Evaluation of the diagnostic accuracy of exome sequencing and its impact on diagnostic thinking for patients with rare disease in a publicly funded health care system: A prospective cohort study.

Purpose: To evaluate the diagnostic utility of publicly funded clinical exome sequencing (ES) for patients with suspected rare genetic diseases.

Methods: We prospectively enrolled 297 probands who met eligibility criteria and received ES across 5 sites in Ontario, Canada, and extracted data from medical records and clinician surveys. Using the Fryback and Thornbury Efficacy Framework, we assessed diagnostic accuracy by examining laboratory interpretation of results and assessed diagnostic thinking by examining the clinical interpretation of results and whether clinical-molecular diagnoses would have been achieved via alternative hypothetical molecular tests.

The clinical utility of integrative genomics in childhood cancer extends beyond targetable mutations.

We conducted integrative somatic-germline analyses by deeply sequencing 864 cancer-associated genes, complete genomes and transcriptomes for 300 mostly previously treated children and adolescents/young adults with cancer of poor prognosis or with rare tumors enrolled in the SickKids Cancer Sequencing (KiCS) program. Clinically actionable variants were identified in 56% of patients. Improved diagnostic accuracy led to modified management in a subset.

Exome sequencing identifies PD-L2 as a potential predisposition gene for lymphoma.

To investigate germline predisposition in lymphoma, we performed whole-exome sequencing and discovered a novel variant (c.817-1G>T) in programmed cell death 1 ligand 2 (PD-L2) in a family with early-onset lymphomas and other cancers. The variant was present in the proband with follicular lymphoma and his son with Hodgkin's lymphoma.

The Clinician-reported Genetic testing Utility InDEx (C-GUIDE): Preliminary evidence of validity and reliability.

Purpose: Demonstrating the clinical utility of genetic testing is fundamental to clinical adoption and reimbursement, but standardized definitions and measurement strategies for this construct do not exist. The Clinician-reported Genetic testing Utility InDEx (C-GUIDE) offers a novel measure to fill this gap. This study assessed its validity and inter-rater reliability.

Comprehensive characterization of a Canadian cohort of von Hippel-Lindau disease patients.

Von Hippel-Lindau disease (VHL) is a heritable condition caused by pathogenic variants in VHL and is characterized by benign and malignant lesions in the central nervous system (CNS) and abdominal viscera. Due to its variable expressivity, existing efforts to collate VHL patient data do not adequately capture all VHL manifestations. We developed a comprehensive and standardized VHL database in the web-based application, REDCap, that thoroughly captures all VHL manifestation data.

New developmental syndromes: Understanding the family experience.

Increased application of next generation sequencing has led to the discovery of a multitude of new neurodevelopmental syndromes, contributing to an increased diagnostic rate for exome sequencing from 25% originally to 40% currently. Owing to the recent recognition of these syndromes, as well as the types of large-scale studies (with limited phenotype information) often making these discoveries, these disorders may be poorly characterized clinically. As a result there is very limited information and disorder-specific support available to patients and families.