Clinical genetics is a field that has traditionally focused on in

Clinical genetics is a field that has traditionally focused on individual gene tests indicated Sunitinib cost by the specific clinical presentation. Recently,

steps toward more comprehensive assessments have been made, including both disease-related gene panels and array-based technology for detecting genome-wide copy-number variation; these offer higher resolution than traditional karyotype analysis. The culmination of these steps toward more comprehensive assessment, however, is clearly next-generation sequencing (NGS). The era of comprehensive NGS in clinical genetics began with diagnostic reports appearing in late 2009 (Choi et al., 2009) and early 2010 (Ng et al., 2010) in the form of whole-exome sequencing (WES). Some recent examples of WES in clinical diagnosis include an infant of consanguinous parents with failure to thrive and dehydration, who was diagnosed with congenital chloride diarrhea due to a homozygous missense Caspase inhibitor mutation in the SLC26A3 gene ( Choi et al., 2009). Similarly, a compound heterozygote mutation in the DHODH gene was discovered in four affected individuals in three independent kindreds as a cause of a multiple-malformation disorder, Miller syndrome, a disorder that had previously been intractable

to more traditional approaches of discovery ( Ng et al., 2010). In addition to new disease gene discovery, WES may also be useful in refining clinical therapeutic decisions in individual patients, as exemplified by the beneficial addition of 5-hydroxytrptophan (a serotonin

precursor) to L-dopa therapy in two twins with dopa-responsive dystonia ( Bainbridge et al., 2011). Another illustrative case is that of a young boy with a severe Crohn’s disease phenotype who was found by exome sequencing to have a novel, hemizygous missense mutation in the X-linked inhibitor of apoptosis gene and who went on to do well following an allogeneic hematopoietic progenitor before cell transplant ( Worthey et al., 2011). Furthermore, in a recent pilot program of WES in 12 patients with unexplained and apparently genetic conditions, a specific genetic diagnosis was made in half of the patients ( Need et al., 2012). Despite some encouraging examples, however, successful diagnoses will not always, or even (at present) often, lead to improved treatments. The reality is that the majority of known Mendelian diseases cannot be effectively treated, at least as of yet. Nevertheless, the importance to affected families of receiving a specific, correct diagnosis after years of uncertainty and soul searching cannot be overstated. Individuals with intellectual disability and epilepsy often require full-time care from a young age, the burden of which falls on the parents and family.

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