Elucidating clinical phenotypic variability associated with the polyT tract and TG repeats in CFTR.

Biallelic pathogenic variants in CFTR manifest as cystic fibrosis (CF) or other CFTR-related disorders (CFTR-RDs). The 5T allele, causing alternative splicing and reduced protein activity, is modulated by the adjacent TG repeat element, though previous data have been limited to small, selective cohorts. Here, the risk and spectrum of phenotypes associated with the CFTR TG-T5 haplotype variants (TG11T5, TG12T5, and TG13T5) in the absence of the p.Arg117His variant are evaluated. Individuals who received physician-ordered next-generation sequencing of CFTR were included. TG[11-13]T5 variant frequencies (biallelic or with another CF-causing variant [CFvar]) were calculated. Clinical information reported by the ordering provider or the individual was examined. Among 548,300 individuals, the T5 minor allele frequency (MAF) was 4.2% (TG repeat distribution: TG11 = 68.1%, TG12 = 29.5%, TG13 = 2.4%). When present with a CFvar, each TG[11-13]T5 variant was significantly enriched in individuals with a high suspicion of CF or CFTR-RD (personal/family history of CF/CFTR-RD) compared to those with a low suspicion for CF or CFTR-RD (hereditary cancer screening, CFTR not requisitioned). Compared to CFvar/CFvar individuals, those with TG[11-13]T5/CFvar generally had single-organ involvement, milder symptoms, variable expressivity, and reduced penetrance. These data improve our understanding of disease risks associated with TG[11-13]T5 variants and have important implications for reproductive genetic counseling.

Towards a Universal Clinical Genomics Database: the 2012 International Standards for Cytogenomic Arrays Consortium Meeting.

The 2012 International Standards for Cytogenomic Arrays (ISCA) Consortium Meeting, "Towards a Universal Clinical Genomic Database," was held in Bethesda, Maryland, May 21-22, 2012, and was attended by over 200 individuals from around the world representing clinical genetic testing laboratories, clinicians, academia, industry, research, and regulatory agencies. The scientific program centered on expanding the current focus of the ISCA Consortium to include the collection and curation of both structural and sequence-level variation into a unified clinical genomics database, available to the public through resources such as the National Center for Biotechnology Information's ClinVar database. Here, we provide an overview of the conference, with summaries of the topics presented for discussion by over 25 different speakers. Presentations are available online at www.iscaconsortium.org.

The laboratory-clinician team: a professional call to action to improve communication and collaboration for optimal patient care in chromosomal microarray testing.

The International Standards for Cytogenomic Arrays (ISCA) Consortium is a worldwide collaborative effort dedicated to optimizing patient care by improving the quality of chromosomal microarray testing. The primary effort of the ISCA Consortium has been the development of a database of copy number variants (CNVs) identified during the course of clinical microarray testing. This database is a powerful resource for clinicians, laboratories, and researchers, and can be utilized for a variety of applications, such as facilitating standardized interpretations of certain CNVs across laboratories or providing phenotypic information for counseling purposes when published data is sparse. A recognized limitation to the clinical utility of this database, however, is the quality of clinical information available for each patient. Clinical genetic counselors are uniquely suited to facilitate the communication of this information to the laboratory by virtue of their existing clinical responsibilities, case management skills, and appreciation of the evolving nature of scientific knowledge. We intend to highlight the critical role that genetic counselors play in ensuring optimal patient care through contributing to the clinical utility of the ISCA Consortium's database, as well as the quality of individual patient microarray reports provided by contributing laboratories. Current tools, paper and electronic forms, created to maximize this collaboration are shared. In addition to making a professional commitment to providing complete clinical information, genetic counselors are invited to become ISCA members and to become involved in the discussions and initiatives within the Consortium.

Multigene Panel Testing in a Large Cohort of Adults With Epilepsy: Diagnostic Yield and Clinically Actionable Genetic Findings.

BACKGROUND AND OBJECTIVES: Although genetic testing among children with epilepsy has demonstrated clinical utility and become a part of routine testing, studies in adults are limited. This study reports the diagnostic yield of genetic testing in adults with epilepsy. METHODS: Unrelated individuals aged 18 years and older who underwent diagnostic genetic testing for epilepsy using a comprehensive, next-generation sequencing-based, targeted gene panel (range 89-189 genes) were included in this cross-sectional study. Clinical information, provided at the discretion of the ordering clinician, was reviewed and analyzed. Diagnostic yield was calculated for all individuals including by age at seizure onset and comorbidities based on clinician-reported information. The proportion of individuals with clinically actionable genetic findings, including instances when a specific treatment would be indicated or contraindicated due to a diagnostic finding, was calculated. RESULTS: Among 2,008 individuals, a diagnostic finding was returned for 218 adults (10.9%), with clinically actionable findings in 55.5% of diagnoses. The highest diagnostic yield was in adults with seizure onset during infancy (29.6%, 0-1 year), followed by in early childhood (13.6%, 2-4 years), late childhood (7.0%, 5-10 years), adolescence (2.4%, 11-17 years), and adulthood (3.7%, ≥18 years). Comorbid intellectual disability (ID) or developmental delay resulted in a high diagnostic yield (16.0%), most notably for females (19.6% in females vs 12.3% in males). Among individuals with pharmacoresistant epilepsy, 13.5% had a diagnostic finding, and of these, 57.4% were clinically actionable genetic findings. DISCUSSION: These data reinforce the utility of genetic testing for adults with epilepsy, particularly for those with childhood-onset seizures, ID, and pharmacoresistance. This is an important consideration due to longer survival and the complexity of the transition from pediatric to adult care. In addition, more than half of diagnostic findings in this study were considered clinically actionable, suggesting that genetic testing could have a direct impact on clinical management and outcomes.

Possible precision medicine implications from genetic testing using combined detection of sequence and intragenic copy number variants in a large cohort with childhood epilepsy.

OBJECTIVE: Molecular genetic etiologies in epilepsy have become better understood in recent years, creating important opportunities for precision medicine. Building on these advances, detailed studies of the complexities and outcomes of genetic testing for epilepsy can provide useful insights that inform and refine diagnostic approaches and illuminate the potential for precision medicine in epilepsy. METHODS: We used a multi-gene next-generation sequencing (NGS) panel with simultaneous sequence and exonic copy number variant detection to investigate up to 183 epilepsy-related genes in 9769 individuals. Clinical variant interpretation was performed using a semi-quantitative scoring system based on existing professional practice guidelines. RESULTS: Molecular genetic testing provided a diagnosis in 14.9%-24.4% of individuals with epilepsy, depending on the NGS panel used. More than half of these diagnoses were in children younger than 5 years. Notably, the testing had possible precision medicine implications in 33% of individuals who received definitive diagnostic results. Only 30 genes provided 80% of molecular diagnoses. While most clinically significant findings were single-nucleotide variants, ~15% were other types that are often challenging to detect with traditional methods. In addition to clinically significant variants, there were many others that initially had uncertain significance; reclassification of 1612 such variants with parental testing or other evidence contributed to 18.5% of diagnostic results overall and 6.1% of results with precision medicine implications. SIGNIFICANCE: Using an NGS gene panel with key high-yield genes and robust analytic sensitivity as a first-tier test early in the diagnostic process, especially for children younger than 5 years, can possibly enable precision medicine approaches in a significant number of individuals with epilepsy.