Publications by authors named "Ann Katherine M Foreman"

19 Publications

  • Page 1 of 1

Actionability of commercial laboratory sequencing panels for newborn screening and the importance of transparency for parental decision-making.

Genome Med 2021 Mar 29;13(1):50. Epub 2021 Mar 29.

Department of Genetics, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, 27599, USA.

Background: Newborn screening aims to identify individual patients who could benefit from early management, treatment, and/or surveillance practices. As sequencing technologies have progressed and we move into the era of precision medicine, genomic sequencing has been introduced to this area with the hopes of detecting variants related to a vastly expanded number of conditions. Though implementation of genomic sequencing for newborn screening in public health and clinical settings is limited, commercial laboratories have begun to offer genomic screening panels for neonates.

Methods: We examined genes listed on four commercial laboratory genomic screening panels for neonates and assessed their clinical actionability using an established age-based semi-quantitative metric to categorize them. We identified genes that were included on multiple panels or distinct between panels.

Results: Three hundred and nine genes appeared on one or more commercial panels: 74 (23.9%) genes were included in all four commercial panels, 45 (14.6%) were on only three panels, 76 (24.6%) were on only two panels, and 114 (36.9%) genes were listed on only one of the four panels. Eighty-two genes (26.5%) listed on one or more panels were assessed by our method to be inappropriate for newborn screening and to require additional parental decision-making. Conversely, 249 genes that we previously identified as being highly actionable were not listed on any of the four commercial laboratory genomic screening panels.

Conclusions: Commercial neonatal genomic screening panels have heterogeneous content and may contain some conditions with lower actionability than would be expected for public health newborn screening; conversely, some conditions with higher actionability may be omitted from these panels. The lack of transparency about how conditions are selected suggests a need for greater detail about panel content in order for parents to make informed decisions. The nuanced activity of gene list selection for genomic screening should be iteratively refined with evidence-based approaches to provide maximal benefit and minimal harm to newborns.
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http://dx.doi.org/10.1186/s13073-021-00867-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8008582PMC
March 2021

A review and definition of 'usual care' in genetic counseling trials to standardize use in research.

J Genet Couns 2021 Feb 5;30(1):42-50. Epub 2020 Dec 5.

Department of Humanities and Social Sciences, University of California, San Francisco, CA, USA.

The descriptor 'usual care' refers to standard or routine care. Yet, no formal definition exists. The need to define what constitutes usual care arises in clinical research. Often one arm in a trial represents usual care in comparison with a novel intervention. Accordingly, usual care in genetic counseling research appears predominantly in randomized controlled trials. Recent standards for reporting genetic counseling research call for standardization, but do not address usual care. We (1) inventoried all seven studies in the Clinical Sequencing Evidence-Generating Consortium (CSER) about how genetic counseling was conceptualized, conducted, and whether a usual care arm was involved; (2) conducted a review of published randomized control trials in genetic counseling, comparing how researchers describe usual care groups; and (3) reviewed existing professionally endorsed definitions and practice descriptions of genetic counseling. We found wide variation in the content and delivery of usual care. Descriptions frequently detailed the content of usual care, most often noting assessment of genetic risk factors, collecting family histories, and offering testing. A minority included addressing psychological concerns or the risks versus benefits of testing. Descriptions of how care was delivered were vague except for mode and type of clinician, which varied. This significant variation, beyond differences expected among subspecialties, reduces the validity and generalizability of genetic counseling research. Ideally, research reflects clinical practice so that evidence generated can be used to improve clinical outcomes. To address this objective, we propose a definition of usual care in genetic counseling research that merges common elements from the National Society of Genetic Counselors' practice definition, the Reciprocal Engagement Model, and the Accreditation Council for Genetic Counselors' practice-based competencies. Promoting consistent execution of usual care in the design of genetic counseling trials can lead to more consistency in representing clinical care and facilitate the generation of evidence to improve it.
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http://dx.doi.org/10.1002/jgc4.1363DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7882019PMC
February 2021

Variant Classification Concordance using the ACMG-AMP Variant Interpretation Guidelines across Nine Genomic Implementation Research Studies.

