American College Of Medical Genetics And Genomics Recommendations Research Articles

Sifrim-Hitz-Weiss/CHD4-related syndrome: A new case report.

Sifrim-Hitz-Weiss/CHD4-related syndrome: A new case report.

O-145 Limitations of designing carrier screening panels based on estimated frequencies. Concordance between recommendations and observed frequencies

Abstract Study question Are recommended carrier screening (CS) panels suitable worldwide or should they be designed taking into account observed carrier frequencies (CF)? Summary answer Limitations of carrier screening panel recommendations based on estimated frequencies could be avoided with a worldwide-database of observed carrier frequencies. What is known already Currently, there is no consensus for specific gene panel for CS, but some scientific societies, based on estimated carrier frequencies, recommend to analyze a narrow panel rather than exome. The American College of Medical Genetics and Genomics (ACMG) recently recommended a 4-tiered system, encouraging to analyze genes in tier 3, genes with less carrier frequency (tier 4) are only recommended to be analyzed on specific cases. Similarly, Sociedad Española de Fertilidad (SEF) recommends in absence of genetic matching (GM) a 6 gene basic panel for donor screening and in a GM context suggests a 50-diseases panel. Study design, size, duration This study includes 8542 patients analyzed with an expanded carrier screening panel of 300 genes, including autosomal recessive (AR) and X-linked (XL) disorders by next-generation sequencing (NGS). ACMG guidelines were followed for variant interpretation and only pathogenic and likely pathogenic variants were reported. The study has been conducted between August 2018 and December 2021. Participants/materials, setting, methods DNA was extracted and sequenced. Obtained data was processed by bioinformatic tools. CF for diseases analyzed was stablished. Genes were categorized according to tier-3 of the ACMG recommendations (112 genes, only 80 included on this study) and also by 50-disease panel of SEF recommendations (49 genes, 40 included on this study). Likewise, analyzed diseases were divided in two groups according to the obtained CF: A (CF ≤ 1/200 - 56 genes); B (CF > 1/200 - 244 genes). Main results and the role of chance The analysis of the 8542 patients showed that 2582 (30.23%) of them were not carriers of any disease analyzed, 2205 (25.81%) of them were only carriers of one or more of the diseases included in the ACMG tier3 panel and 3755 (43.96%) were carriers of at least one disease not included this category. When diseases analyzed were categorized by SEF 50-disease panel, 2280 (26.69%) patients were only carriers of one or more of the diseases included in this panel and 3680 (43.08%) were carriers of at least one disease that would not be analyzed by this panel. On the other hand, when diseases were divided by observed carrier frequency, a total of 3476 patients (40.69%) were carriers only of a disease(s) included in A group. With this panel, only 2484 (29.08%) of the 8542 patients would not have been correctly diagnosed. Moreover, the variants undetected would affect less frequent diseases (B group). It is important to notice that group A has been created regarding the data of a 300 gene panel. If another panel would have been analyzed, the group of genes may have changed, but the data collected highlights the importance of observed CF on panel design. Limitations, reasons for caution Not all Tier3 ACMG and 50-disease SEF genes are included due to original panel limitations. Observed CF may vary depending on the population analyzed. NGS panel design does not cover variants in regulatory or deep intronic regions. Pseudogenes can interfere. Not all structural variants can be detected by NGS. Wider implications of the findings These data highlight the importance of reviewing the genes included in carrier screening panels by their frequency. Furthermore, it points out the need to have updated databases with observed CF available so an universal panel can be designed or adapted to patient’s needs. Trial registration number Not applicable

Newly identified molecular and genetic characteristics of primary mediastinal large B-cell lymphoma.

