orexin Looking to the future the development of effective an

Looking to the future, the development of effective anti-RV vaccines may be further complicated by other picornavirus strains that can cause orexin attacks, including enterovirus-68 which recently caused hospital admissions and ER visits for asthma in the U.S. this fall. Thus, other treatment strategies remain under investigation and include the development of innate anti-viral therapies (e.g., administering type I or type III interferons); however, costs, side effects, and how these drugs should be administered (seasonally, or at the time of an acute infection) will need to be considered. Alternatively, treatments to reduce allergic inflammation in the airway may also help to counter the asthmatic effects of RV. In support of this approach, the administration of omalizumab (anti-IgE antibody) to inner-city children with asthma in the US virtually illuminated the seasonal increases in asthma exacerbations in the spring and fall (). This treatment effect included a subset of children who tested positive for RV. As these treatment strategies are compared and evaluated, the research results described by Niespodziana et al. clearly represent a step in the right direction to help us develop new methods to minimize the adverse effects of RV infections in the asthmatic population. Conflicts of Interest
Funding Support The author is supported by the National Institutes of Health Grants: U01-AI100799 and R01-AI020565.
Patients with a family history of cancer are being evaluated with single-gene or gene panel tests (). The decreasing cost and potential to provide comprehensive genetic risk assessment makes whole genome sequencing (WGS) an attractive tool for understanding the genetic risk for cancer (). Despite such potential, the empirical value of WGS in cancer genetics clinics is unknown: whether WGS can replicate previous findings in single/multi-gene testing, and whether it will increase the rate of identification. In this issue of , Foley et al. describes their results obtained from analyzing the WGS data from the blood samples of two cohorts of cancer genetics patients: those with 1/2 mutations (n=176) and those without (n=82) (). In their analysis, they focus on a set of 163 clinically relevant genes, including those on commercial cancer-susceptibility gene panels, recommended by American College of Medical Genetics (), and those that might impact reproductive decision-making (). They find that in each 1/2 patient there is an average of 6.8–6.9 potentially pathogenic variants (PPVs), defined as nonsynonymous variants with allele frequency <1% in a normal human population (ESP6500). All the previously known 1/2 mutations are detected, proving the sensitivity of WGS. As anticipated, most of these PPVs are missense variants, the majority of which will be classified as variants of unknown significance (VUS) based on existing knowledge (). To facilitate diagnoses, Foley et al. further restrict analyses to only loss-of-function (LoF) PPVs, including nonsense, nonstop single nucleotide variants (SNVs) and frame-shift indels (). In six patients, they identify LoF PPVs in four dominant cancer-associated genes (, , , and ), in addition to original clinically diagnosed 1/2 mutations. These variants that carry additional cancer risk may be of use for counseling and then screening of the patient\'s family members. Interestingly, they find that previously reported pathogenic missense variants in several genes do not associate with their predicted diseases. For example, the missense variant p.N1978S is previously reported as pathogenic and diagnostic for Rubenstein Taybi syndrome (RTS) (). However, a patient carrying this variant and her family members that carried the variant have no symptoms consistent with a RTS diagnosis. The missense variant p.N29I is previously associated with hereditary pancreatitis and subsequent pancreatic cancer. None of nine patients that carried the -variant report any pancreatic problems. These results indicate that while WGS can expand the breadth of disease risk analysis, clinical interpretation of WGS results, particularly for missense variants, requires detailed medical histories and results from extended family members to derive confident diagnoses for appropriate genetic counseling. Moreover, previously reported disease associations should be understood with caution and be interpreted in light of available family medical history.