Classic Dravet syndrome is also termed severe myoclonic epilepsy of infancy (SMEI). There are subtle phenotypic variants of Dravet which may have all the features of the syndrome except one, such as without myoclonic seizures, onset in the second year or without generalized spike and wave on EEG. These have been termed borderline variants of SMEI. Rather than ascribing multiple different names to marginally different phenotypes, the term Dravet syndrome is now preferred to describe the group of severe infantile onset epilepsies (OMIM #607208, #182389, #604403) associated with mutations in SCN1A (OMIM *182389).

SCN1A-related seizure disorders can be inherited in an autosomal dominant manner but most are due to de novo mutations. SCN1A testing can be done through bi-directional DNA sequencing and multiplex ligation-dependent probe amplification (MLPA) for:
1) individuals with electroclinical phenotype of Dravet Syndrome or clinical sub-types – several seizure types in one individual with onset in infancy, refractory to medication and with generalised spike and wave on EEG, or
2) infants less than 1 year old with 2 or more prolonged hemiclonic febrile seizures in early infancy.

Disclaimer: This summary is based on a UK Genetic Testing Network (UKGTN) approved Gene Dossier application.

Uveal melanoma (UM) is the most common primary cancer of the eye and has a strong propensity for metastasis. Although there have been many recent improvements in the diagnosis and treatment of UM, and only 2-4% of patients present with detectable metastasis, up to half of patients are at risk for dying of metastatic disease. Clinicopathologic factors are not accurate enough for individualized patient care. Chromosomal alterations have been used for prognostic purposes, but the routine clinical use of these methods is limited by their susceptibility to sampling error resulting from tumor heterogeneity, limited clinical validation, lack of standardized testing platforms, and high technical failure rates. In contrast, the DecisionDx-UM gene expression profile test is a stand-alone platform which requires no other information for maximal prognostic accuracy and which circumvents many of the drawbacks of chromosomal methods through the use of a highly sensitive microfluidics, PCR-based platform that simultaneously measures the expression of 15 carefully selected genes from primary uveal melanoma samples obtained by fine needle biopsy. Low metastatic risk is reported as Class 1, and high metastatic risk as Class 2. The test allows patients to be stratified into risk categories such that high-risk patients can be offered intensive metastatic surveillance and adjuvant therapy while low-risk patients can be spared these interventions. This test is now used as part of the standard of care in many ocular oncology centers.

Ruling out malignancy in thyroid nodules historically depended on thyroid resection and histopathological evaluation until fine needle aspiration (FNA) biopsy was introduced into the United States in the 1970′s. Thyroid FNA biopsy identified a majority of thyroid nodules as benign, obviating the need for surgery in over half of the patients. However, 15%-30% of thyroid FNAs have indeterminate cytology that still requires operation, even though most of these operated nodules prove to be benign post-operatively. In order to predict which cytologically indeterminate thyroid nodules are benign and to potentially avoid surgery on these nodules, a recently described commercially available Gene Expression Classifier (GEC) test (Afirma®, Veracyte, Inc., South San Francisco, CA) has been developed that can be run on the FNA sample. This paper reviews the published literature and technology assessments/guidelines by independent parties and professional groups regarding the clinical utility as well as the analytic and clinical validity of the Afirma GEC.

Cardiac ion channel mutational analysis is a category of genetic testing used in clinical practice for determining the status of long QT syndrome, short QT syndrome, catecholaminergic polymorphic ventricular tachycardia, and Brugada syndrome genes in blood, saliva, or tissue from patients and family members at risk for cardiac events such as syncope and sudden death. Such testing is most informative following careful phenotypic characterization. Individuals with ion channelopathies may benefit from prevention (avoidance of triggers and predisposing drugs) and treatment (e.g., beta blocker therapy, implantable cardioverter-defibrillator (ICD) placement) modalities.

Of 7,028 disorders with suspected Mendelian inheritance, 1,139 are recessive and have an established molecular basis. Although individually uncommon, Mendelian diseases collectively account for ~20% of infant mortality and ~18% of pediatric hospitalizations. Molecular diagnostic testing is currently available for only ~300 recessive disorders. Preconception screening, together with genetic counseling of carriers, has resulted in remarkable declines in the incidence of several severe recessive diseases including Tay-Sachs disease and cystic fibrosis. However, extension of preconception screening and molecular diagnostic testing to most recessive disease genes has hitherto been impractical. Recently, we reported a preconception carrier screen / molecular diagnostic test for 448 recessive childhood diseases. The current status of this test is reviewed here. Currently, this reports analytical validity of the comprehensive carrier test. As the clinical validity and clinical utility in the contexts described is ascertained, this article will be updated.