e19580 Background: Many studies have been devoted to the molecular profile of diffuse large B-cell lymphoma; however, a clear molecular and genetic picture of primary mediastinal large B-cell lymphoma (PMBLC) has not yet been described. Studies have reported various signaling pathways involved in PMBCL pathogenesis, with the best known JAK-STAT and NF-kB. This study was aimed at the detection of previously undescribed mutations, as well as the identification of signaling pathways that may be of interest in the search for new therapeutic targets for PMBCL. Methods: Tumor biopsy specimens from 23 PMBCL patients were examined by next-generation sequencing (NGS) on the Illumina NextSeq 550 system with an average coverage of at least 100x using the AVENIO Tumor Expanded Panel (Roche, USA) containing 77 genes. Analytical sensitivity of mutation detection was 5%. The pathogenicity of the identified nucleotide substitutions was assessed according to ACMG (American College of Medical Genetics and Genomics) and AMP (Association of Molecular Pathology) recommendations. Genomic DNAs were extracted from FFPE blocks using the Gene Read DNA FFPE Kit panel (Qiagen, USA) according to the standard protocol. DNA concentrations were measured fluorimetrically on the Qubit 2.0 fluorometer (Life Technologies, USA). The AVENIO Oncology Analysis Software was used to process the data and to search for clinically significant mutations. The genetic material was analyzed for clinically significant mutations among well-known databases: COSMIC: V83, TCGA 9.0, Exac: 1.0, DBSNP: 150, 1000 Genomes: phase_3_v5b, Snpeff: 4.2. Results: The targeted high-performance sequencing of PMBLC samples showed a newly revealed range of polymorphisms in 9 genes in patients with PMBLC (Alk, TP53, CCND3, RNF43, PIK3CA, FGFR3, SMO, MET, EZH2), previously not described for this cancer. We also interpreted signal pathways related to the mutated genes. Conclusions: The identified polymorphisms and the relationship of mutated genes with PMBLC signaling paths can serve as new therapeutic targets for patients with PMBLC.

EP344: Making the grade: How carrier screening panels score against the American College of Medical Genetics and Genomics “Tier 3” recommendations

Laboratories take many considerations when curating expanded carrier screening panels. Criteria considered when choosing conditions to include on panels often consists of condition severity, carrier frequency, ability and accuracy of testing strategies, well-established genotype-phenotype correlations, and reproductive testing options. The American College of Medical Genetics and Genomics (ACMG) recently issued a practice resource entitled “Screening for autosomal recessive and X-linked conditions during pregnancy and preconception: a practice resource of the American College of Medical Genetics and Genomics and Genomics (ACMG)”. Because their previous documents were published before the current advancements in gene sequencing technology, they have since updated their recommendations for carrier screening panel curation, and shifted their focus from ethnic based carrier screening to equity of care. ACMG’s new recommendation states that all preconception and pregnant patients be offered Tier 3 carrier screening. Conditions qualifying for Tier 3 are defined as autosomal recessive conditions with a carrier frequency of greater than or equal to 1 in 200. ACMG did not specify if the carrier frequency should apply to the global population or specific ethnic groups. However, they do acknowledge that many genetic conditions do not have a pan-ethnic carrier frequency of 1 in 200, but do meet this criteria in a subpopulation that is well-represented in the United States. In this study, we examined expanded carrier screening panels from five different laboratories to determine what percentage of each panel meets the Tier 3 recommendations based on both the pan-ethnic carrier frequency and subpopulation carrier frequency for those ethnic backgrounds that have at least 1% representation in the United States. A total of five expanded carrier screening (ECS) panels from differing genetic testing laboratories were reviewed. Information regarding the conditions included on the panel as well as carrier frequencies were obtained from each laboratory’s website. The largest panels offered by each lab were selected, excluding any optional add-ons. The panels which varied in size by the number of conditions screened for were as follows: 113 (NxGen MDx), 172, 274, 287 and 501 conditions, respectively. Data was analyzed to determine how the different ECS panels scored when compared to the Tier 3 recommendations set forward by the American College of Medical Genetics and Genomics. Scoring was first determined through a percentage basis of how many conditions included on the ECS had a pan-ethnic carrier frequency of 1 in 200 or greater. Each panel was then scored based on how many conditions included on the ECS had a carrier frequency of 1 in 200 or greater in subpopulations that have at least 1% representation in the United States. ACMG suggested that X-linked conditions be included on an ECS based on a prevalence of 1/40,000 or greater. The X-linked conditions included in the scoring for these panels are the specific conditions recommended by ACMG in the practice resource. When scoring based on pan-ethnic carrier frequency alone, the 172 condition panel received the highest score with a 39.0%. NxGen MDx’s 113 condition panel received the second highest score at 33.6%. The remaining scores were as follows: 27.5% for the 287 condition panel, 24.5% for the 274 condition panel, and 18.2% for the 501 condition panel. When scoring with the addition of subpopulations that have at least 1% representation in the United States, NxGen MDx’s 113 condition panel received the highest score of 64.6%. The 172 condition panel received the second highest score at 63.4%. The remaining scores were as follows: 44.9% for the 274 condition panel, 42.9% for the 287 condition panel and 34.9% for the 501 condition panel. Interestingly, among the panels reviewed, the score appears to decrease as the panel size is expanded. None of the ECS panels examined in this study had over 50% of the conditions included on their panel that meet ACMG’s Tier 3 criteria when going by pan-ethnic carrier frequency alone. However, when including other subpopulation carrier frequencies, the two smallest panels had over 50% of their conditions meet Tier 3 criteria. Our analysis highlights the incongruity between ECS panels routinely offered in clinical settings and current ACMG recommendations. Though Tier 3 criteria should be considered in panel curation, selecting conditions solely on pan-ethnic carrier frequency may not be sufficient in addressing patient needs, as certain ethnicities may have a higher carrier frequency for conditions that otherwise have over a 1/200 pan-ethnic carrier frequency. Including these specific conditions on ECS panels addresses any concerns regarding the shift away from using self-reported patient ancestry for panel selection. As ECS panel curation continues to evolve, it will be important to consider more robust panel criteria that acknowledge other factors pertinent to patient care.

