Principles of Genetic Counseling in the Era of Next-Generation Sequencing PDF

Review Article Diagnostic Genetics CROSSMARK_logo_3_Test 1/1 Ann Lab Med 2018;38:291-295...

Review Article Diagnostic Genetics CROSSMARK_logo_3_Test 1/1 Ann Lab Med 2018;38:291-295 https://doi.org/10.3343/alm.2018.38.4.291 ISSN 2234-3806 eISSN 2234-3814 https://crossmark-cdn.crossref.org/widget/v2.0/logos/CROSSMARK_Color_square.svg 2017-03-16 Principles of Genetic Counseling in the Era of Next- Generation Sequencing Mina Yang, M.D. and Jong-Won Kim, M.D. Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea Traditional genetic counseling has focused on the target gene and its natural progress with Received: September 29, 2017 Revision received: December 14, 2017 respect to disease risk. Next-generation sequencing (NGS) can produce information on Accepted: March 12, 2018 several genetic variants simultaneously, with different functions and consequences for each. Accordingly, determining the status of the patient or consultant and interpreting se- Corresponding author: Jong-Won Kim Department of Laboratory Medicine & quencing results from many genes can largely increase the complexity of genetic counsel- Genetics, Samsung Medical Center, ing. Moreover, the current environment of big data that can be readily shared via the inter- Sungkyunkwan University School of net and a ubiquitous network provides many different avenues for which a consultant Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Korea must handle the traditional principle of genetic counseling in different ways. Thus, further Tel: +82-2-3410-2705 consideration and rethinking of genetic counseling principles are necessary in the era of Fax: +82-2-3410-2719 NGS. In this review, we discuss several aspects of genetic counseling that one can en- E-mail: [email protected] counter when faced with NGS data. © Korean Society for Laboratory Medicine This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecom- mons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the Key Words: Genetic counseling, Next-generation sequencing, Incidental finding original work is properly cited. INTRODUCTION cancer risk in BRCA1 and BRCA2 mutation carriers. In ad- dition, next-generation sequencing (NGS) technology enables Genetic counseling is the process by which patients or relatives analyses of multiple genes simultaneously, producing output on at risk of developing a disorder with a potential hereditary com- multiple variants, which makes the subsequent genetic coun- ponent are advised of the consequences of the disorder, the seling more demanding and complicated. This complexity arises probability of developing or transmitting it, and the ways in which because of the possibility of thousands of scenarios, which re- the risk may be prevented, avoided, or ameliorated. It is also quire different approaches to be assessed on a case-by-case defined as an educational process that seeks to assist affected basis. and/or at-risk individuals to better understand the nature of a Within this context, it is essential to establish a general princi- genetic disorder, its transmission, and the options open to them ple and new viewpoint for genetic counseling in the genomic in management and family planning. age, as well as in the era of big data and ubiquitous networks Traditionally, genetic counseling largely dealt with single-gene (Fig. 1). In particular, application of genetic counseling should disorders or Mendelian diseases. However, with the progress of be specific for the context of the current culture of a society. Ac- genomic technologies, a new era of multifactorial disease is on cordingly, the guidelines established for genetic counseling should the horizon. Even a single-gene disorder is modified by the pa- vary depending on the cultural background. The Korean society tient’s background genetic make-up such as the presence of has rapidly changed from an extended family to a nuclear fam- single nucleotide polymorphisms. For example, one study fo- ily, thereby enhancing the concept of individualism; thus, these cused on the association of other genetic factors with ovarian modern family dynamics should be considered in genetic coun- https://doi.org/10.3343/alm.2018.38.4.291 www.annlabmed.org 291  Yang M, et al. Genetic counseling in the NGS era 2) Choice of tests Traditional issues - Autonomy Besides molecular genetic tests, other laboratory tests such as - Privacy biochemical tests are often included to provide complementary - Right to know/right not to know information during genetic counseling. It should be carefully - Coercion considered whether or not to proceed with parental tests because - Confidentiality Issues by NGS techniques these results can create a sense of guilt for the parents. Most of - Secondary finding/unsolicited the relevant knowledge of a disease and its related genomics finding (UF) could be essentially gained through review of the literature; how- - Variants of unknown significance - UF in the research setting ever, acquisition of information from websites or colleagues is - Gene editing equally important considering the rapid progress in the field. A Genetic counseling in the NGS Era mutation could be observed either directly in a patient or through indirect linkage analysis. When multiple variants of unknown Fig. 1. Influence of the issues of NGS technology on traditional ge- significance (VUS) are found, indirect linkage analysis can help netic counseling. determine which VUS is more likely to be pathogenic. NGS, a Abbreviation: NGS, next-generation sequencing. revolutionary technology in genomics, consists of a gene panel, whole-exome sequencing (WES), or whole-genome sequencing seling. (WGS) data. While performing NGS, it is important to check that In this review, we address the general topics of genetic coun- the individual gene is covered and performance is adequate. seling with a focus on the specific considerations one might en- counter when dealing with NGS data. Before starting this dis- 3) Limitation of diagnosis cussion, the terminology needs to be clarified. The term “inci- Diagnosis of a genetic disease and prenatal tests are defined by dental finding” is commonly used to refer to a finding not related the Bioethics Law and Mother and Child Health Law in Korea to the primary diagnostic question. However, the American Col- (http://www.law.go.kr/lsInfoP.do?lsiSeq=188088&efYd=20170603 lege of Medical Genetics (ACMG) has revised the term “inciden- #0000). Since there are sets of disorders for which tests can le- tal finding” to “secondary finding (SF)” because the designated gally be conducted in Korea, one should check whether tests genes to be studied are intentionally being analyzed as opposed are legally permitted for the disease in question before perform- to a genetic variant that is found incidentally. By contrast, ing the genetic test. Testing for late-onset disorders should nor- the European Society for Human Genetics (ESHG) prefers the mally be postponed until the individual can provide full informed term “unsolicited finding (UF)”. In this article, both SF and consent. UF will be used within the appropriate context. 