Bladder cancer is the fourth most common cancer in males worldwide and also the most expensive cancer to treat. Approximately 25% of patients with muscle invasive disease are found to harbor occult lymph node involvement at the time of cystectomy and this finding is associated with a 5-year survival rate of <30%. If these patients could be identified pre-operatively, use of neoadjuvant chemotherapy may be advantageous because this approach has been shown to confer a small survival advantage in patients with muscle invasive disease. However, because only a few patients benefit from this approach it has not been used extensively in the United States with fewer than 2% of patients undergoing this treatment. This is largely due to concerns that since neoadjuvant therapy is beneficial for only a few patients, it has the potential to delay surgery in the majority who do not benefit. However, since neoadjuvant therapy is most likely to benefit those patients at highest risk for progression of disease, it follows that patients with lymph node metastases would constitute an ideal group for such treatment. Hence, if patients with occult node involvement prior to cystectomy could be identified, they would constitute an ideal group for application of neoadjuvant therapy as they are most likely to benefit. In this summary, we describe the first multi-analyte gene expression model developed for predicting occult nodal involvement at cystectomy in bladder cancer patients, for the purpose of making better informed decisions regarding neoadjuvant therapy. The 20 gene model, which was developed on Affymetrix Human Genome U133A and U133 Plus 2.0 arrays, identified individuals with high relative risk (RR) of nodal involvement (RR = 1.74, 95% CI, 1.03 – 2.93) intermediate risk (RR = 1.05, 95% CI, .45 – 2.41), and low risk (RR = 0.74, 95% CI, 0.51 – 0.96), when evaluated in an independent test dataset. The 20 gene model can be applied to formalin-fixed paraffin embedded tissue with sufficient tumor content, making implementation in routine diagnostic tissue highly feasible. Although a clinical assay for the gene panel has not undergone analytic validation in a clinical laboratory setting, multiple platforms are available which could be utilized for routine testing, including real-time reverse transcriptase PCR directed against individual analytes as well as microarray approaches.

Women with early stage breast cancer frequently receive adjuvant chemotherapy to prevent recurrence; however, not all patients benefit. Recently, gene expression marker panels, such as Oncotype DX, that may better predict risk of breast cancer recurrence have become commercially available and are being used to guide treatment decisions. Oncotype DX analyzes the expression of 21 genes within a tumor to determine a recurrence score that corresponds to a specific likelihood of breast cancer recurrence within 10 years of the initial diagnosis, as well as response to adjuvant treatment. We examined the published literature on the analytic validity, clinical validity, and clinical utility of Oncotype DX in guiding adjuvant treatment decisions in women with lymph node-positive breast cancer.

Lung cancer is the second most common cancer and the leading cause of cancer-related deaths in the United States. Moreover, advanced non-small-cell lung cancer (NSCLC) is considered an incurable disease and current treatment approaches provide marginal improvement in overall survival at the expense of substantial morbidity and mortality, highlighting the need for new, less toxic treatment approaches. Tyrosine kinase inhibitors, such as erlotinib (Tarceva®), have been developed and approved as maintenance, second- and third-line treatment options in unselected advanced NSCLC patients (2, 15). However, subgroup analyses from the initial clinical trials consistently showed that patients with epidermal growth factor receptor (EGFR) mutations who received erlotinib had higher rates of response and better progression-free and overall survival, leading to clinical trials specifically focused on the use of tyrosine kinase inhibitors as first-line therapy in these patients. We examined the published literature on the analytic validity, clinical validity, and clinical utility of EGFR mutational testing in guiding first-line therapy use of erlotinib to treat advanced NSCLC and we briefly summarized the current lung cancer screening guidelines. The primary goal was to provide a basic overview of EGFR mutational testing and use of erlotinib as first-line therapy and identify gaps in knowledge and evidence that affect the recommendation and adoption of the test in advanced NSCLC treatment management strategies.

Individuals with Lynch syndrome, sometimes referred to as hereditary non-polyposis colorectal cancer (HNPCC), have an increased risk of developing colorectal cancer (CRC) as well as other cancers. The increased risk is due to inherited mutations in mismatch repair (MMR) genes, which reduce the ability of cells to repair DNA damage. Screening for Lynch syndrome in individuals newly diagnosed with colorectal cancer has been proposed as part of a strategy that combines tests and interventions to reduce the risk of colorectal cancer in the relatives of the colorectal cancer patients with Lynch Syndrome.

Familial hypercholesterolemia (FH) is an autosomal dominant disorder characterized by abnormally high concentrations of low-density lipoprotein (LDL) cholesterol in the blood, which predisposes affected persons to premature coronary heart disease (CHD) and death. FH is one of the most common inherited disorders and the most common one known to cause premature CHD in people of European descent. The vast majority of people with FH have inherited a single mutation from one parent in either the LDL receptor (LDLR), apolipoprotein B (APOB), or proprotein convertase subtilisin/kexin type 9 (PCSK9) genes. Despite their greatly elevated risk of coronary heart disease, most individuals with FH remain undiagnosed, untreated, or inadequately treated.

Cascade screening is a mechanism for identifying people at risk for a genetic condition by a process of systematic family tracing. The National Institute for Health and Clinical Excellence in the United Kingdom recommends cascade screening of close biological relatives of people with a clinical diagnosis of FH in order to effectively identify additional FH patients. The ultimate goal of this testing is to reduce morbidity and mortality from heart disease in persons with FH through early diagnosis and effective disease management. The goal of this article is to outline the available evidence on the clinical validity and utility of cascade screening for FH, while emphasizing the availability, usefulness, and recommendation for including DNA testing (if the disease-causing mutation has been identified).