Purpose Pre-fALS is a longitudinal study of individuals potentially at risk for developing familial amyotrophic lateral sclerosis (fALS). Our goals were to: 1) explore participants’ decisions whether or not to learn results of pre-symptomatic testing; 2) understand the psychosocial impact of these decisions; 3) assess preferences for receiving results by telephone or in-person. Methods The sample for this sub-study comprised 20 participants drawn randomly from autosomal dominant mutant SOD1 (mtSOD1) families in the Pre-fALS study. Twenty participants completed a semi-structured phone interview; prominent themes were identified and rated. Results Fourteen participants chose to learn results; 6 had mtSOD1 and 8 had wtSOD1. Of the 6 who initially elected non-disclosure, 3 were reconsidering their decision. Regardless of the results and method of counseling, participants had adapted well, at least in the short-term. Conclusion We recommend: 1) those considering pre-symptomatic genetic testing should undergo professional counseling to help decide whether to learn results; 2) discussion should include the option of telephone genetic counseling for those without easy access to in-person counseling; 3) those who initially decline to learn results should be offered the opportunity to learn their mutation status as their decision evolves.

Remarkable advances in our understanding of the genetic contributions to amyotrophic lateral sclerosis (ALS) have sparked discussion and debate about whether clinical genetic testing should routinely be offered to patients with ALS. A related, but distinct, question is whether presymptomatic genetic testing should be offered to family members who may be at risk for developing ALS. Existing guidelines for presymptomatic counseling and testing are mostly based on small number of individuals, clinical judgment, and experience from other neurodegenerative disorders. Over the course of the last 8 years, we have provided testing and 317 genetic counseling sessions (including predecision, pretest, posttest, and ad hoc counseling) to 161 first-degree family members participating in the Pre-Symptomatic Familial ALS Study (Pre-fALS), as well as testing and 75 posttest counseling sessions to 63 individuals with familial ALS. Based on this experience, and the real-world challenges we have had to overcome in the process, we recommend an updated set of guidelines for providing presymptomatic genetic counseling and testing to people at high genetic risk for developing ALS. These recommendations are especially timely and relevant given the growing interest in studying presymptomatic ALS. Published guidelines for presymptomatic genetic testing (psGT) in amyotrophic lateral sclerosis (ALS) [1][2][3] have been based in part on experience in Huntington disease (HD) 4,5 and other lateonset neurodegenerative diseases such as Alzheimer disease, 6,7 and in part on experience in a small number of first-degree relatives of patients with superoxide dismutase-1 (SOD1) familial ALS.8 As the spectrum of identified genetic causes of ALS expands and the landscape of ALS genetics becomes ever more complex, 9,10 there is an increasing need to revisit the proposed guidelines. In this article, we highlight clinically relevant aspects of the genetic complexity of ALS and, drawing on the extensive experience acquired through the ongoing Pre-Symptomatic Familial ALS Study (Pre-fALS), present an approach to psGT that we have developed and refined over the last 8 years. While our experience derives from, and is most relevant to, psGT in the research arena, it may also inform the more controversial endeavor of psGT in a clinical setting.BACKGROUND AND RATIONALE "Familial," "sporadic," and "genetic" ALS. Traditionally, a distinction has been drawn between familial ALS (fALS) and sporadic ALS (sALS) based on the presence or absence of a family history of ALS, with a genetic etiology presupposed for fALS, but not for those without a family history. This distinction, however, is artificial and the inference about genetic etiology incorrect, as all the genes known to cause fALS have also been identified in patients with (seemingly) sALS.9 Some have proposed as an alternative the term hereditary ALS.11 While there are many reasons why ALS with a known genetic cause may not reveal a family history (e.g., recessive inheritance, compound heterozygosity, ...

