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Familial hypercholesterolemia (FH, OMIM no. 143890) is a common autosomal dominant condition with a prevalence of 1 in 500. Patients with FH have raised serum cholesterol levels and increased arterial deposition of low-density lipoprotein (LDL) cholesterol, leading to premature coronary heart disease. Despite the fact that early-onset coronary heart disease can be prevented by cholesterol-lowering drugs such as statins, less than a quarter of FH patients have currently been identified in the United Kingdom.1 Several diagnostic criteria have been developed to identify individuals with FH, including the Dutch Lipid Clinic 2 criteria and the MedPed 3 criteria. In the United Kingdom, the clinical diagnosis of FH is based on the Simon Broome criteria of cholesterol levels, presence of tendon xanthomata, family history, and genetic testing. 4 The UK National Institute for Health and Clinical Excellence guidelines recommend initial mutation screening of index cases fulfilling Simon Broome criteria followed by cascade screening in at least firstand second-degree relatives. 5Most cases of FH are caused by mutations in the LDLR gene that encodes the LDL receptor protein, which binds LDL particles at the hepatic cell membrane and internalizes them for processing and excretion. FH-causing mutations in LDLR are found throughout the gene and include missense, truncating, and splice site mutations; small insertion/deletion mutations; and large insertions/deletions that can encompass multiple exons. Some mutations have been found in many unrelated individuals with FH, whereas others are found rarely. 6 Mutations in two other genes, PCSK9 and APOB, can also cause the FH phenotype but in <20% of cases.7 Rare autosomal-recessive hypercholesterolemia is caused by mutations in the LDLRAP1 gene. 8Conventional DNA testing of FH disease-causing genes is mostly based on direct capillary sequencing, with multiplex ligation-dependent probe amplification (MLPA) used for the detection of large insertions or deletions.9 These molecular techniques are sensitive and specific, but because of the cost and time involved, they are impractical for screening large numbers of patients. To overcome some of these limitations, assays such as the Amplification Refractory Mutation System (Elucigene FH20; Tepnel Molecular Diagnostics, Abingdon, UK) or arraybased sequencing methods (LIPOchip; Progenika Biopharma, Derio, Spain) have been developed. These assays are tailored to Purpose: Familial hypercholesterolemia is a common Mendelian disorder associated with early-onset coronary heart disease that can be treated by cholesterol-lowering drugs. The majority of cases in the United Kingdom are currently without a molecular diagnosis, which is partly due to the cost and time associated with standard screening techniques. The main purpose of this study was to test the sensitivity and specificity of two next-generation sequencing protocols for genetic diagnosis of familial hypercholesterolemia. Methods:Libraries were prepared for next-generation sequencing by tw...

The mutational landscape is shaped by many processes. Genic regions are vulnerable to mutation but are preferentially protected by transcription-coupled repair1. In microorganisms, transcription has been demonstrated to be mutagenic2,3; however, the impact of transcription-associated mutagenesis remains to be established in higher eukaryotes4. Here we show that ID4—a cancer insertion–deletion (indel) mutation signature of unknown aetiology5 characterized by short (2 to 5 base pair) deletions —is due to a transcription-associated mutagenesis process. We demonstrate that defective ribonucleotide excision repair in mammals is associated with the ID4 signature, with mutations occurring at a TNT sequence motif, implicating topoisomerase 1 (TOP1) activity at sites of genome-embedded ribonucleotides as a mechanistic basis. Such TOP1-mediated deletions occur somatically in cancer, and the ID-TOP1 signature is also found in physiological settings, contributing to genic de novo indel mutations in the germline. Thus, although topoisomerases protect against genome instability by relieving topological stress6, their activity may also be an important source of mutations in the human genome.

Scuba diving can offer significant therapeutic benefits, particularly for ex-military amputees experiencing co-morbid anxiety and/or chronic psychological adjustment disorders, notably in terms of improvements in social dysfunction and symptomology of depression. Implications for Rehabilitation Scuba Diving as a Therapy Military combat can result in devastating, chronic physical and/or psychological injury. Current research suggests that a combination of medical and psychological therapy may prove to be the most beneficial for military veterans. Scuba diving has the potential to benefit injured veterans due the requirement of complete focus and the feeling of weightlessness when underwater. This article evaluates whether scuba diving is an effective physical and psychological therapy through GHQ-28 analysis and veteran interviews. Scuba diving benefited injured veterans in terms of chronic pain relief and depression symptoms alleviation.