Welcome to the new genomics: an introduction to the NHS Genomic Medicine Service for oral healthcare professionals.

Genomic medicine is on the threshold of a significant advance in the United Kingdom (UK) with the introduction of a National Health Service (NHS) Genomic Medicine Service. This world-leading initiative aims to integrate genomic medicine into routine NHS care and has the potential to revolutionise healthcare in the UK, including dentistry. The initial focus will be on increasing diagnostic services for rare diseases and cancer, while also harnessing the use of personalised medicine for therapeutic interventions in multiple disorders.

Using the Findings of a National Survey to Inform the Work of England's Genomics Education Programme.

A national coordinated approach to workforce education and training in genomics is essential for the successful implementation of whole genome sequencing and, more broadly, genomic medicine within the National Health Service (NHS) in England. However, there have been no workforce wide assessments of genomics education and training needs that can be used to inform the strategic approach to be taken. In order to assess these needs the Genomics Education Programme (GEP) undertook a cross-professional training needs analysis.

Genomic Education at Scale: The Benefits of Massive Open Online Courses for the Healthcare Workforce.

To support the delivery of the UK's 100,000 Genomes Project, Health Education England's Genomics Education Programme developed a suite of resources, including a 3-week Massive Open Online Course (MOOC) on whole genome sequencing the FutureLearn platform. This MOOC is a synchronous learning event, with course educators and mentors (NHS healthcare science trainees in genomics) facilitating the experience in real time. Crucially, the platform allows participants to interact and learn from each other's experiences.

Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples.

Purpose: The accurate interpretation of variation in Mendelian disease genes has lagged behind data generation as sequencing has become increasingly accessible. Ongoing large sequencing efforts present huge interpretive challenges, but they also provide an invaluable opportunity to characterize the spectrum and importance of rare variation.

Methods: We analyzed sequence data from 7,855 clinical cardiomyopathy cases and 60,706 Exome Aggregation Consortium (ExAC) reference samples to obtain a better understanding of genetic variation in a representative autosomal dominant disorder.

Next generation sequencing for molecular diagnosis of neurological disorders using ataxias as a model.

Many neurological conditions are caused by immensely heterogeneous gene mutations. The diagnostic process is often long and complex with most patients undergoing multiple invasive and costly investigations without ever reaching a conclusive molecular diagnosis. The advent of massively parallel, next-generation sequencing promises to revolutionize genetic testing and shorten the 'diagnostic odyssey' for many of these patients.

Clinical, biochemical, cellular and molecular characterization of mitochondrial DNA depletion syndrome due to novel mutations in the MPV17 gene.

Mitochondrial DNA (mtDNA) depletion syndromes (MDS) are severe autosomal recessive disorders associated with decreased mtDNA copy number in clinically affected tissues. The hepatocerebral form (mtDNA depletion in liver and brain) has been associated with mutations in the POLG, PEO1 (Twinkle), DGUOK and MPV17 genes, the latter encoding a mitochondrial inner membrane protein of unknown function. The aims of this study were to clarify further the clinical, biochemical, cellular and molecular genetic features associated with MDS due to MPV17 gene mutations.

Next-generation sequencing (NGS) as a diagnostic tool for retinal degeneration reveals a much higher detection rate in early-onset disease.

Inherited retinal degeneration (IRD) is a common cause of visual impairment (prevalence ∼1/3500). There is considerable phenotype and genotype heterogeneity, making a specific diagnosis very difficult without molecular testing. We investigated targeted capture combined with next-generation sequencing using Nimblegen 12plex arrays and the Roche 454 sequencing platform to explore its potential for clinical diagnostics in two common types of IRD, retinitis pigmentosa and cone-rod dystrophy.

Gross deletions in TCOF1 are a cause of Treacher-Collins-Franceschetti syndrome.

Treacher-Collins-Franceschetti syndrome (TCS) is an autosomal dominant craniofacial disorder characterised by midface hypoplasia, micrognathia, downslanting palpebral fissures, eyelid colobomata, and ear deformities that often lead to conductive deafness. A total of 182 patients with signs consistent with a diagnosis of TCS were screened by DNA sequence and dosage analysis of the TCOF1 gene. In all, 92 cases were found to have a pathogenic mutation by sequencing and 5 to have a partial gene deletion.

DNA testing for hypertrophic cardiomyopathy: a cost-effectiveness model.

Aims To explore the cost-effectiveness of alternative methods of screening family members for hypertrophic cardiomyopathy (HCM), the most common monogenic cardiac disorder and the most frequent cause of sudden cardiac death (SCD) in young people. Methods and results Economic decision model comparing cascade screening by genetic, as opposed to clinical methods. The incremental cost per life year saved was 14,397 euro for the cascade genetic compared with the cascade clinical approach.

Clinical dividends from the molecular genetic diagnosis of craniosynostosis.

A dozen years have passed since the first genetic lesion was identified in a family with craniosynostosis, the premature fusion of the cranial sutures. Subsequently, mutations in the FGFR2, FGFR3, TWIST1, and EFNB1 genes have been shown to account for approximately 25% of craniosynostosis, whilst several additional genes make minor contributions. Using specific examples, we show how these discoveries have enabled refinement of information on diagnosis, recurrence risk, prognosis for mental development, and surgical planning.

QuantiSNP: an Objective Bayes Hidden-Markov Model to detect and accurately map copy number variation using SNP genotyping data.

Array-based technologies have been used to detect chromosomal copy number changes (aneuploidies) in the human genome. Recent studies identified numerous copy number variants (CNV) and some are common polymorphisms that may contribute to disease susceptibility. We developed, and experimentally validated, a novel computational framework (QuantiSNP) for detecting regions of copy number variation from BeadArray SNP genotyping data using an Objective Bayes Hidden-Markov Model (OB-HMM).

Clinical dividends from the molecular genetic diagnosis of craniosynostosis.

A dozen years have passed since the first genetic lesion was identified in a family with craniosynostosis, the premature fusion of the cranial sutures. Subsequently, mutations in the FGFR2, FGFR3, TWIST1, and EFNB1 genes have been shown to account for approximately 25% of craniosynostosis, whilst several additional genes make minor contributions. Using specific examples, we show how these discoveries have enabled refinement of information on diagnosis, recurrence risk, prognosis for mental development, and surgical planning.

Accurate detection and quantitation of heteroplasmic mitochondrial point mutations by pyrosequencing.

Disease-causing mutations in mitochondrial DNA (mtDNA) are typically heteroplasmic and therefore interpretation of genetic tests for mitochondrial disorders can be problematic. Detection of low level heteroplasmy is technically demanding and it is often difficult to discriminate between the absence of a mutation or the failure of a technique to detect the mutation in a particular tissue. The reliable measurement of heteroplasmy in different tissues may help identify individuals who are at risk of developing specific complications and allow improved prognostic advice for patients and family members.