The clinical presentation of multiple, rare, skin appendage tumours called cylindromas has been attributed to germline mutations in the tumour suppressor gene CYLD (OMIM 605018). Brooke-Spiegler Syndrome (BSS), familial cylindromatosis (FC) and multiple familial trichoepitheliomas (MFT) (OMIM #605041, #132700, #601606 respectively) differ due to the types of other skin appendage tumour seen together with cylindroma, such as spiradenoma and trichoepithelioma. Previously thought to be separate entities, they are now viewed as allelic variants with overlapping phenotypes, supported by mutation analysis of CYLD . The conditions display autosomal dominant inheritance and affected individuals develop multiple benign skin tumours most commonly on the head and neck.

CYLD testing can be performed using PCR and Sanger sequencing for patients with:
1. Multiple cylindromas, spiradenomas or trichoepitheliomas.
2. A single cylindroma, spiradenoma or trichoepithelioma and an affected first-degree relative with any of these tumours.
3. An asymptomatic family member at 50% risk with a known mutation in the family.

Endometrial cancer is the first malignancy in 50% of women with Lynch syndrome, an autosomal dominant cancer-prone syndrome caused by germline mutations in genes encoding components of the DNA mismatch repair (MMR) pathway. These women (2-4% of all those with endometrial cancer) are at risk of metachronous colorectal cancer and other Lynch syndrome-associated cancers, and their first-degree relatives are at 50% risk of Lynch syndrome. Testing all women newly diagnosed with endometrial cancer for Lynch syndrome may have clinical utility for the index case and her relatives by alerting them to the benefits of surveillance and preventive options, primarily for colorectal cancer. The strategy involves offering germline DNA mutation testing to those whose tumour shows loss-of-function of MMR protein(s) when analysed for microsatellite instability (MSI) and/or by immunohistochemisty (IHC). In endometrial tumours from unselected patients, MSI and IHC have a sensitivity of 80-100% and specificity of 60-80% for detecting a mutation in an MMR gene, though the number of suitable studies for determining clinical validity is small. The clinical validity of strategies to exclude those with false-positive tumour test results due to somatic hypermethylation of the MLH1 gene promoter has not been determined. Options include direct methylation testing, and excluding those over the age of 60 who have no concerning family history or clinical features. The clinical utility of Lynch syndrome testing for the index case depends on her age and the MMR gene mutated: the net benefit is lower for those diagnosed at older ages and with less-penetrant MSH6 mutations. To date, women with these features are the majority of those diagnosed through screening unselected endometrial cancer patients but the number of studies is small. Similarly, clinical utility to relatives of the index case is higher if the family’s mutation is in MLH1 or MSH2 than for MSH6 or PMS2. Gaps in current evidence include a need for large, prospective studies on unselected endometrial cancer patients, and for health-economic analysis based on appropriate assumptions.

The determination of the underlying etiology of symptoms suggestive of obstructive coronary artery disease (CAD, ≥50% stenosis in a major coronary artery) is a common clinical challenge in both primary care and cardiology clinics. Usual care in low to medium risk patients often involves a family history, risk factor assessment, and then stress testing with or without non-invasive imaging. If positive, this is often followed by invasive coronary angiography (ICA). Despite extensive adoption of this usual care paradigm, more than 60% of patients referred for angiography do not have obstructive CAD. In order to robustly identify those symptomatic patients without obstructive CAD, who can avoid subsequent cardiac testing and look elsewhere for the cause of their symptoms, a recently described whole blood gene expression score (GES: Corus® CAD, CardioDx, Inc., Palo Alto, CA) has been developed and validated in two multi-center trials. This paper reviews the published literature and assessments by independent parties regarding the analytical and clinical validity as well as the clinical utility of the Corus® CAD test.

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.

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.