2. Estimation of risks ASPECTS OF GENETIC COUNSELING Estimation of risks becomes much more important in the face of NGS data because multiple pathogenic variants or VUS could 1. Diagnosis be obtained from one individual. To best explain the meaning of 1) History taking each variant to the P/C, the counselors should estimate the risks The proband’s/consultand’s (P/C) medical and family history associated with the observed variants. For example, a VUS can should be taken in a private room individually. Construction of a be reclassified into other types of variants using different meth- clear and detailed pedigree lays the foundation for good genetic ods [5, 6]. counseling. Only definite information should be used while constructing a pedigree. If possible, it is advisable to confirm the 3. Communication and support P/C’s responses with objective evidence. It is important to always When the test result is first announced, it is very important to keep in mind that the P/C might provide some incorrect infor- find a way to present the finding in a positive way to the P/C. In mation during an interview, including details on family relation- addition, since information on the mode of inheritance might ships. The same level of effort should be made with respect to create a feeling of guilt in the parents, a careful and prudent ap- gathering information for both the paternal and maternal sides proach is needed while discussing this topic. of the family. 292 www.annlabmed.org https://doi.org/10.3343/alm.2018.38.4.291  Yang M, et al. Genetic counseling in the NGS era BASIC PRINCIPLES disclosing one’s genetic test result represents an infringement upon one’s privacy, even when sharing among family members. 1. Autonomy P/C autonomy refers to the P/C’s right to make his/her own med- ETHICAL ISSUES ical decision without considering the value judgment of others. However, individuals must first be deemed capable of making 1. The right to know/the right not to know autonomous decisions in order to be awarded the rights of deci- The concept of the “right not to know” in genetic counseling sion-making and privacy. Non-autonomous individuals in- has been heavily debated [9-12]. Hofmann insisted that as clude minors (children), people with mental disability or illness, long as the information is not accurate and/or actionable, igno- and prisoners. Persons in a certain age range, e.g., adolescents rance is bliss. According to several studies performed around or younger children, could be considered to have some aspects the world, approximately 80% of individuals at risk for Hunting- of autonomy. Although respect for autonomy is an essential qual- ton’s disease did not want to know their carrier status. Even ity in genetic counseling, there are nevertheless some limitations for medically actionable diseases, some individuals feel comfort-. For example, not all P/Cs have equal access to all medical able not knowing their risk status. Moreover, it is not tech- choices owing to economic and social considerations. Indeed, nically simple to secure the right not to know with WES or WGS autonomy is an ethical construct particular to Westernized cul- data, or even with a multiple gene panel test, as this would re- tures. quire a tremendous amount of time and effort to help the P/C Uncritical dependence or overreliance on autonomy can re- decide what he/she wants to know and what he/she does not sult in a non-favorable outcome for patients and families. Famil- want to know among the large amount of data generated. ial autonomy may sometimes be more important than individual autonomy. Thus, although P/C autonomy is a fundamental prin- 2. Coercion ciple of genetic counseling, this does not imply that autonomy True coercion involves some type of harm or the threat of harm; should dominate over all other values in all situations. Rather, however, there are many other types of more subtle pressure the concept of autonomy in genetic counseling should be ap- tactics possible, including persuasion and manipulation. For plied in accordance with the cultural norms of a given society. example, the P/C might be persuaded by his/her relatives to un- Another important concept to consider is non-directiveness dergo a genetic test. In this case, the counselor can provide other that is a genetic counseling strategy, in which the genetic coun- options such as offering a genetic test to other relatives. selor tries to avoid influencing a P/C’s decision. “What would you do if you were in my place?” is the most commonly encoun- 3. Confidentiality tered question of a P/C during genetic counseling. The traditional Counselors need to respect client confidentiality by not releasing and theoretical response is to avoid answering this question. How- any client data to a third party, including the P/C’s relatives. ever, such avoidance could make a P/C feel helpless and aban- Ethical dilemmas can occur when the P/C does not want to share doned. Counselors can help the patient imagine the full extent genetic test results with relatives or wants to share genetic test of the consequences by explaining and providing examples based results with some but not all relatives. However, some research- on rational and objective facts. By using this technique, the coun- ers have pointed out that the doctor’s duty of confidentiality is selors engage in a process that can help promote patient deci- not absolute. In some very special circumstances, confi- sion-making. dentiality may be overruled for the public interest or to prevent injury or severe health damage to other individuals. 