Recommendations for clinical interpretation of variants found in non-coding regions of the genome

Purpose: The majority of clinical genetic testing focuses almost exclusively on regions of the genome that directly encode proteins. The important role of variants in non-coding regions in penetrant disease is, however, increasingly being demonstrated, and the use of whole genome sequencing in clinical diagnostic settings is rising across a large range of genetic disorders. Despite this, there is no existing guidance on how current guidelines designed primarily for variants in protein-coding regions should be adapted for variants identified in other genomic contexts. Methods: We convened a panel of clinical and research scientists with wide-ranging expertise in clinical variant interpretation, with specific experience in variants within non-coding regions. This panel discussed and refined an initial draft of the guidelines which were then extensively tested and reviewed by external groups. Results: We discuss considerations specifically for variants in non-coding regions of the genome. We outline how to define candidate regulatory elements, highlight examples of mechanisms through which non-coding region variants can lead to penetrant monogenic disease, and outline how existing guidelines can be adapted for these variants. Conclusion: These recommendations aim to increase the number and range of non-coding region variants that can be clinically interpreted, which, together with a compatible phenotype, can lead to new diagnoses and catalyse the discovery of novel disease mechanisms.

Access, utilization, and awareness for clinical genetic testing in autism spectrum disorder in Sweden: A survey study

Clinical genetic testing is recommended for individuals diagnosed with autism spectrum disorder. There are only a few reports of how these recommendations are followed and especially missing for European countries. We aimed to analyze the rate of access, utilization, and awareness of clinical genetic testing among autistic individuals in Sweden through online surveys targeting parents with at least one autistic child and autistic adolescents (from 15 years) and adults. In total, 868 parents of autistic children and 213 autistic adolescents or adults completed the survey. Only 9.1% ( n = 79) of parents and 2.8% ( n = 6) of autistic adolescents/adults reported having received a referral for clinical genetic testing after autism spectrum disorder diagnosis. The autistic children offered a referral were younger at diagnosis ( p < 0.001) and more likely to have an additional neurodevelopmental diagnosis ( p < 0.01), including intellectual disability ( p < 0.001) or a language disorder ( p < 0.001). Genetic counseling was provided to less than half of the families that were referred for clinical genetic testing. Finally, we report that both respondent groups preferred to be informed by written text and an expert in genetics about clinical genetic testing. This study highlights a lack of awareness and access to clinical genetic testing after autism spectrum disorder diagnosis in Sweden and demonstrates the need for additional studies on how clinical guidelines for genetic testing are followed in different countries. Lay abstract Several medical professional societies recommend clinical genetic testing for autistic individuals as many genetic conditions are linked to autism. However, it is unclear to what extent autistic individuals and parents of autistic children are offered clinical genetic testing. We conducted a community-based survey to estimate the access, utilization, and awareness for clinical genetic testing in Sweden. In total, 868 parents of autistic children and 213 autistic adolescents or adults participated as respondents. The referral rate for clinical genetic testing after autism spectrum disorder diagnosis was low, with only 9.1% for the autistic children as reported by their parents and 2.8% for autistic adolescents/adults. The autistic children who got referrals were more likely to have intellectual disability and language disorder. We also report that awareness of the clinical genetic testing possibility was low in both respondent groups. We also highlight preferred communication means and needs for information before clinical genetic testing. Our results show that utilization and access are low in Sweden, and more studies should be conducted to report these rates in different countries to analyze the effects of clinical genetic testing on healthcare for autistic individuals. Our results highlight the most important information for the families and how the information should be communicated prior to clinical genetic testing.

Clinical genetics laboratories use divergent demographic frameworks across countries: comparing data structures for race, ethnicity, and ancestry on test requisition forms

Purpose. The goal of this study is to investigate how population groups are represented on requisition forms for clinical genetic testing in different laboratories. Methods. Clinical laboratory test requisition forms (RFs) were obtained from 70 laboratories in the US, Canada, Europe, and Australia. Details about the laboratories and how RFs represent patient demographics were extracted and analyzed for trends between forms in the U.S. (N=213) and other countries (N=203). Results. Clinical genetics laboratories included in the analysis vary widely regarding the format of demographic data collected on test requisition forms. US-based laboratory RFs are more likely than those from other countries to include race or ethnicity. These are most often represented as categorical data, with multiple-choice options. RFs from laboratories in other countries do not include race, and those that include ethnicity most often provide a blank space for open-ended responses. Conclusions. These results are consistent with existing research on heterogeneity in the nomenclature and number of categories used to describe patient populations across clinical genetics laboratories in the US. It also suggests systemic differences in the way measures of diversity are conceptualized in the US compared to other countries.

