br Methods br Results br Discussion Sequencing of the

Methods
Results
Discussion Sequencing of the first human genome took more than a decade, completing in 2001, and costing more than US$2.7 million (Lander et al., 2001; Venter et al., 2001; NHGRI, 2010). In the subsequent decade, newer high-throughput genomic technologies, known as the Next-Generation sequencing technologies, have been able to sequence and detect genetic variation in humans with high levels of accuracy, at breakneck speeds and at a fraction of that cost: offering the promise of fundamentally changing medical practice and finally delivering personalized medicine (Manolio et al., 2013; Mayer et al., 2011). Next-generation clinical genomics has potential to transform healthcare by bringing us closer to delivering optimal treatment, prescribed based on an individual\'s genetic profile. With improvement in genomic technologies, our ability to collect, analyze and aggregate data from large-scale sequencing continues to expand. The complexity of results generated from genomic sequencing thus presents unique challenges to clinicians, patients and their Neuronal Signaling Library in the areas of informed consent, genetic counseling and return of results (Green et al., 2012; Wolf et al., 2012; Roche and Berg, 2015; Hegde et al., 2015; Krier and Green, 2015; Burke et al., 2013; Kleiderman et al., 2014; Yu et al., 2014a, 2014b). There are many aspects requiring clarity and attention. Patients will need to understand the implications of pathogenic mutations, and what it means for family members who may be carriers of the mutation. Referring clinicians will need to understand that not all mutations (more accurately called variants) are necessarily pathogenic although they may occur in disease causing genes. Genetic counseling will need to address issues of possible pathogenic variants, variants of unknown significance, di-genic or multi-genic inheritance, and disease penetrance. After clarifying the implications from results in genes related to the primary condition, we are then faced with the equally, if not more challenging issue of variants in other “medically important” genes, that may be unrelated to the patient\'s primary medical condition or that may be confounded by one\'s ethnicity. In our busy and time-constrained health care systems, explaining the complexities of the genomic sequencing process is a challenge and will need deliberate effort to address. We anticipate an increase in the use of genomics in clinics in the coming years, some of which may be driven by well-informed patients themselves or by commercial entities. There is undoubtedly an urgent need for recommendations and a build-up of reliable experience. Detection of IFs has implications not only for the individual, but also his/her family members (McLaughlin et al., 2014). For example, WES on a patient with intellectual disability may detect pathogenic variants in BRCA1. This mutation could be inherited from the parents, which means that the affected parent (and his/her siblings) is at risk of developing cancer and would require surveillance and monitoring. This family may or may not be prepared to receive such information and this issue needs to be discussed during the informed consent process. While the Genetic Information Non-discrimination Act (GINA 2008) in USA offers protection to individuals against discrimination for health insurance and employment based on their genetic information, it is not comprehensive and excludes life insurance; and similar laws are lacking in other countries (Dorschner et al., 2013). Indeed individuals with a genetic diagnosis, especially those with incidental findings, may face discrimination at work or be denied of medical insurance without any avenue for legal redress. Our study detected a combined prevalence of IFs at 1.6% among a representative South East Asian population, which is similar to the prevalence in other ethnic groups and is consistent with the rates of prevalence of these disorders. In addition, a majority of individuals (83%) responded favorably to the return of IFs, which highlights the importance of including the patient in the decision making process. Four of the 6 variants are in cardiac-related genes (SCN5A, TNNT2 and COL3A1). Mutations in SCN5A and TNNT2 are associated with Brugada syndrome and cardiomyopathy, respectively, and can present with sudden death as their first presentation. Detection of carrier status for the mutations allows for anticipatory guidance in the form of regular electrocardiogram and echocardiography, and avoidance of triggers such as certain medications like macrolides. These measures can avert the usual catastrophic presentation of these disorders (Priori et al., 2013). In addition, cascade screening of family members can identify other at-risk individuals who can then be managed accordingly (Priori et al., 2013). Similarly, guidelines and recommendations exist for patients with mutations in BRCA2, TP53, and COL3A1 which allows for anticipatory management and minimizes mortality and long-term morbidity (Warner et al., 2004; Ballinger et al., 2015; Lum et al., 2011). These results suggest that comprehensiveness of WES/WGS tests should be explained to the interested patients and treated as an opportunity to provide important health information.