Am J Hum Genet 2020 11 26;107(5):932-941. Epub 2020 Oct 26.

Department of Medicine, Division of Medical Genetics, University of Washington Medical Center, Seattle, WA 98195, USA.

Harmonization of variant pathogenicity classification across laboratories is important for advancing clinical genomics. The two CLIA-accredited Electronic Medical Record and Genomics Network sequencing centers and the six CLIA-accredited laboratories and one research laboratory performing genome or exome sequencing in the Clinical Sequencing Evidence-Generating Research Consortium collaborated to explore current sources of discordance in classification. Eight laboratories each submitted 20 classified variants in the ACMG secondary finding v.2.0 genes. After removing duplicates, each of the 158 variants was annotated and independently classified by two additional laboratories using the ACMG-AMP guidelines. Overall concordance across three laboratories was assessed and discordant variants were reviewed via teleconference and email. The submitted variant set included 28 P/LP variants, 96 VUS, and 34 LB/B variants, mostly in cancer (40%) and cardiac (27%) risk genes. Eighty-six (54%) variants reached complete five-category (i.e., P, LP, VUS, LB, B) concordance, and 17 (11%) had a discordance that could affect clinical recommendations (P/LP versus VUS/LB/B). 21% and 63% of variants submitted as P and LP, respectively, were discordant with VUS. Of the 54 originally discordant variants that underwent further review, 32 reached agreement, for a post-review concordance rate of 84% (118/140 variants). This project provides an updated estimate of variant concordance, identifies considerations for LP classified variants, and highlights ongoing sources of discordance. Continued and increased sharing of variant classifications and evidence across laboratories, and the ongoing work of ClinGen to provide general as well as gene- and disease-specific guidance, will lead to continued increases in concordance.
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http://dx.doi.org/10.1016/j.ajhg.2020.09.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7675005PMC
November 2020

Genomic Sequencing for Newborn Screening: Results of the NC NEXUS Project.

Am J Hum Genet 2020 10 26;107(4):596-611. Epub 2020 Aug 26.

Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Electronic address:

Newborn screening (NBS) was established as a public health program in the 1960s and is crucial for facilitating detection of certain medical conditions in which early intervention can prevent serious, life-threatening health problems. Genomic sequencing can potentially expand the screening for rare hereditary disorders, but many questions surround its possible use for this purpose. We examined the use of exome sequencing (ES) for NBS in the North Carolina Newborn Exome Sequencing for Universal Screening (NC NEXUS) project, comparing the yield from ES used in a screening versus a diagnostic context. We enrolled healthy newborns and children with metabolic diseases or hearing loss (106 participants total). ES confirmed the participant's underlying diagnosis in 15 out of 17 (88%) children with metabolic disorders and in 5 out of 28 (∼18%) children with hearing loss. We discovered actionable findings in four participants that would not have been detected by standard NBS. A subset of parents was eligible to receive additional information for their child about childhood-onset conditions with low or no clinical actionability, clinically actionable adult-onset conditions, and carrier status for autosomal-recessive conditions. We found pathogenic variants associated with hereditary breast and/or ovarian cancer in two children, a likely pathogenic variant in the gene associated with Lowe syndrome in one child, and an average of 1.8 reportable variants per child for carrier results. These results highlight the benefits and limitations of using genomic sequencing for NBS and the challenges of using such technology in future precision medicine approaches.
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http://dx.doi.org/10.1016/j.ajhg.2020.08.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7536575PMC
October 2020

Correction: An approach to integrating exome sequencing for fetal structural anomalies into clinical practice.

Genet Med 2020 Aug;22(8):1426

Department of Genetics, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41436-020-0870-xDOI Listing
August 2020

Congenital Midline Cervical Cleft: First Report and Genetic Analysis of Two Related Patients.

Ann Otol Rhinol Laryngol 2020 Jul 6;129(7):653-656. Epub 2020 Feb 6.

Department of Otolaryngology-Head and Neck Surgery, School of Medicine, University of North Carolina, Chapel Hill, NC, USA.

Objectives: Congenital midline cervical cleft (CMCC) is a rare congenital anterior neck anatomical anomaly. We present the case of two related patients (grandchild and maternal grandmother) who were both born with a congenital midline cervical cleft along with genetic analysis.

