An international effort towards developing standards for best practices in analysis, interpretation and reporting of clinical genome sequencing results in the CLARITY Challenge

There is tremendous potential for genome sequencing to improve clinical diagnosis and care once it becomes routinely accessible, but this will require formalizing research methods into clinical best practices in the areas of sequence data generation, analysis, interpretation and reporting. The CLARITY Challenge was designed to spur convergence in methods for diagnosing genetic disease starting from clinical case history and genome sequencing data. DNA samples were obtained from three families with heritable genetic disorders and genomic sequence data were donated by sequencing platform vendors. The challenge was to analyze and interpret these data with the goals of identifying disease-causing variants and reporting the findings in a clinically useful format. Participating contestant groups were solicited broadly, and an independent panel of judges evaluated their performance. RESULTS: A total of 30 international groups were engaged. The entries reveal a general convergence of practices on most elements of the analysis and interpretation process. However, even given this commonality of approach, only two groups identified the consensus candidate variants in all disease cases, demonstrating a need for consistent fine-tuning of the generally accepted methods. There was greater diversity of the final clinical report content and in the patient consenting process, demonstrating that these areas require additional exploration and standardization. CONCLUSIONS: The CLARITY Challenge provides a comprehensive assessment of current practices for using genome sequencing to diagnose and report genetic diseases. There is remarkable convergence in bioinformatic techniques, but medical interpretation and reporting are areas that require further development by many groups

Associations of autozygosity with a broad range of human phenotypes

In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (F-ROH) for >1.4 million individuals, we show that F-ROH is significantly associated (p <0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: F-ROH equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44-66%] in the odds of having children. Finally, the effects of F-ROH are confirmed within full-sibling pairs, where the variation in F-ROH is independent of all environmental confounding.Peer reviewe

The Majorana Demonstrator: Progress towards showing the feasibility of a tonne-scale 76Ge neutrinoless double-beta decay experiment

The Majorana Demonstrator will search for the neutrinoless double-beta decay (0vββ) of the 76Ge isotope with a mixed array of enriched and natural germanium detectors. The observation of this rare decay would indicate the neutrino is its own anti-particle, demonstrate that lepton number is not conserved, and provide information on the absolute mass-scale of the neutrino. The Demonstrator is being assembled at the 4850 foot level of the Sanford Underground Research Facility in Lead, South Dakota. The array will be contained in a low-background environment and surrounded by passive and active shielding. The goals for the Demonstrator are: demonstrating a background rate less than 3 t-1 y-1 in the 4 keV region of interest (ROI) surrounding the 2039 keV 76Ge endpoint energy; establishing the technology required to build a tonne-scale germanium based double-beta decay experiment; testing the recent claim of observation of 0vββ [1]; and performing a direct search for light WIMPs (3-10 GeV/c2)

Characteristics of signals originating near the lithium-diffused N+ contact of high purity germanium p-type point contact detectors

A study of signals originating near the lithium-diffused n+ contact of p-type point contact (PPC) high purity germanium detectors (HPGe) is presented. The transition region between the active germanium and the fully dead layer of the n+ contact is examined. Energy depositions in this transition region are shown to result in partial charge collection. This provides a mechanism for events with a well defined energy to contribute to the continuum of the energy spectrum at lower energies. A novel technique to quantify the contribution from this source of background is introduced. Experiments that operate germanium detectors with a very low energy threshold may benefit from the methods presented herein

Search for Neutrinoless Double- β Decay in Ge 76 with the Majorana Demonstrator

The Majorana Collaboration is operating an array of high purity Ge detectors to search for neutrinoless double-β decay in Ge76. The Majorana Demonstrator comprises 44.1 kg of Ge detectors (29.7 kg enriched in Ge76) split between two modules contained in a low background shield at the Sanford Underground Research Facility in Lead, South Dakota. Here we present results from data taken during construction, commissioning, and the start of full operations. We achieve unprecedented energy resolution of 2.5 keV FWHM at Qββ and a very low background with no observed candidate events in 9.95 kg yr of enriched Ge exposure, resulting in a lower limit on the half-life of 1.9×1025 yr (90% C.L.). This result constrains the effective Majorana neutrino mass to below 240-520 meV, depending on the matrix elements used. In our experimental configuration with the lowest background, the background is 4.0-2.5+3.1 counts/(FWHM t yr)