The GeneInsight Suite: a platform to support laboratory and provider use of DNA-based genetic testing.

The future of personalized medicine will hinge on effective management of patient genetic profiles. Molecular diagnostic testing laboratories need to track knowledge surrounding an increasingly large number of genetic variants, incorporate this knowledge into interpretative reports, and keep ordering clinicians up to date as this knowledge evolves. Treating clinicians need to track which variants have been identified in each of their patients along with the significance of these variants.

Evaluation of second-generation sequencing of 19 dilated cardiomyopathy genes for clinical applications.

Medical sequencing for diseases with locus and allelic heterogeneities has been limited by the high cost and low throughput of traditional sequencing technologies. "Second-generation" sequencing (SGS) technologies allow the parallel processing of a large number of genes and, therefore, offer great promise for medical sequencing; however, their use in clinical laboratories is still in its infancy. Our laboratory offers clinical resequencing for dilated cardiomyopathy (DCM) using an array-based platform that interrogates 19 of more than 30 genes known to cause DCM.

A novel custom resequencing array for dilated cardiomyopathy.

Purpose: Genetic tests for the most commonly mutated genes in dilated cardiomyopathy (DCM) can confirm a clinical diagnosis in the proband and inform family management. Presymptomatic family members can be identified, allowing for targeted clinical monitoring to minimize adverse outcomes. However, the marked locus and allelic heterogeneity associated with DCM have made clinical genetic testing challenging.

Platform evaluation for rapid genotyping of CYP2C9 and VKORC1 alleles.

Aims: Warfarin is a commonly prescribed drug with a narrow therapeutic index. Adverse drug reactions owing to over- or under-dosing are common. It is now established that genetic differences between individuals play a major role in warfarin metabolism.

DNA sequencing of cancer-related genes for biomarker discovery.

Dideoxy DNA sequencing is routinely used in research and, increasingly, in clinical care for the detection of DNA sequence variants, single nucleotide changes, or small insertions or deletions, when the spectrum of DNA variation is unknown. DNA sequence variation can be present in tumor tissue that is not present in the normal tissue from the same individual. This somatic DNA sequence variation is often the cause of abnormal cell growth and/or regulation and, ultimately, tumorigenesis.

Evaluating the role of the 620W allele of protein tyrosine phosphatase PTPN22 in Crohn's disease and multiple sclerosis.

The 620W allele of PTPN22 has been associated with susceptibility to several different forms of chronic inflammatory disease, including Type 1 diabetes (T1D), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and autoimmune thyroiditis (AIT). We set out to explore its possible role in two other inflammatory diseases: multiple sclerosis (MS) and Crohn's disease (CD). In our cohort of 496 MS trios from the United Kingdom, we observed reduced transmission of the PTPN22 620W allele.

Haplotype analysis of tumour necrosis factor receptor genes in 1p36: no evidence for association with systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease with partially understood aetiology. The 1p36 region has been previously linked with SLE and harbours tumour necrosis factor receptor (TNFR) genes. Functional and genetic data implicate their gene products in SLE and other autoimmune diseases.

Association analysis of the R620W polymorphism of protein tyrosine phosphatase PTPN22 in systemic lupus erythematosus families: increased T allele frequency in systemic lupus erythematosus patients with autoimmune thyroid disease.

Objective: Recent case-control studies show associations of the minor T allele (of the C1858T single-nucleotide polymorphism corresponding to the R620W amino acid substitution) of PTPN22 with multiple autoimmune diseases, including systemic lupus erythematosus (SLE). We performed family-based association studies of this polymorphism in 4 independent cohorts containing SLE patients and their parents and/or other family members.

Methods: A total of 2,689 individuals from 902 independent Caucasian families with SLE were genotyped using polymerase chain reaction pyrosequencing (cohorts 1 and 2) and the Sequenom MassArray system (cohorts 3 and 4).

Mapping autoimmune disease genes in humans: lessons from IBD and SLE.

The inflammatory bowel diseases (IBD) and systemic lupus erythematosus (SLE) are common autoimmune diseases that affect 2-3 million people in the USA alone. Crohn's disease (CD) and ulcerative colitis (UC), the inflammatory bowel diseases, are idiopathic, chronic inflammatory disorders of the gastrointestinal tract. SLE is a chronic, multi-system autoimmune disease that generally presents in women of childbearing age as fatigue, arthralgia and rash.

Association of DLG5 R30Q variant with inflammatory bowel disease.

Crohn's disease (CD) and ulcerative colitis (UC) are chronic inflammatory diseases of the gastrointestinal system known as the inflammatory bowel diseases (IBD). Recently, Stoll and colleagues reported a novel finding of genetic variation in the DLG5 gene that is associated with IBD (CD and UC combined). We present here a study of the genetic variation described in that report in two well-powered, independent case-control cohorts and one family-based collection, and confirm the proposed association between IBD and the R30Q variant of DLG5 in two of the three studies.

Haplotype structure of TNFRSF5-TNFSF5 (CD40-CD40L) and association analysis in systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease that is caused by genetic and environmental factors. The tumour necrosis factor (TNF) superfamily of genes play a central role in immune regulation and have been proposed to be involved in the development of SLE. TNFRSF5 (CD40) falls on 20q11-13, a region linked with SLE in three independent genome-wide studies.

An integrated haplotype map of the human major histocompatibility complex.

Numerous studies have clearly indicated a role for the major histocompatibility complex (MHC) in susceptibility to autoimmune diseases. Such studies have focused on the genetic variation of a small number of classical human-leukocyte-antigen (HLA) genes in the region. Although these genes represent good candidates, given their immunological roles, linkage disequilibrium (LD) surrounding these genes has made it difficult to rule out neighboring genes, many with immune function, as influencing disease susceptibility.