Methods: Clinical examination of both patients and surgical excision of the grandchild was performed. Genetic analysis with exome sequencing (ES) was conducted for both patients.

Results: Genetic analysis with exome sequencing (ES) revealed apparently novel single nucleotide variants in 66 genes present in both proband and grandmother. Five of these variants are predicted to cause frameshifting in the coding region of the respective genes and truncated proteins (). Two of these genes () have homozygous indel mutations in both patients.

Conclusions: To our knowledge, this is the first case of two related patients with a congenital midline cervical cleft. The results of our genetic analysis reveal potential relevance to CMCC development.
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http://dx.doi.org/10.1177/0003489420906180DOI Listing
July 2020

An approach to integrating exome sequencing for fetal structural anomalies into clinical practice.

Genet Med 2020 05 24;22(5):954-961. Epub 2020 Jan 24.

Department of Genetics, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

Purpose: We investigated the diagnostic and clinical performance of trio exome sequencing (ES) in parent-fetus trios where the fetus had sonographic abnormalities but normal karyotype, microarray and, in some cases, normal gene-specific sequencing.

Methods: ES was performed from DNA of 102 anomalous fetuses and from peripheral blood from their parents. Parents provided consent for the return of diagnostic results in the fetus, medically actionable findings in the parents, and identification as carrier couple for significant autosomal recessive conditions.

Results: In 21/102 (20.6%) fetuses, ES provided a positive-definitive or positive-probable diagnosis. In 10/102 (9.8%), ES provided an inconclusive-possible result. At least 2/102 (2.0%) had a repeat pregnancy during the study period and used the information from the study for prenatal diagnosis in the next pregnancy. Six of 204 (2.9%) parents received medically actionable results that affected their own health and 3/102 (2.9%) of couples received results that they were carriers for the same autosomal recessive condition.

Conclusion: ES has diagnostic utility in a select population of fetuses where a genetic diagnosis was highly suspected. Challenges related to genetics literacy, variant interpretation, and various types of diagnostic results affecting both fetal and parental health must be addressed by highly tailored pre- and post-test genetic counseling.
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http://dx.doi.org/10.1038/s41436-020-0750-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7205580PMC
May 2020

Referencing BRCA in hereditary cancer risk discussions: In search of an anchor in a sea of uncertainty.

J Genet Couns 2020 12 22;29(6):949-959. Epub 2020 Jan 22.

Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.

As panel testing and exome sequencing are increasingly incorporated into clinical care, clinicians must grapple with how to communicate the risks and treatment decisions surrounding breast cancer genes beyond BRCA1 and BRCA2. In this paper, we examine clinicians' practice of employing BRCA1 and BRCA2 to help contextualize less certain genetic information regarding cancer risk and the possible implications of this practice for patients within the context of an exome sequencing study, NCGENES. We audio-recorded return of results appointments for 14 women who participated in NCGENES, previously had breast cancer, and were suspected of having a hereditary cancer predisposition. These patients were also interviewed four weeks later regarding their understanding of their results. We found that BRCA1 and BRCA2 were held as the gold standard, where clinicians compared what is known about BRCA to the limited understanding of other breast cancer-related genes. BRCA1 and BRCA2 were used as anchors to shape patients' understandings of genetic knowledge, risk, and management, illustrating how the information clinicians provide to patients may work as an external anchor. Yet, presenting BRCA1 and BRCA2 as a means of scientific reassurance can run the risk of patients conflating knowledge about certainty of risk with degree of risk after receiving a result for a moderate penetrance gene. This can be further complicated by misperceptions of the precision of cancer predictability attributed to these or other described 'cancer genes' in public media.
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http://dx.doi.org/10.1002/jgc4.1219DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7374021PMC
December 2020

Correction: Genomic knowledge in the context of diagnostic exome sequencing: changes over time, persistent subgroup differences, and associations with psychological sequencing outcomes.

Genet Med 2019 12;21(12):2846

Center for Genomics and Society, University of North Carolina, Chapel Hill, NC, USA.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41436-019-0622-yDOI Listing
December 2019

Genomic knowledge in the context of diagnostic exome sequencing: changes over time, persistent subgroup differences, and associations with psychological sequencing outcomes.