Discerning the Ambiguous Role of Missense TTN Variants in Inherited Arrhythmogenic Syndromes.

The titin gene (TTN) is associated with several diseases, including inherited arrhythmias. Most of these diagnoses are attributed to rare TTN variants encoding truncated forms, but missense variants represent a diagnostic challenge for clinical genetics. The proper interpretation of genetic data is critical for translation into the clinical setting. Notably, many TTN variants were classified before 2015, when the American College of Medical Genetics and Genomics (ACMG) published recommendations to accurately classify genetic variants. Our aim was to perform an exhaustive reanalysis of rare missense TTN variants that were classified before 2015, and that have ambiguous roles in inherited arrhythmogenic syndromes. Rare missense TTN variants classified before 2015 were updated following the ACMG recommendations and according to all the currently available data. Our cohort included 193 individuals definitively diagnosed with an inherited arrhythmogenic syndrome before 2015. Our analysis resulted in the reclassification of 36.8% of the missense variants from unknown to benign/likely benign. Of all the remaining variants, currently classified as of unknown significance, 38.3% showed a potential, but not confirmed, deleterious role. Most of these rare missense TTN variants with a suspected deleterious role were identified in patients diagnosed with hypertrophic cardiomyopathy. More than 35% of the rare missense TTN variants previously classified as ambiguous were reclassified as not deleterious, mainly because of improved population frequencies. Despite being inconclusive, almost 40% of the variants showed a potentially deleterious role in inherited arrhythmogenic syndromes. Our results highlight the importance of the periodical reclassification of rare missense TTN variants to improve genetic diagnoses and help increase the accuracy of personalized medicine.

Does the law require reinterpretation and return of revised genomic results?

Does the law require reinterpretation and return of revised genomic results?

Adherence of Cell-Free DNA Noninvasive Prenatal Screens to ACMG Recommendations

Noninvasive prenatal screening (NIPS) for fetal aneuploidy via cell-free DNA has been commercially available in the United States since 2011. In 2016, the American College of Medical Genetics and Genomics (ACMG) issued a position statement with specific recommendations for testing laboratories. We sought to evaluate adherence to these recommendations. We focused on commercial laboratories performing NIPS testing in the United States as of 1 January 2018. Sample laboratory reports and other materials were scored for compliance with ACMG recommendations. Variables scored for common and sex chromosome aneuploidy detection included detection rate, specificity, positive and negative predictive value, and fetal fraction. Labs that performed analysis of copy-number variants and results for aneuploidies other than those commonly reported were identified. Available patient education materials were similarly evaluated. Nine of 10 companies reported fetal fraction in their reports, and 8 of 10 did not offer screening for autosomal aneuploidies beyond trisomy 13, 18, and 21. There was inconsistency in the application and reporting of other measures recommended by ACMG. Laboratories varied in the degree to which they met ACMG position statement recommendations. No company adhered to all laboratory guidance.

