PolyPhred analysis software for mutation detection from fluorescence-based sequence data.

The ability to search for genetic variants that may be related to human disease is one of the most exciting consequences of the availability of the sequence of the human genome. Large cohorts of individuals exhibiting certain phenotypes can be studied and candidate genes resequenced. However, the challenge of analyzing sequence data from many individuals with accuracy, speed, and economy is great.

Mutation detection using automated fluorescence-based sequencing.

The development of high-throughput DNA sequencing techniques has made direct DNA sequencing of PCR-amplified genomic DNA a rapid and economical approach to the identification of polymorphisms that may play a role in disease. Point mutations as well as small insertions or deletions are readily identified by DNA sequencing. The mutations may be heterozygous (occurring in one allele while the other allele retains the normal sequence) or homozygous (occurring in both alleles).

Selection of a platform for mutation detection.

New mutation detection technologies must keep pace by becoming more cost-effective while offering improved technical sensitivity and higher throughput capacity. In recent years, the number of mutation detection platforms available to the clinical researcher has grown to a point where it is difficult to keep track of all available options as well as their benefits and pitfalls. This unit provides an entry point for a variety of researchers who wish to analyze samples for known or novel mutations and need to determine which platform is most suited for their particular needs.

Pharmacogenomics of lung cancer: with a view to address EGFR-targeted therapies.

Epidermal growth factor receptor (EGFR)-targeted therapies have demonstrated variable success in treating individuals with non-small-cell lung cancer. Understanding the molecular mechanisms of response and resistance to this class of treatment has led to patient selection strategies that may improve outcomes. The second generation of EGFR-targeted therapies is now under clinical evaluation and may prove to be successful at circumventing a portion of primary or acquired resistance to first-generation tyrosine kinase inhibitors.

A novel, single nucleotide polymorphism-based assay to detect 22q11 deletions.

Velocardiofacial syndrome, DiGeorge syndrome, and conotruncal anomaly face syndrome, now collectively referred to as 22q11deletion syndrome (22q11DS) are caused by microdeletions on chromosome 22q11. The great majority ( approximately 90%) of these deletions are 3 Mb in size. The remaining deleted patients have nested break-points resulting in overlapping regions of hemizygosity.

Response to treatment and survival of patients with non-small cell lung cancer undergoing somatic EGFR mutation testing.

Somatic mutations in the epidermal growth factor receptor (EGFR) gene are associated with clinical response and prolonged survival in patients with non-small cell lung cancer (NSCLC) treated with EGFR tyrosine kinase inhibitors (TKIs). We began screening patients for somatic EGFR mutations by DNA sequencing as part of clinical care in 2004. We performed a retrospective cohort study of 278 patients with NSCLC referred for EGFR testing over a 10-month period.

Increased susceptibility to UV-induced skin carcinogenesis in polymerase eta-deficient mice.

Xeroderma pigmentosum variant (XPV) patients with mutations in the DNA polymerase eta (pol eta) gene are hypersensitive to sunlight and have greatly increased susceptibility to sunlight-induced skin cancer. Consistent with the ability of Pol eta to efficiently bypass UV light-induced cyclobutane pyrimidine dimers, XPV cells lacking Pol eta have diminished capacity to replicate UV-damaged DNA and are sensitive to UV light-induced killing and mutagenesis. To better understand these and other Pol eta functions, we generated Pol eta-deficient mice.

A genetic approach to the child with sensorineural hearing loss.

This article presents an overview of current topics related to the genetics of hearing loss. The review focuses on the approach toward a child with a sensorineural hearing loss of unknown etiology and the incorporation of genetic testing into the workup. Nongenetic causes of hearing loss are reviewed, as they are important in the differential diagnosis when considering a genetic basis for a child's hearing loss.