Genet Med 2020 01 17;22(1):60-68. Epub 2019 Jul 17.

Center for Genomics and Society, University of North Carolina, Chapel Hill, NC, USA.

Purpose: People undergoing diagnostic genome-scale sequencing are expected to have better psychological outcomes when they can incorporate and act on accurate, relevant knowledge that supports informed decision making.

Methods: This longitudinal study used data from the North Carolina Clinical Genomic Evaluation by NextGen Exome Sequencing Study (NCGENES) of diagnostic exome sequencing to evaluate associations between factual genomic knowledge (measured with the University of North Carolina Genomic Knowledge Scale at three assessments from baseline to after return of results) and sequencing outcomes that reflected participants' perceived understanding of the study and sequencing, regret for joining the study, and responses to learning sequencing results. It also investigated differences in genomic knowledge associated with subgroups differing in race/ethnicity, income, education, health literacy, English proficiency, and prior genetic testing.

Results: Multivariate models revealed higher genomic knowledge at baseline for non-Hispanic Whites and those with higher income, education, and health literacy (p values < 0.001). These subgroup differences persisted across study assessments despite a general increase in knowledge among all groups. Greater baseline genomic knowledge was associated with lower test-related distress (p = 0.047) and greater perceived understanding of diagnostic genomic sequencing (p values 0.04 to <0.001).

Conclusion: Findings extend understanding of the role of genomic knowledge in psychological outcomes of diagnostic exome sequencing, providing guidance for additional research and interventions.
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http://dx.doi.org/10.1038/s41436-019-0600-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6946868PMC
January 2020

An Age-Based Framework for Evaluating Genome-Scale Sequencing Results in Newborn Screening.

J Pediatr 2019 06 7;209:68-76. Epub 2019 Mar 7.

Department of Genetics, UNC Chapel Hill, Chapel Hill, NC. Electronic address:

Objective: To assess the performance of a standardized, age-based metric for scoring clinical actionability to evaluate conditions for inclusion in newborn screening and compare it with the results from other contemporary methods.

Study Design: The North Carolina Newborn Exome Sequencing for Universal Screening study developed an age-based, semiquantitative metric to assess the clinical actionability of gene-disease pairs and classify them with respect to age of onset or timing of interventions. This categorization was compared with the gold standard Recommended Uniform Screening Panel and other methods to evaluate gene-disease pairs for newborn genomic sequencing.

Results: We assessed 822 gene-disease pairs, enriched for pediatric onset of disease and suspected actionability. Of these, 466 were classified as having childhood onset and high actionability, analogous to conditions selected for the Recommended Uniform Screening Panel core panel. Another 245 were classified as having childhood onset and low to no actionability, 25 were classified as having adult onset and high actionability, 19 were classified as having adult onset and low to no actionability, and 67 were excluded due to controversial evidence and/or prenatal onset.

Conclusions: This study describes a novel method to facilitate decisions about the potential use of genomic sequencing for newborn screening. These categories may assist parents and physicians in making informed decisions about the disclosure of results from voluntary genomic sequencing in children.
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http://dx.doi.org/10.1016/j.jpeds.2018.12.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6535354PMC
June 2019

An examination of the factors contributing to the expansion of subspecialty genetic counseling.

J Genet Couns 2019 06 1;28(3):616-625. Epub 2019 Feb 1.

MS Genetic Counseling Program, University of North Carolina at Greensboro, Greensboro, North Carolina.