Adherence of cell-free DNA noninvasive prenatal screens to ACMG recommendations

PurposeNoninvasive prenatal screening (NIPS) for fetal aneuploidy via cell-free DNA has been commercially available in the United States since 2011. In 2016, the American College of Medical Genetics and Genomics (ACMG) issued a position statement with specific recommendations for testing laboratories. We sought to evaluate adherence to these recommendations. MethodsWe focused on commercial laboratories performing NIPS testing in the United States as of 1 January 2018. Sample laboratory reports and other materials were scored for compliance with ACMG recommendations. Variables scored for common and sex chromosome aneuploidy detection included detection rate, specificity, positive and negative predictive value, and fetal fraction. Labs that performed analysis of copy-number variants and results for aneuploidies other than those commonly reported were identified. Available patient education materials were similarly evaluated. ResultsNine of 10 companies reported fetal fraction in their reports, and 8 of 10 did not offer screening for autosomal aneuploidies beyond trisomy 13, 18, and 21. There was inconsistency in the application and reporting of other measures recommended by ACMG. ConclusionsLaboratories varied in the degree to which they met ACMG position statement recommendations. No company adhered to all laboratory guidance.

Mucopolysaccharidosis type VI (MPS VI) and molecular analysis: Review and classification of published variants in the ARSB gene.

Maroteaux–Lamy syndrome (MPS VI) is an autosomal recessive lysosomal storage disorder caused by pathogenic ARSB gene variants, commonly diagnosed through clinical findings and deficiency of the arylsulfatase B (ASB) enzyme. Detection of ARSB pathogenic variants can independently confirm diagnosis and render genetic counseling possible. In this review, we collect and summarize 908 alleles (201 distinct variants, including 3 polymorphisms previously considered as disease‐causing variants) from 478 individuals diagnosed with MPS VI, identified from literature and public databases. Each variant is further analyzed for clinical classification according to American College of Medical Genetics and Genomics (ACMG) guidelines. Results highlight the heterogeneity of ARSB alleles, with most unique variants (59.5%) identified as missense and 31.7% of unique alleles appearing once. Only 18% of distinct variants were previously recorded in public databases with supporting evidence and clinical significance. ACMG recommends publishing clinical and biochemical data that accurately characterize pathogenicity of new variants in association with reporting specific alleles. Variants analyzed were sent to ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/), and MPS VI locus‐specific database (http://mps6-database.org) where they will be available. High clinical suspicion coupled with diagnostic testing for deficient ASB activity and timely submission and classification of ARSB variants with biochemical and clinical data in public databases is essential for timely diagnosis of MPS VI.

Variation among Consent Forms for Clinical Whole Exome Sequencing

The goal of this study was to explore variation among informed consent documents for clinical whole exome sequencing (WES) in order to identify the level of consistency with the recommendations from the American College of Medical Genetics and Genomics (ACMG) and the Presidential Commission for the Study of Bioethical Issues (Bioethics Commission) regarding informed consent for clinical WES. Recommendations were organized into a framework of key points for analysis. Content analysis was conducted on a sample of informed consent documents for clinical WES downloaded from 18 laboratory websites. We observed considerable variability in the content of informed consent documents among the sample of 18 laboratories. The mean Flesch-Kincaid Grade Level, a measure of readability, of the consent forms was 10.8, above the recommended 8th grade level. For each of the individual ACMG and Bioethics Commission recommendations, the frequency of inclusion ranged from 11% to 100%. For the overall list of 18 consent items, inclusion ranged from 11 to 17 items (Mean = 13.44, Mode = 14). This analysis will be useful to laboratories that wish to create informed consent documents that comply with these recommendations. The consistent use of standardized informed consent process could improve communication between clinicians and patients and increase understanding of genetic testing.

