Clinical Variant Reclassification in Hereditary Disease Genetic Testing.

Importance: Because accurate and consistent classification of DNA sequence variants is fundamental to germline genetic testing, understanding patterns of initial variant classification (VC) and subsequent reclassification from large-scale, empirical data can help improve VC methods, promote equity among race, ethnicity, and ancestry (REA) groups, and provide insights to inform clinical practice.

Objectives: To measure the degree to which initial VCs met certainty thresholds set by professional guidelines and quantify the rates of, the factors associated with, and the impact of reclassification among more than 2 million variants.

Design, Setting, And Participants: This cohort study used clinical multigene panel and exome sequencing data from diagnostic testing for hereditary disorders, carrier screening, or preventive genetic screening from individuals for whom genetic testing was performed between January 1, 2015, and June 30, 2023.

Rates and Classification of Variants of Uncertain Significance in Hereditary Disease Genetic Testing.

Importance: Variants of uncertain significance (VUSs) are rampant in clinical genetic testing, frustrating clinicians, patients, and laboratories because the uncertainty hinders diagnoses and clinical management. A comprehensive assessment of VUSs across many disease genes is needed to guide efforts to reduce uncertainty.

Objective: To describe the sources, gene distribution, and population-level attributes of VUSs and to evaluate the impact of the different types of evidence used to reclassify them.

Applications of artificial intelligence in clinical laboratory genomics.

The transition from analog to digital technologies in clinical laboratory genomics is ushering in an era of "big data" in ways that will exceed human capacity to rapidly and reproducibly analyze those data using conventional approaches. Accurately evaluating complex molecular data to facilitate timely diagnosis and management of genomic disorders will require supportive artificial intelligence methods. These are already being introduced into clinical laboratory genomics to identify variants in DNA sequencing data, predict the effects of DNA variants on protein structure and function to inform clinical interpretation of pathogenicity, link phenotype ontologies to genetic variants identified through exome or genome sequencing to help clinicians reach diagnostic answers faster, correlate genomic data with tumor staging and treatment approaches, utilize natural language processing to identify critical published medical literature during analysis of genomic data, and use interactive chatbots to identify individuals who qualify for genetic testing or to provide pre-test and post-test education.

Noncoding variants alter GATA2 expression in rhombomere 4 motor neurons and cause dominant hereditary congenital facial paresis.

Hereditary congenital facial paresis type 1 (HCFP1) is an autosomal dominant disorder of absent or limited facial movement that maps to chromosome 3q21-q22 and is hypothesized to result from facial branchial motor neuron (FBMN) maldevelopment. In the present study, we report that HCFP1 results from heterozygous duplications within a neuron-specific GATA2 regulatory region that includes two enhancers and one silencer, and from noncoding single-nucleotide variants (SNVs) within the silencer. Some SNVs impair binding of NR2F1 to the silencer in vitro and in vivo and attenuate in vivo enhancer reporter expression in FBMNs.

TUBB3 Arg262His causes a recognizable syndrome including CFEOM3, facial palsy, joint contractures, and early-onset peripheral neuropathy.

Microtubules are formed from heterodimers of alpha- and beta-tubulin, each of which has multiple isoforms encoded by separate genes. Pathogenic missense variants in multiple different tubulin isoforms cause brain malformations. Missense mutations in TUBB3, which encodes the neuron-specific beta-tubulin isotype, can cause congenital fibrosis of the extraocular muscles type 3 (CFEOM3) and/or malformations of cortical development, with distinct genotype-phenotype correlations.

A systematic literature review of disclosure practices and reported outcomes for medically actionable genomic secondary findings.

Purpose: Secondary findings (SFs) are present in 1-4% of individuals undergoing genome/exome sequencing. A review of how SFs are disclosed and what outcomes result from their receipt is urgent and timely.

Methods: We conducted a systematic literature review of SF disclosure practices and outcomes after receipt including cascade testing, family and provider communication, and health-care actions.

Differentiating Moebius syndrome and other congenital facial weakness disorders with electrodiagnostic studies.

Introduction: Congenital facial weakness (CFW) can result from facial nerve paresis with or without other cranial nerve and systemic involvement, or generalized neuropathic and myopathic disorders. Moebius syndrome is one type of CFW. In this study we explored the utility of electrodiagnostic studies (EDx) in the evaluation of individuals with CFW.

Using the diffusion of innovations model to guide participant engagement in the genomics era.

Exome and genome sequencing (EGS) are increasingly the genetic testing modalities of choice among researchers owing to their ready availability, low cost, and large data output. Recruitment of larger, more diverse cohorts into long-term studies with extensive data collection is fundamental to the success of EGS research and to the widespread benefit of genomic medicine to various populations. Effective engagement will be critical to meeting this demand.

Preliminary validation of a consumer-oriented colorectal cancer risk assessment tool compatible with the US Surgeon General's My Family Health Portrait.

