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.
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 Ͻ 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. Genet Med 2005:7(6): 417-421. Key Words: pleural effusion, hydrops, aneuploidy, prenatal diagnosis, Turner syndromeFetal pleural effusions may occur as an isolated finding or in association with other abnormalities such as fetal hydrops, lung tumors, cardiac anomalies, arrhythmias, and other congenital defects. Primary pleural effusions are most often chylous and constitute the majority of isolated fetal pleural effusions. Secondary effusions most commonly result from nonimmune hydrops. The incidence of fetal pleural effusion has been estimated to be one in 15,000 pregnancies. 1,2 However, a recent prospective study performed in low-risk obstetric cases at 7 to 10 weeks gestation showed that fetal pleural effusion may be found in as high as 1.2% of all pregnancies. 3 The association of aneuploidy with prenatally diagnosed fetal pleural effusion is well known. 2,4,5 In these reports, aneuploidy rates for second and third trimester fetuses with pleural effusions have ranged from 3.2% to 5.8%. The risk of aneuploidy with first trimester diagnosis of pleural effusion is significantly greater. Hashimoto et al. identified chromosome abnormalities in 9 of 11 (82%) first trimester embryos and fetuses with pleural effusions. 3 Most series of prenatally diagnosed pleural effusions involve relatively small numbers of cases. A direct comparison of the aneuploidy rate between fetuses with isolated pleural effusions and those with other congenital anomalies or significant ultrasound findings has not, to our knowledge, been previously performed. This information may be valuable in providing genetic counseling and prognostic information to couples with a fetus prenatally diagnosed with a pleural effusion. We present our data involving the chromosome analysis of 246 fetuses with pleural effusions detected on prenatal ultrasonography to ...
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