Clinical genome sequencing and population preferences for information about 'incidental' findings-From medically actionable genes (MAGs) to patient actionable genes (PAGs).

Whole genome or exome sequencing is increasingly used in the clinical contexts, and ‘incidental’ findings are generated. There is need for an adequate policy for the reporting of these findings to individuals. Such a policy has been suggested by the American College of Medical Genetics and Genomics (ACMG). We argue that ACMG’s policy is overly paternalistic, and that an adequate policy must take into account population preferences. We conducted a choice based conjoint survey of population preferences for reporting in a representative sample of the Danish population. In a 12 task survey respondents were asked about their preference for reporting in relation to three scenarios with seven different attributes. Of 1200 respondents 66.4% participated. We show that population preferences for reporting differs from ACMG’s recommendations, and suggest a new policy based on both medically and patient actionable genes.

Abstract 12059: Incidental Findings in Cardiomyopathy and Channelopathy Genes Among 5891 Individuals Undergoing Whole-exome Sequencing. What Should be Reported?

Background: Whole-exome-sequencing (WES) is becoming a common molecular diagnostic test for patients with genetic disorders. However, this technique allows the identification not only of mutations responsible for the disease under investigation, but also of variants potentially causing other diseases, the so called “incidental findings” (IFs). The American College of Medical Genetics and Genomics (ACMG) stated that IFs should be reported based on clinical validity and utility and indicated a list of 56 actionable genes. Among these, nearly half (20/56) are major genes associated with channelopathies and cardiomyopathies. Despite these recommendations, most of the studies so far published, reported also mutations in minor genes among the actionable findings. Methods: WES was performed in 5891 individuals without known channelopathies or cardiomyopathies. Exome data were first filtered based on genotype quality. Subsequently, a frequency filter was applied, considering 1000 Genomes, ExAC and our internal exome database. Variants reported as pathogenic in ClinVar or novel but expected to be pathogenic (nonsense, frameshift and splice) were further investigated, following the ACMG guidelines. Major (20) and minor (73) genes associated with channelopathies and cardiomyopathies were evaluated. Results: We identified 3514 variants in the 93 genes under investigation, after applying the quality and frequency filters. Eight variants were classified as pathogenic and 52 as likely pathogenic and they were detected in around 1% of the individuals. The vast majority (85%) of pathogenic or likely pathogenic variants were located in the 20 actionable genes indicated by ACMG. The inclusion of minor genes increased the number of variants of unknown significance (VUS), from 865 to 3454. Conclusion: Our data support the ACMG recommendations in reporting only IFs identified in the 20 major cardiac actionable genes. Indeed, the inclusion of minor genes is mainly increasing the number of VUS, without significantly impacting the number of pathogenic and likely pathogenic variants. The percentage of individuals with potentially clinical relevant variants in these genes is too high in relation to the disease-prevalence: a cardiologic evaluation is warranted.

Identification of Medically Actionable Secondary Findings in the 1000 Genomes

The American College of Medical Genetics and Genomics (ACMG) recommends that clinical sequencing laboratories return secondary findings in 56 genes associated with medically actionable conditions. Our goal was to apply a systematic, stringent approach consistent with clinical standards to estimate the prevalence of pathogenic variants associated with such conditions using a diverse sequencing reference sample. Candidate variants in the 56 ACMG genes were selected from Phase 1 of the 1000 Genomes dataset, which contains sequencing information on 1,092 unrelated individuals from across the world. These variants were filtered using the Human Gene Mutation Database (HGMD) Professional version and defined parameters, appraised through literature review, and examined by a clinical laboratory specialist and expert physician. Over 70,000 genetic variants were extracted from the 56 genes, and filtering identified 237 variants annotated as disease causing by HGMD Professional. Literature review and expert evaluation determined that 7 of these variants were pathogenic or likely pathogenic. Furthermore, 5 additional truncating variants not listed as disease causing in HGMD Professional were identified as likely pathogenic. These 12 secondary findings are associated with diseases that could inform medical follow-up, including cancer predisposition syndromes, cardiac conditions, and familial hypercholesterolemia. The majority of the identified medically actionable findings were in individuals from the European (5/379) and Americas (4/181) ancestry groups, with fewer findings in Asian (2/286) and African (1/246) ancestry groups. Our results suggest that medically relevant secondary findings can be identified in approximately 1% (12/1092) of individuals in a diverse reference sample. As clinical sequencing laboratories continue to implement the ACMG recommendations, our results highlight that at least a small number of potentially important secondary findings can be selected for return. Our results also confirm that understudied populations will not reap proportionate benefits of genomic medicine, highlighting the need for continued research efforts on genetic diseases in these populations.

