What's New in Genetic Testing for Cancer Susceptibility?

The advent of next-generation sequencing, and its transition further into the clinic with the US Food and Drug Administration approval of a cystic fibrosis assay in 2013, have increased the speed and reduced the cost of DNA sequencing. Coupled with a historic ruling by the Supreme Court of the United States that human genes are not patentable, these events have caused a seismic shift in genetic testing in clinical medicine. More labs are offering genetic testing services; more multigene panels are available for gene testing; more genes and gene mutations are being identified; and more variants of uncertain significance, which may or may not be clinically actionable, have been found.

A public resource facilitating clinical use of genomes.

Rapid advances in DNA sequencing promise to enable new diagnostics and individualized therapies. Achieving personalized medicine, however, will require extensive research on highly reidentifiable, integrated datasets of genomic and health information. To assist with this, participants in the Personal Genome Project choose to forgo privacy via our institutional review board- approved "open consent" process.

Back to the future: from genome to metabolome.

In the traditional medical genetics setting, metabolic disorders, identified either clinically or through biochemical screening, undergo subsequent single gene testing to molecularly confirm diagnosis, provide further insight on natural disease history, and inform on disease management, treatment, familial testing, and reproductive options. For decades now, this process has been responsible for saving many lives worldwide. Only recently, though, has it become possible to move in the opposite direction by starting with an individual's whole genome or exome, and, guided by this data, study more minor perturbations in the absolute values and substrate ratios of clinically important biochemical analytes.

Direct tissue evaluation via immunofluorescence: in the diagnosis of hereditary transthyretin cardiac amyloidosis.

Multiple precursor proteins have been shown to cause cardiac amyloidosis. The most common forms are due either to immunoglobulin light chains or to transthyretin proteins (either wild-type or mutant forms). Correct subclassification of the amyloid is paramount because treatment differs in accordance with the type of amyloidosis.

Phased whole-genome genetic risk in a family quartet using a major allele reference sequence.

Whole-genome sequencing harbors unprecedented potential for characterization of individual and family genetic variation. Here, we develop a novel synthetic human reference sequence that is ethnically concordant and use it for the analysis of genomes from a nuclear family with history of familial thrombophilia. We demonstrate that the use of the major allele reference sequence results in improved genotype accuracy for disease-associated variant loci.

Ethical and practical guidelines for reporting genetic research results to study participants: updated guidelines from a National Heart, Lung, and Blood Institute working group.

In January 2009, the National Heart, Lung, and Blood Institute convened a 28-member multidisciplinary Working Group to update the recommendations of a 2004 National Heart, Lung, and Blood Institute Working Group focused on Guidelines to the Return of Genetic Research Results. Changes in the genetic and societal landscape over the intervening 5 years raise multiple questions and challenges. The group noted the complex issues arising from the fact that technological and bioinformatic progress has made it possible to obtain considerable information on individuals that would not have been possible a decade ago.

Clinical assessment incorporating a personal genome.

Background: The cost of genomic information has fallen steeply, but the clinical translation of genetic risk estimates remains unclear. We aimed to undertake an integrated analysis of a complete human genome in a clinical context.

Methods: We assessed a patient with a family history of vascular disease and early sudden death.

Personal genomes in progress: from the human genome project to the personal genome project.

The cost of a diploid human genome sequence has dropped from about $70M to $2000 since 2007--even as the standards for redundancy have increased from 7x to 40x in order to improve call rates. Coupled with the low return on investment for common single-nucleotide polylmorphisms, this has caused a significant rise in interest in correlating genome sequences with comprehensive environmental and trait data (GET). The cost of electronic health records, imaging, and microbial, immunological, and behavioral data are also dropping quickly.

Novel CHD7 and FBN1 mutations in an infant with multiple congenital anamolies.

The first case of an infant with a dual genetic diagnosis of CHARGE and Marfan syndrome is reported here. The patient had multiple congenital anamolies, many of them consistent with CHARGE syndrome and genetic testing identified a heterozygous mutation c.3806_11del6insA in the CHD7 gene.

Human genome sequencing using unchained base reads on self-assembling DNA nanoarrays.

Genome sequencing of large numbers of individuals promises to advance the understanding, treatment, and prevention of human diseases, among other applications. We describe a genome sequencing platform that achieves efficient imaging and low reagent consumption with combinatorial probe anchor ligation chemistry to independently assay each base from patterned nanoarrays of self-assembling DNA nanoballs. We sequenced three human genomes with this platform, generating an average of 45- to 87-fold coverage per genome and identifying 3.

A highly annotated whole-genome sequence of a Korean individual.

Recent advances in sequencing technologies have initiated an era of personal genome sequences. To date, human genome sequences have been reported for individuals with ancestry in three distinct geographical regions: a Yoruba African, two individuals of northwest European origin, and a person from China. Here we provide a highly annotated, whole-genome sequence for a Korean individual, known as AK1.

Subglossopalatal synechia in association with cardiac and digital anomalies.

A 1-day-old boy in respiratory distress had a midline soft tissue band between the floor of the mouth and the posterior edge of the hard palate. There was also a soft palatal cleft, cardiac anomalies, and a hypoplastic right fifth finger and toe. Although his airway initially improved following urgent excision of the subglossopalatal band, he continued to have episodic desaturations.