Defining the Critical Components of Informed Consent for Genetic Testing

Purpose: Informed consent for genetic testing has historically been acquired during pretest genetic counseling, without specific guidance defining which core concepts are required. Methods: The Clinical Genome Resource (ClinGen) Consent and Disclosure Recommendations Workgroup (CADRe) used an expert consensus process to identify the core concepts essential to consent for clinical genetic testing. A literature review identified 77 concepts that are included in informed consent for genetic tests. Twenty-five experts (9 medical geneticists, 8 genetic counselors, and 9 bioethicists) completed two rounds of surveys ranking concepts’ importance to informed consent. Results: The most highly ranked concepts included: (1) genetic testing is voluntary; (2) why is the test recommended and what does it test for?; (3) what results will be returned and to whom?; (4) are there other types of potential results, and what choices exist?; (5) how will the prognosis and management be impacted by results?; (6) what is the potential family impact?; (7) what are the test limitations and next steps?; and (8) potential risk of genetic discrimination and legal protections. Conclusion: Defining the core concepts necessary for informed consent for genetic testing provides a foundation for quality patient care across a variety of healthcare providers and clinical indications.

Genetic Testing for Heritable Cardiovascular Diseases in Pediatric Patients: A Scientific Statement From the American Heart Association

Genetic diseases that affect the cardiovascular system are relatively common and include cardiac channelopathies, cardiomyopathies, aortopathies, hypercholesterolemias, and structural diseases of the heart and great vessels. The rapidly expanding availability of clinical genetic testing leverages decades of research into the genetic origins of these diseases, helping inform diagnosis, clinical management, and prognosis. Although a number of guidelines and statements detail best practices for cardiovascular genetic testing, there is a paucity of pediatric-focused statements addressing the unique challenges in testing in this vulnerable population. In this scientific statement, we seek to coalesce the existing literature around the use of genetic testing for cardiovascular disease in infants, children, and adolescents.

Interpretation of Incidental Genetic Findings Localizing to Genes Associated With Cardiac Channelopathies and Cardiomyopathies

Recent advances in next-genetic sequencing technology have facilitated an expansion in the use of exome and genome sequencing in the research and clinical settings. While this has aided in the genetic diagnosis of individuals with atypical clinical presentations, there has been a marked increase in the number of incidentally identified variants of uncertain diagnostic significance in genes identified as clinically actionable by the American College of Medical Genetics guidelines. Approximately 20 of these genes are associated with cardiac diseases, which carry a significant risk of sudden cardiac death. While identification of at-risk individuals is paramount, increased discovery of incidental variants of uncertain diagnostic significance has placed a burden on the clinician tasked with determining the diagnostic significance of these findings. Herein, we describe the scope of this emerging problem using cardiovascular genetics to illustrate the challenges associated with variants of uncertain diagnostic significance interpretation. We review the evidence for diagnostic weight of these variants, discuss the role of clinical genetics providers in patient care, and put forward general recommendations about the interpretation of incidentally identified variants found with clinical genetic testing.

Amyotrophic Lateral Sclerosis Genetic Access Program

ObjectiveTo report the frequency of amyotrophic lateral sclerosis (ALS) genetic variants in a nationwide cohort of clinic-based patients with ALS with a family history of ALS (fALS), dementia (dALS), or both ALS and dementia (fALS/dALS).MethodsA multicenter, prospective cohort of 573 patients with fALS, dALS, or fALS/dALS, underwent genetic testing in the ALS Genetic Access Program (ALS GAP), a clinical program for clinics of the Northeast ALS Consortium. Patients with dALS underwent C9orf72 hexanucleotide repeat expansion (HRE) testing; those with fALS or fALS/dALS underwent C9orf72 HRE testing, followed by sequencing of SOD1, FUS, TARDBP, TBK1, and VCP.ResultsA pathogenic (P) or likely pathogenic (LP) variant was identified in 171/573 (30%) of program participants. About half of patients with fALS or fALS/dALS (138/301, 45.8%) had either a C9orf72 HRE or a P or LP variant identified in SOD1, FUS, TARDBP, TBK1, or VCP. The use of a targeted, 5-gene sequencing panel resulted in far fewer uncertain test outcomes in familial cases compared with larger panels used in other in clinic-based cohorts. Among dALS cases 11.8% (32/270) were found to have the C9orf72 HRE. Patients of non-Caucasian geoancestry were less likely to test positive for the C9orf72 HRE, but were more likely to test positive on panel testing, compared with those of Caucasian ancestry.ConclusionsThe ALS GAP program provided a genetic diagnosis to ∼1 in 3 participants and may serve as a model for clinical genetic testing in ALS.