Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications.

Ascertaining a diagnosis through exome sequencing can provide potential benefits to patients, insurance companies, and the healthcare system. Yet, as diagnostic sequencing is increasingly employed, vast amounts of human genetic data are produced that need careful curation. We discuss methods for accurately assessing the clinical validity of gene-disease relationships to interpret new research findings in a clinical context and increase the diagnostic rate. The specifics of a gene-disease scoring system adapted for use in a clinical laboratory are described. In turn, clinical validity scoring of gene-disease relationships can inform exome reporting for the identification of new or the upgrade of previous, clinically relevant gene findings. Our retrospective analysis of all reclassification reports from the first 4 years of diagnostic exome sequencing showed that 78% were due to new gene-disease discoveries published in the literature. Among all exome positive/likely positive findings in characterized genes, 32% were in genetic etiologies that were discovered after 2010. Our data underscore the importance and benefits of active and up-to-date curation of a gene-disease database combined with critical clinical validity scoring and proactive reanalysis in the clinical genomics era.

Chromosomal abnormalities among 246 fetuses with pleural effusions detected on prenatal ultrasound examination: factors associated with an increased risk of aneuploidy.

PURPOSE: To determine the prevalence of chromosomal abnormalities in fetuses with prenatally diagnosed pleural effusions and to identify factors associated with an increased risk of aneuploidy. METHODS: A retrospective analysis of the Genzyme Genetics database was performed for samples submitted from October 1994 to April 2003 with an indication of fetal pleural effusion. RESULTS: There were 246 samples in which pleural effusion was identified as an indication for prenatal chromosome analysis. Ninety-four were from fetuses with isolated pleural effusions and 152 had other abnormalities in addition to pleural effusion. The prevalence of chromosome abnormalities was 35.4% (95% confidence interval, 29.2-41.4%). Among the eight first trimester samples, the aneuploidy rate was 63%. Pleural effusion cases associated with additional sonographic findings had a significantly higher aneuploidy rate than the isolated pleural effusion cases (50% vs. 12%, P < 0.001). CONCLUSIONS: Chromosome analysis is warranted after the prenatal detection of a fetal pleural effusion. The risk of aneuploidy is greater with first trimester detection and is significantly increased in the presence of other associated anomalies.