Exome sequencing efficacy and phenotypic expansions involving esophageal atresia/tracheoesophageal fistula plus.

Esophageal atresia/tracheoesophageal fistula (EA/TEF) is a life-threatening birth defect that often occurs with other major birth defects (EA/TEF+). Despite advances in genetic testing, a molecular diagnosis can only be made in a minority of EA/TEF+ cases. Here, we analyzed clinical exome sequencing data and data from the DECIPHER database to determine the efficacy of exome sequencing in cases of EA/TEF+ and to identify phenotypic expansions involving EA/TEF. Among 67 individuals with EA/TEF+ referred for clinical exome sequencing, a definitive or probable diagnosis was made in 11 cases for an efficacy rate of 16% (11/67). This efficacy rate is significantly lower than that reported for other major birth defects, suggesting that polygenic, multifactorial, epigenetic, and/or environmental factors may play a particularly important role in EA/TEF pathogenesis. Our cohort included individuals with pathogenic or likely pathogenic variants that affect TCF4 and its downstream target NRXN1, and FANCA, FANCB, and FANCC, which are associated with Fanconi anemia. These cases, previously published case reports, and comparisons to other EA/TEF genes made using a machine learning algorithm, provide evidence in support of a potential pathogenic role for these genes in the development of EA/TEF.

HIV testing of health care workers in England--a flawed policy.

A new Department of Health policy in England, published in 2007, recommended changes to the pre-employment health checks performed on health care workers before taking up their employment. The policy proposed that all new health care workers should receive immunization against TB and hepatitis B and should be offered testing for hepatitis C and HIV. It also advanced a new requirement that staff who perform exposure-prone procedures must be tested for TB, hepatitis B and C and HIV and must test negative for these diseases. Essentially mandatory HIV testing has been introduced for a large number of health care workers. The aim of the recommendations is to protect patients from contracting serious communicable diseases from health care professionals. Secondary objectives of the directive are to maintain confidence in the workforce and reduce the burden of patient notification exercises. This essay explores some of the shortcomings of this policy and examines the reasons why this policy will fail to meet its objectives. The justification for this new guidance is questioned and some of the ethical issues are highlighted.