Purpose: This study examines the analytic validity of a software tool designed to provide individuals with risk assessments for colorectal cancer based on personal health and family history information. The software is compatible with the US Surgeon General's My Family Health Portrait (MFHP).

Methods: An algorithm for risk assessment was created using accepted colorectal risk assessment guidelines and programmed into a software tool (MFHP).

Research participants' attitudes towards the confidentiality of genomic sequence information.

Respecting the confidentiality of personal data contributed to genomic studies is an important issue for researchers using genomic sequencing in humans. Although most studies adhere to rules of confidentiality, there are different conceptions of confidentiality and why it is important. The resulting ambiguity obscures what is at stake when making tradeoffs between data protection and other goals in research, such as transparency, reciprocity, and public benefit.

A genetic counselor's guide to using next-generation sequencing in clinical practice.

Advances in next-generation sequencing (NGS) and rapid reductions in cost have increased the use of such technologies in research and clinical practice. However, many barriers exist to translating NGS for routine clinical use, including issues related to the interpretation of results, and the potential to find results that are secondary or incidental to the specific application of NGS. Nonetheless, NGS has become sufficiently affordable to be offered by several clinical laboratories, and increasingly it is becoming an attractive and viable option for clinicians and patients.

Approaches to informed consent for hypothesis-testing and hypothesis-generating clinical genomics research.

Background: Massively-parallel sequencing (MPS) technologies create challenges for informed consent of research participants given the enormous scale of the data and the wide range of potential results.

Discussion: We propose that the consent process in these studies be based on whether they use MPS to test a hypothesis or to generate hypotheses. To demonstrate the differences in these approaches to informed consent, we describe the consent processes for two MPS studies.

Genomic inheritances: disclosing individual research results from whole-exome sequencing to deceased participants' relatives.

Whole-genome analysis and whole-exome analysis generate many more clinically actionable findings than traditional targeted genetic analysis. These findings may be relevant to research participants themselves as well as for members of their families. Though researchers performing genomic analyses are likely to find medically significant genetic variations for nearly every research participant, what they will find for any given participant is unpredictable.

Intentions to receive individual results from whole-genome sequencing among participants in the ClinSeq study.

Genome sequencing has been rapidly integrated into clinical research and is currently marketed to health-care practitioners and consumers alike. The volume of sequencing data generated for a single individual and the wide range of findings from whole-genome sequencing raise critical questions about the return of results and their potential value for end-users. We conducted a mixed-methods study of 311 sequential participants in the NIH ClinSeq study to assess general preferences and specific attitudes toward learning results.

Secondary variants in individuals undergoing exome sequencing: screening of 572 individuals identifies high-penetrance mutations in cancer-susceptibility genes.

Genome- and exome-sequencing costs are continuing to fall, and many individuals are undergoing these assessments as research participants and patients. The issue of secondary (so-called incidental) findings in exome analysis is controversial, and data are needed on methods of detection and their frequency. We piloted secondary variant detection by analyzing exomes for mutations in cancer-susceptibility syndromes in subjects ascertained for atherosclerosis phenotypes.

Motivators for participation in a whole-genome sequencing study: implications for translational genomics research.

The promise of personalized medicine depends on the ability to integrate genetic sequencing information into disease risk assessment for individuals. As genomic sequencing technology enters the realm of clinical care, its scale necessitates answers to key social and behavioral research questions about the complexities of understanding, communicating, and ultimately using sequence information to improve health. Our study captured the motivations and expectations of research participants who consented to participate in a research protocol, ClinSeq, which offers to return a subset of the data generated through high-throughput sequencing.

FOS expression in blood as a LDL-independent marker of statin treatment.

Objectives: The expression of FOS, a gene critical for monocyte and macrophage function, can be inhibited by statins through the disruption of a cholesterol-independent signaling pathway. In this pilot study, we hypothesized that blood FOS mRNA levels will be sensitive to statin treatment independent of LDL cholesterol levels.

Methods: Three cohorts at increased risk of or with cardiovascular disease (CVD) were studied.

Validation of My Family Health Portrait for six common heritable conditions.

Purpose: To assess the ability of My Family Health Portrait to accurately collect family history for six common heritable disorders.

Background: Family history is useful to assess disease risk but is not widely used. We compared the pedigree from My Family Health Portrait, an online tool for collection of family history, to a pedigree supplemented by a genetics professional.

The ClinSeq Project: piloting large-scale genome sequencing for research in genomic medicine.

ClinSeq is a pilot project to investigate the use of whole-genome sequencing as a tool for clinical research. By piloting the acquisition of large amounts of DNA sequence data from individual human subjects, we are fostering the development of hypothesis-generating approaches for performing research in genomic medicine, including the exploration of issues related to the genetic architecture of disease, implementation of genomic technology, informed consent, disclosure of genetic information, and archiving, analyzing, and displaying sequence data. In the initial phase of ClinSeq, we are enrolling roughly 1000 participants; the evaluation of each includes obtaining a detailed family and medical history, as well as a clinical evaluation.