In recent years, genetic counselors have moved into increasingly varied areas of patient care. Yet limited information is known about how these genetic counselors transitioned from more general clinical practice to subspecialized practice. This study was designed to answer three research questions: (1) What common factors establish a need for a genetic counselor in a subspecialty setting? (2) How do genetic counselors in subspecialties establish their positions? (3) Once established, how do the positions of these genetic counselors evolve as the subspecialty expands? Phone interviews with subspecialized genetic counselors led to the development of an online survey distributed through the National Society of Genetic Counselors ListServ. Sixty-eight of the 144 initial participants met eligibility criteria for participation as subspecialty genetic counselors in a clinical role. Physician interest in hiring a genetic counselor, clinical need, genetic counselor interest in subspecialty area, and available genetic testing were commonly reported as contributing factors to position creation. Most subspecialty genetic counseling positions were created as new positions, rather than evolved from a previous position. Over time, subspecialty positions drew more departmental funding and included increased clinical coordination or administrative responsibilities. The results of this study can encourage genetic counselors to collaborate with their medical institutions to utilize their skill-set in diverse areas of patient care.
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http://dx.doi.org/10.1002/jgc4.1077DOI Listing
June 2019

Factors influencing NCGENES research participants' requests for non-medically actionable secondary findings.

Genet Med 2019 05 21;21(5):1092-1099. Epub 2018 Sep 21.

John Theuer Cancer Center, Hackensack University Medical Center, Hackensack, NJ, USA.

Purpose: Genomic sequencing can reveal variants with limited to no medical actionability. Previous research has assessed individuals' intentions to learn this information, but few report the decisions they made and why.

Methods: The North Carolina Clinical Genomic Evaluation by Next Generation Exome Sequencing (NCGENES) project evaluated adult patients randomized to learn up to six types of non-medically actionable secondary findings (NMASF). We previously found that most participants intended to request NMASF and intentions were strongly predicted by anticipated regret. Here we examine discrepancies between intentions and decisions to request NMASF, hypothesizing that anticipated regret would predict requests but that this association would be mediated by participants' intentions.

Results: Of the 76% who expressed intentions to learn results, only 42% made one or more requests. Overall, only 32% of the 155 eligible participants requested NMASF. Analyses support a plausible causal link between anticipated regret, intentions, and requests.

Conclusions: The discordance between participants' expressed intentions and their actions provides insight into factors that influence patients' preferences for genomic information that has little to no actionability. These findings have implications for the timing and methods of eliciting preferences for NMASF and suggest that decisions to learn this information have cognitive and emotional components.
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http://dx.doi.org/10.1038/s41436-018-0294-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6522134PMC
May 2019

The who, what, and why of research participants' intentions to request a broad range of secondary findings in a diagnostic genomic sequencing study.

Genet Med 2018 07 26;20(7):760-769. Epub 2017 Oct 26.

Center for Genomics and Society, University of North Carolina, Chapel Hill, North Carolina, USA.

Purpose: In a diagnostic exome sequencing study (the North Carolina Clinical Genomic Evaluation by Next-Generation Exome Sequencing project, NCGENES), we investigated adult patients' intentions to request six categories of secondary findings (SFs) with low or no medical actionability and correlates of their intentions.

Methods: At enrollment, eligible participants (n = 152) completed measures assessing their sociodemographic, clinical, and literacy-related characteristics. Prior to and during an in-person diagnostic result disclosure visit, they received education about categories of SFs they could request. Immediately after receiving education at the visit, participants completed measures of intention to learn SFs, interest in each category, and anticipated regret for learning and not learning each category.

Results: Seventy-eight percent of participants intended to learn at least some SFs. Logistic regressions examined their intention to learn any or all of these findings (versus none) and interest in each of the six individual categories (yes/no). Results revealed little association between intentions and sociodemographic, clinical, or literacy-related factors. Across outcomes, participants who anticipated regret for learning SFs reported weaker intention to learn them (odds ratios (ORs) from 0.47 to 0.71), and participants who anticipated regret for not learning these findings reported stronger intention to learn them (OR 1.61-2.22).

Conclusion: Intentions to request SFs with low or no medical actionability may be strongly influenced by participants' desire to avoid regret.
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http://dx.doi.org/10.1038/gim.2017.176DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5920790PMC
July 2018

Prenatal exome sequencing in anomalous fetuses: new opportunities and challenges.

Genet Med 2017 11 18;19(11):1207-1216. Epub 2017 May 18.