2. Privacy The principle of privacy is also highly dependent on the cultural 4. Reproductive decision making background, and thus varies from society to society or even from In the United States, there is no single overarching legal author- one group to another group in a single society. The Korean soci- ity dictating the requirements or limitations of prenatal testing or ety is currently in a transitional phase, in which the value of pri- the clinical practices that surround how healthcare profession- vacy differs between elderly and young people. Elderly people als offer screening or explain or treat genetic disorders. By tend to have no issues with sharing genetic test results among contrast, in Korea, the Bioethics Law and the Mother and Child family members, whereas younger people might consider that Health Law permit prenatal test and preimplantation genetic di- https://doi.org/10.3343/alm.2018.38.4.291 www.annlabmed.org 293  Yang M, et al. Genetic counseling in the NGS era agnosis (PGD) only for particular sets of diseases, for e.g., test- However, the ESHG has still not reached a consensus with re- ing for Duchenne muscular dystrophy is permitted, while that gard to reporting VUS. With respect to the recommendation of for Wilson’s disease is not. We suggest that different criteria should the ACMG, there was no limitation placed on children when re- be applied to prenatal diagnosis and PGD owing to the possibil- porting SF. However, stricter rules are needed regarding chil- ity of eugenics. This is an important consideration in terms of dren in societies with little solicitude for children, such as those genetic diversity, because it is not known which genomes were in Korea. present prior to survival in a particular environment. According Other aspects worthy of consideration include attitudes to- to Sparrow , one could assert that it is not fair to compro- ward disease, as well as the values and culture of the society. mise on the welfare of individuals in order to maintain diversity. Thus, in the Korean society, which is vulnerable to eugenics be- We believe that society should come together in solidarity to sup- cause of a fierce competitive environment, there is arguably port and protect individuals with diseases. greater importance in reporting UF or VUS. Hence, full discus- Gene editing methods such as clustered regularly interspaced sion on reporting UF and VUS is absolutely necessary before short palindromic repeats (CRISPR)/Cas9 are complicated tech- application in practice. One strategy might be context-specific niques that could be applied toward the creation of so-called counseling based on the life stage. “designer babies” toward eliminating disease-causing gene vari- Another aspect to consider is reporting UF in a research set- ants from the population; thus, this possibility should be urgently ting. Decisions about the disclosure of WGS and WES findings discussed in depth. Other issues related to gene editing should generated in a research setting are generally much more ethi- also be discussed based on the concept of social solidarity. cally contentious than decision-making in a clinical setting. Thus, Hallowell et al called for greater transparency related to the 5. Testing of minors purpose of sample collection, more explicit protocols for transi- Whenever possible, children and adolescents should provide tioning between research and clinical contexts, and more de- assent for testing and treatment. There is no precise age at tailed warnings provided to patients and research participants of which an adolescent’s wishes should be considered to be equally the potential for incidental findings to be generated, as well as important as those of the parents. This decision will vary on a their potential significance and actions that might be taken as a cultural, familial, legal, and individual basis. Upon reflection, result. adolescents of varying ages at the time of genetic counseling felt A recent study assessed the preference for disclosure of SF that they had a greater sense of stability when they were 15 to results based on the responses of 200 families surveyed , 16 years of age compared to the transition between elementary which revealed various reactions to the topic. There may also be school and high school at age 13, which was associated with different opinions among different societies; thus, research on significant social adjustment and fears of not being accepted the preference for SF/UF should be conducted in the Korean. population. PERSPECTIVE 1: GENETIC COUNSELING IN PERSPECTIVE 2: WHO CAN PROVIDE GENETIC THE ERA OF NGS COUNSELING? The ACMG has updated the recommendations for reporting of The Professional Society of Genetic Counselors in Asia recently SF based on clinical genome sequencing data, which includes provided an overview of the current status and challenges faced 59 medically actionable genes. The ESHG has also recom- in 10 Asia-Pacific countries, and proposed a course of unified mended reporting only clinically actionable UF. There is a actions for the future of the genetic counseling profession. wide spectrum of opinions regarding reporting VUS. The ACMG In Korea, a certificate is given to non-medical personnel who classified variants that should be reported as SF into known path- have working experience in the field of genetic counseling. How- ogenic and expected pathogenic variants, the latter of which be- ever, there are intrinsic ethical and legal problems in this sys- ing indicative of a “Sequence variation which is previously unre- tem, because these non-medical personnel do not have knowl- ported and is of the type which is expected to cause the disor- edge of relevant medical ethics or a legal obligation of patient der”. This recommendation classified genes for which ex- confidentiality. The current Korean medical law prohibits medi- pected pathogenic variants should or should not be reported. cal personnel from disclosing a patient’s private information. In 294 www.annlabmed.org https://doi.org/10.3343/alm.2018.38.4.291  Yang M, et al. 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