Economic evidence on identifying clinically actionable findings with whole-genome sequencing: a scoping review.

The American College of Medical Genetics and Genomics (ACMG) recommends that mutations in 56 genes for 24 conditions are clinically actionable and should be reported as secondary findings after whole-genome sequencing (WGS). Our aim was to identify published economic evaluations of detecting mutations in these genes among the general population or among targeted/high-risk populations and conditions and identify gaps in knowledge. A targeted PubMed search from 1994 through November 2014 was performed, and we included original, English-language articles reporting cost-effectiveness or a cost-to-utility ratio or net benefits/benefit-cost focused on screening (not treatment) for conditions and genes listed by the ACMG. Articles were screened, classified as targeting a high-risk or general population, and abstracted by two reviewers. General population studies were evaluated for actual cost-effectiveness measures (e.g., incremental cost-effectiveness ratios (ICER)), whereas studies of targeted populations were evaluated for whether at least one scenario proposed was cost-effective (e.g., ICER of ≤$100,000 per life-year or quality-adjusted life-year gained). A total of 607 studies were identified, and 32 relevant studies were included. Identified studies addressed fewer than one-third (7 of 24; 29%) of the ACMG conditions. The cost-effectiveness of screening in the general population was examined for only 2 of 24 conditions (8%). The cost-effectiveness of most genetic findings that the ACMG recommends for return has not been evaluated in economic studies or in the context of screening in the general population. The individual studies do not directly address the cost-effectiveness of WGS.

WHATIF: An open-source desktop application for extraction and management of the incidental findings from next-generation sequencing variant data

BackgroundIdentification and evaluation of incidental findings in patients following whole exome (WGS) or whole genome sequencing (WGS) is challenging for both practicing physicians and researchers. The American College of Medical Genetics and Genomics (ACMG) recently recommended a list of reportable incidental genetic findings. However, no informatics tools are currently available to support evaluation of incidental findings in next-generation sequencing data. MethodsThe Wisconsin Hierarchical Analysis Tool for Incidental Findings (WHATIF), was developed as a stand-alone Windows-based desktop executable, to support the interactive analysis of incidental findings in the context of the ACMG recommendations. WHATIF integrates the European Bioinformatics Institute Variant Effect Predictor (VEP) tool for biological interpretation and the National Center for Biotechnology Information ClinVar tool for clinical interpretation. ResultsAn open-source desktop program was created to annotate incidental findings and present the results with a user-friendly interface. Further, a meaningful index (WHATIF Index) was devised for each gene to facilitate ranking of the relative importance of the variants and estimate the potential workload associated with further evaluation of the variants. Our WHATIF application is available at: http://tinyurl.com/WHATIF-SOFTWARE ConclusionsThe WHATIF application offers a user-friendly interface and allows users to investigate the extracted variant information efficiently and intuitively while always accessing the up to date information on variants via application programming interfaces (API) connections. WHATIF׳s highly flexible design and straightforward implementation aids users in customizing the source code to meet their own special needs.

On the Justifiability of ACMG Recommendations for Reporting of Incidental Findings in Clinical Exome and Genome Sequencing

This paper examines three possible justifications for original ACMG recommendations to return incidental findings from whole exome or genome sequencing independent of patient preferences. The first two potential justifications, based on a patient's authentic values, then on harms to others, are founding lacking as a basis of justification for these recommendations. The third, grounded in analogous professional practices, might serve as a potential justification if several controversies can be avoided. However, given the nature of these controversies and the need to instill public trust in this newly emerging science, the paper finds that updated ACMG recommendations that recognize opt-out rights on behalf of patients is the most prudent, and justifiable, approach.