After repeated media attention in 2013 due to the Angelina Jolie disclosure and the Supreme Court decision to ban gene patents, the demand for cancer genetic counseling and testing services has never been greater. Debate has arisen regarding who should provide such services and the quality of genetics services being offered. In this ongoing case series, we document 35 new cases from 7 states (California, Connecticut, Florida, Georgia, Missouri, Pennsylvania, and Utah) and the District of Columbia of adverse outcomes in cancer genetic testing when performed without the involvement of a certified genetic counselor. We identified 3 major themes of errors: wrong genetic tests ordered, genetic test results misinterpreted, and inadequate genetic counseling. Patient morbidity and mortality were an issue in several of these cases. The complexity of cancer genetic testing and counseling has grown exponentially with the advent of multigene panels that include rare genes and the potential for more variants of uncertain significance. We conclude that genetic counseling and testing should be offered by certified genetics providers to minimize the risks, maximize the benefits, and utilize health care dollars most efficiently.

Significant progress has been made in understanding the pre-symptomatic phase of amyotrophic lateral sclerosis (ALS). While much is still unknown, advances in other neurodegenerative diseases offer valuable insights. Indeed, it is increasingly clear that the well-recognized clinical syndromes of Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), spinal muscular atrophy, and frontotemporal dementia are also each preceded by a pre-symptomatic or prodromal period of varying duration, during which the underlying disease process unfolds, with associated compensatory changes and loss of inherent system redundancy. Key insights from these diseases highlight opportunities for discovery in ALS. The development of biomarkers reflecting amyloid and tau has led to a shift in defining AD based on inferred underlying histopathology. PD is unique among neurodegenerative diseases in the number and diversity of non-genetic biomarkers of pre-symptomatic disease, most notably REM-sleep behavior disorder. HD benefits from an ability to predict the likely timing of clinically manifest disease based on age and CAG-repeat length alongside reliable neuroimaging markers of atrophy. SMA clinical trials have highlighted the transformational value of early therapeutic intervention, and studies in FTD illustrate the differential role of biomarkers based on genotype. Similar advances in ALS would transform our understanding of key events in pathogenesis, thereby dramatically accelerating progress towards disease prevention. Deciphering the biology of pre-symptomatic ALS relies upon a clear conceptual framework for defining the earliest stages of disease. Clinically manifest ALS may emerge abruptly, especially among those who harbor genetic mutations associated with rapidly progressive ALS. However, the disease may also evolve more gradually, revealing a prodromal period of mild motor impairment preceding phenoconversion to clinically manifest disease. Similarly, cognitive and behavioral impairment, when present, may emerge gradually, evolving through a prodromal period of mild cognitive impairment or mild behavioral impairment before progression to ALS. Biomarkers are critically important to studying pre-symptomatic ALS and essential to efforts to intervene therapeutically before clinically manifest disease emerges. The use of non-genetic biomarkers, however, presents challenges related to counseling, informed consent, communication of results, and limited protections afforded by existing legislation. Experiences from pre-symptomatic genetic testing and counseling, and the legal protections against discrimination based on genetic data, may serve as a guide. Building upon what we have learned—more broadly from other pre-symptomatic neurodegenerative diseases and specifically from ALS gene mutation carriers—we present a roadmap to early intervention, and perhaps even disease prevention, for all forms of ALS.

The introduction of next-generation sequencing (NGS) technology in testing for hereditary cancer susceptibility allows testing of multiple cancer susceptibility genes simultaneously. While there are many potential benefits to utilizing this technology in the hereditary cancer clinic, including efficiency of time and cost, there are also important limitations that must be considered. The best panel for the given clinical situation should be selected to minimize the number of variants of unknown significance. The inclusion in panels of low penetrance or newly identified genes without specific actionability can be problematic for interpretation. Genetic counselors are an essential part of the hereditary cancer risk assessment team, helping the medical team select the most appropriate test and interpret the often complex results. Genetic counselors obtain an extended family history, counsel patients on the available tests and the potential implications of results for themselves and their family members (pre-test counseling), explain to patients the implications of the test results (post-test counseling), and assist in testing family members at risk.