Department of Genetics, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

PurposeWe investigated the diagnostic and clinical performance of exome sequencing in fetuses with sonographic abnormalities with normal karyotype and microarray and, in some cases, normal gene-specific sequencing.MethodsExome sequencing was performed on DNA from 15 anomalous fetuses and from the peripheral blood of their parents. Parents provided consent to be informed of diagnostic results in the fetus, medically actionable findings in the parents, and their identification as carrier couples for significant autosomal recessive conditions. We assessed the perceptions and understanding of exome sequencing using mixed methods in 15 mother-father dyads.ResultsIn seven (47%) of 15 fetuses, exome sequencing provided a diagnosis or possible diagnosis with identification of variants in the following genes: COL1A1, MUSK, KCTD1, RTTN, TMEM67, PIEZO1 and DYNC2H1. One additional case revealed a de novo nonsense mutation in a novel candidate gene (MAP4K4). The perceived likelihood that exome sequencing would explain the results (5.2 on a 10-point scale) was higher than the approximately 30% diagnostic yield discussed in pretest counseling.ConclusionExome sequencing had diagnostic utility in a highly select population of fetuses where a genetic diagnosis was highly suspected. Challenges related to genetics literacy and variant interpretation must be addressed by highly tailored pre- and posttest genetic counseling.
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http://dx.doi.org/10.1038/gim.2017.33DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5675748PMC
November 2017

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

Genet Med 2016 05 13;18(5):467-75. Epub 2015 Aug 13.

Department of Genetics, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

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.
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http://dx.doi.org/10.1038/gim.2015.104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4752935PMC
May 2016

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

Am J Med Genet A 2015 Sep 29;167A(9):2176-81. Epub 2015 Apr 29.

Department of Pediatrics, University of North Carolina School of Medicine, Chapel Hill, North Carolina.

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.
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http://dx.doi.org/10.1002/ajmg.a.37129DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6108425PMC
September 2015

Actionable exomic incidental findings in 6503 participants: challenges of variant classification.

Genome Res 2015 Mar 30;25(3):305-15. Epub 2015 Jan 30.

Department of Medicine, Division of Medical Genetics, University of Washington, Seattle, Washington 98195, USA; Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA;

Recommendations for laboratories to report incidental findings from genomic tests have stimulated interest in such results. In order to investigate the criteria and processes for assigning the pathogenicity of specific variants and to estimate the frequency of such incidental findings in patients of European and African ancestry, we classified potentially actionable pathogenic single-nucleotide variants (SNVs) in all 4300 European- and 2203 African-ancestry participants sequenced by the NHLBI Exome Sequencing Project (ESP). We considered 112 gene-disease pairs selected by an expert panel as associated with medically actionable genetic disorders that may be undiagnosed in adults. The resulting classifications were compared to classifications from other clinical and research genetic testing laboratories, as well as with in silico pathogenicity scores. Among European-ancestry participants, 30 of 4300 (0.7%) had a pathogenic SNV and six (0.1%) had a disruptive variant that was expected to be pathogenic, whereas 52 (1.2%) had likely pathogenic SNVs. For African-ancestry participants, six of 2203 (0.3%) had a pathogenic SNV and six (0.3%) had an expected pathogenic disruptive variant, whereas 13 (0.6%) had likely pathogenic SNVs. Genomic Evolutionary Rate Profiling mammalian conservation score and the Combined Annotation Dependent Depletion summary score of conservation, substitution, regulation, and other evidence were compared across pathogenicity assignments and appear to have utility in variant classification. This work provides a refined estimate of the burden of adult onset, medically actionable incidental findings expected from exome sequencing, highlights challenges in variant classification, and demonstrates the need for a better curated variant interpretation knowledge base.
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http://dx.doi.org/10.1101/gr.183483.114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4352885PMC
March 2015

The NCGENES project: exploring the new world of genome sequencing.

N C Med J 2013 Nov-Dec;74(6):500-4

Department of Genetics, School of Medicine, University of North Carolina at Chapel Hill, CB 7264, Chapel Hill, NC 27599, USA.

Massively parallel sequencing (MPS) is now a clinical reality, promising improved diagnosis, targeted therapies, and population-based screening. To realize the potential of genomics, we must learn how to apply this technology optimally. The NCGENES project is designed to address several challenges that must be overcome in order to integrate MPS into clinical care.
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January 2014