Reporting Incidental Findings in Clinical Whole Exome Sequencing: Incorporation of the 2013 ACMG Recommendations into Current Practices of Genetic Counseling.

The purpose of this study was to investigate how the American College of Medical Genetics and Genomics (ACMG) March 2013 recommendations for reporting incidental findings (IFs) have influenced current practices of genetic counselors involved in utilizing whole exome sequencing (WES) for clinical diagnosis. An online survey was sent to all members of the National Society of Genetic Counselors; members were eligible to participate if they currently offered WES for clinical diagnosis. Forty-six respondents completed the survey of whom 34 were in practice prior to the March 2013 ACMG recommendations. Half of respondents (N = 19, 54.9%) in practice prior to March 2013 reported that the ACMG recommendations have had a significant impact on the content of their counseling sessions. Approximately half of respondents (N = 21, 45.5%) report all IFs, regardless of patient age, while one third (N = 14, 30.4%) consider factors such as age and parent preference in reporting IFs. Approximately 40% (N = 18) of respondents reported that the testing laboratory's policy for returning IFs has an influence on their choice of laboratory; of those, 72.2% (N = 13) reported that the option to opt out of receiving reports of IFs has a significant influence on their choice of laboratory. A majority of respondents (N = 43, 93.5%) found that most patients want to receive reports of IFs. However, respondents report there are patients who wish to decline receiving this information. This study querying genetic counselors identified benefits and challenges that the 2013 ACMG recommendations elicited. Some challenges, such as not having the option to opt out of IFs, have been addressed by the ACMG's most recent updates to their recommendations. Further investigation into larger and more inclusive provider populations as well as patient populations will be valuable for the ongoing discussion surrounding IFs in WES.

Genomic screening of the general adult population: key concepts for assessing net benefit with systematic evidence reviews.

Genomic screening of the general adult population: key concepts for assessing net benefit with systematic evidence reviews

Incidental findings and future testing methodologies: potential application of the ACMG 2013 recommendations.

Reactions to the first clinical recommendations for the return of incidental findings (IFs) from genomic sequencing published by the American College of Medical Genetics and Genomics (ACMG) were polarized and resolute. Exploring the three main points of controversy: mandatory testing, testing children for adult conditions, and selection of conditions to be reported on, illuminates concerns for and conservation of bioethical principles—specifically, autonomy and non-directiveness. With the historical context of genetic testing in mind, this article studies the potential application of the ACMG recommendations to embryonic testing in the form of preimplantation genetic diagnosis. Theoretical extension of the current recommendations assists in the identification of bioethical dilemmas and possible societal impacts. The recommendations make a statement on the importance of diagnosis and intervention for specific genetic conditions, setting a precedent for disease classification and patient autonomy. In the extreme, the clinical application of such recommendations prenatally may result in discarded embryos, and less societal tolerance of specific conditions. Skilled professionals, such as genetic counselors, researchers, and lawmakers must work together to maintain patient autonomy, providing care in the best interest of each patient.

Incidental Finding in Copy Number Variation (CNV) Analysis

When interrogating the human genome, the most significant finding at times might not even be the one related to the referring diagnosis. Such incidental findings (IFs) can pose challenges with regard to which results should be revealed? Such issues have begun to be addressed with the recent American College of Medical Genetics and Genomics (ACMG) recommendations for reporting IFs in clinical exome and genome sequencing; however, copy number variants (CNV) were not specifically addressed. The recommendations found that while some incidental CNV findings are currently of uncertain clinical significance, others are medically actionable. The reporting of the incidental CNVs can have a significant impact on risk counseling for future pregnancies and other family members at risk as well as enabling interventions to improve health outcomes. According to the ACMG recommendations, in the course of performing chromosomal microarray analysis in 3,500 “normal” parental samples for interpretation of variants of unknown clinical significance in the proband, we incidentally found 28 (0.8 %) clinically relevant CNVs that were reported back to the physician to be communicated to the patient. Reporting of IFs is not new to medicine, so should reporting IF in whole genome analysis be any different? Should the current ACMG recommendations for reporting IFs be updated to incorporate incidental CNVs?