon analysis of an “actionable diagnostic gene list”, a heterozygous mutation in the GCH1 gene (c. 646 C>T; p. Arg216X) was discovered, which had been previously reported as causal for dopa-responsive-dystonia, a phenotype that can resemble spastic paraplegia. The patient was started on a low dose of L-dopa with slow titration. She noticed improvement of stiffness in her legs within the first week. She continued to improve during the titration. Eight weeks later she walked independently without crutches for the first time in 17 years. She reports feeling like a “whole new person now”. Conclusion: Whole-exome-sequencing may improve outcomes by enhancing our ability to accurately diagnose complex neurological conditions. Study Supported by: U01 HG006487, NHGRI, NIH, PI James Evans, MD, PhD Disclosure: Dr. Fan has nothing to disclose. Dr. Greenwood has nothing to disclose. Dr. Felix has received research support from Pfizer Inc. and Bristol-Myers Squibb Co. Dr. Shiloh-Malawsky has nothing to disclose. Dr. Roche has nothing to disclose. Dr. Crooks has nothing to disclose. Dr. Berg has nothing to disclose. Dr. Evans has nothing to disclose.