Actionable exomic incidental findings in 6503 participants: challenges of variant classification.

Recommendations for laboratories to report incidental findings from genomic tests have stimulated interest in such results. In order to investigate the criteria and processes for assigning the pathogenicity of specific variants and to estimate the frequency of such incidental findings in patients of European and African ancestry, we classified potentially actionable pathogenic single-nucleotide variants (SNVs) in all 4300 European- and 2203 African-ancestry participants sequenced by the NHLBI Exome Sequencing Project (ESP). We considered 112 gene-disease pairs selected by an expert panel as associated with medically actionable genetic disorders that may be undiagnosed in adults. The resulting classifications were compared to classifications from other clinical and research genetic testing laboratories, as well as with in silico pathogenicity scores. Among European-ancestry participants, 30 of 4300 (0.7%) had a pathogenic SNV and six (0.1%) had a disruptive variant that was expected to be pathogenic, whereas 52 (1.2%) had likely pathogenic SNVs. For African-ancestry participants, six of 2203 (0.3%) had a pathogenic SNV and six (0.3%) had an expected pathogenic disruptive variant, whereas 13 (0.6%) had likely pathogenic SNVs. Genomic Evolutionary Rate Profiling mammalian conservation score and the Combined Annotation Dependent Depletion summary score of conservation, substitution, regulation, and other evidence were compared across pathogenicity assignments and appear to have utility in variant classification. This work provides a refined estimate of the burden of adult onset, medically actionable incidental findings expected from exome sequencing, highlights challenges in variant classification, and demonstrates the need for a better curated variant interpretation knowledge base.

Weighing the evidence for newborn screening for Hemoglobin H disease.

OBJECTIVE: To conduct a systematic review to assist the United States Secretary of Health and Human Services Advisory Committee on Heritable Disorders in Newborns and Children (SACHDNC) to determine whether Hemoglobin H screening should be included among the core recommended conditions for newborn screening. STUDY DESIGN: We identified 21 articles in MEDLINE from 1989 to March 2010 that provided evidence regarding screening, treatment, and outcomes associated with Hemoglobin H disease. RESULTS: In California, newborn screening has identified 9 cases per 100 000 of deletional hemoglobin H disease and 0.6 cases per 100 000 of nondeletional hemoglobin H disease. Five cases of hemoglobin Bart's hydrops fetalis syndrome were also identified in over ten years of screening for Hemoglobin H disease. Although Hemoglobin H disease is associated with a wide range of morbidity, no studies were found that evaluated the benefits of early identification and treatment. CONCLUSIONS: The SACHDNC found the data insufficient to recommend that states adopt newborn screening for Hemoglobin H disease.

Weighing the evidence for newborn screening for early-infantile Krabbe disease.

PURPOSE: To summarize the evidence regarding screening, diagnosis, and treatment of early-infantile Krabbe disease in consideration of its addition to the core panel for newborn screening as has been done in New York state. METHODS: Systematic review of articles indexed in MEDLINE and Embase published between January 1988 and July 2009. Thirteen articles describing studies related to screening, diagnosis, or treatment were included in this review. RESULTS: Case series studies suggest that allogeneic hematopoietic stem-cell transplantation soon after the development of signs or symptoms of early-infantile Krabbe disease decreases early-childhood mortality and may improve neurodevelopment. However, limited data suggest there may be loss of motor function among some children who undergo transplantation. No long-term follow-up data are available from these case series. Of the ∼550,000 newborns reported to have been screened in New York, 25 tested positive. None of these were clinically recognized to have Krabbe disease prior these results. Four were considered to be high risk for early-onset Krabbe disease. Two were subsequently diagnosed and underwent stem-cell transplantation, of whom one died from complications. No data are available regarding the impact on families of a positive newborn screen. CONCLUSIONS: Although early treatment with hematopoietic stem-cell transplant seems to alter early-childhood mortality and some of the morbidity associated with early-infantile Krabbe disease, significant gaps in knowledge exist regarding the accuracy of screening, the strategy for establishing diagnosis, the affect of a positive screen on families, the benefits and harms of treatment, and long-term prognosis.