Specifications of the ACMG/AMP variant curation guidelines for the analysis of germline CDH1 sequence variants

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A feasibility study for high-resolution silicon array detector performance in the magnetic field of a permanent magnet system

© 2019 American Association of Physicists in Medicine Purpose: Magnetic field effects on dose distribution and detector functionality must be well understood. The detector utilized to investigate these magnetic field effects was the DUO silicon array detector; the performance of this high spatial resolution detector was assessed under these conditions. The results were compared to Gafchromic EBT3 film to highlight any intrinsic magnetic field effects in the silicon. The results were also compared to previously published MagicPlate-512 (M512) data. The DUO has an improved spatial resolution (200 µm) over the M512 (2 mm). Methods: A permanent magnet named Magnetic Apparatus for RaDiation Oncology Studies (MARDOS) paired with a standard linear accelerator (linac) enables either transverse (1.2 T) or inline (0.95 T) orientations of the magnetic field with respect to the radiation beam. A 6 MV Varian 2100C Linac provided the radiation component for the measurements. The DUO detector has 505 sensitive volumes (each volume measuring 800 × 40 × 100 µm3) organized in two orthogonal, linear arrays. The DUO was embedded in a solid water phantom in the first set-up and then a solid lung phantom in the second set-up and placed between the magnet cones. Beam profiles were compared under the magnetic field conditions and 0 T. Small field sizes from 0.8 × 0.8 cm2 up to 2.3 × 2.3 cm2 were investigated. The size of the air gap above the sensitive volumes of the DUO was investigated in the transverse orientation to assess the anticipated magnetic field effects. Full width at half maximum (FWHM), 80–20% penumbral widths and maximum dose differences between detectors and between the presence/absence of a magnetic field were investigated. Symmetry was also assessed for investigation of profile skewness under the transverse field. Results: The penumbral widths measured by the DUO detector demonstrated good agreement with film and the M512 to within an average of 0.5 mm (within uncertainty: ±1 mm). The static inline magnetic field had minimal effect on the profiles in solid water. As expected, the lower density of solid lung meant that this material was more susceptible to demonstrating magnetic field effects in the dose deposited. The greatest penumbral narrowing due to the inline field (0.7 mm) occurred in lung. Central axis dose increase was greatest in lung (maximum: 9%). The transverse field widened penumbra, most notably in the solid lung phantom, by a maximum of 2.3 mm. The largest asymmetry due to the transverse field (4.6%) was also in solid lung. When the air gap above the DUO was filled with bolus, the dose maximum measured by the DUO was within 1.4% of film. Conclusions: The DUO detector has been shown to be successful in accurately describing the dose changes for small field sizes to within a 200-µm resolution in an environment resembling that of an MRI-linac. The DUO measurements were in agreement with both film and the M512 measurements, and therefore the DUO was found to be an appropriate alternative to the M512, with improvement in terms of its higher spatial resolution. MARDOS provided a suitable environment for these preliminary tests before progressing to the MRI-linac

High resolution silicon array detector implementation in an inline MRI-linac

2020 American Association of Physicists in Medicine Purpose: Dynamic dosimaging is a concept whereby a detector in motion is tracked with magnetic resonance imaging (MRI) to validate the amount and position of dose in a radiation therapy treatment on an MRI-linac. This work takes steps toward the realization of dynamic dosimaging with the novel high resolution silicon array detector: MagicPlate-512 (M512). The performance of the M512 was assessed in a 1.0 T inline MRI-linac, without simultaneous imaging and then during an imaging sequence, both during dosimetry. MR images were acquired to determine the effect of the detector and its components on image quality. Methods: Beam profiles were measured using the M512 on the Australian MRI-Linac and a comparison made with Gafchromic EBT3 film to investigate any intrinsic magnetic field effects in the silicon. The M512 has 512 sensitive volumes, each 0.5 x 0.5 x 0.037 mm3 in dimension, organized in a two-dimensional array. Small field sizes up to 4.2 x 3.8 cm2 were investigated in both solid water and then solid lung phantoms. Beam profiles taken at 1.0 T were compared to 0 T conditions, and also to profiles taken during a gradient echo (GRE) imaging sequence. Differences in 80%-20% penumbral width and full width at half maximum (FWHM) were investigated. Localizer MR images were acquired of the detector adjacent to a water phantom. Results: Good agreement was observed between the M512 and film, with average differences in penumbral width and FWHM of detector; film profiles were unchanged. Magnetic resonance images were affected by noise, in particular, due to the large amount of aluminum present, as well as from the USB cable, which acted as an antenna. Unfortunately, due to these issues, suitable dynamic dose imaging was not achieved with the current M512/phantom configuration and the MRI-linac. However, progress was made toward achieving this goal for future work. Conclusions: The M512 silicon array detector successfully measured high-resolution beam profiles in agreement with Gafchromic film to within an average of future

Optimising clinical care through CDH1-specific germline variant curation: improvement of clinical assertions and updated curation guidelines

BackgroundGermline pathogenic variants in CDH1 are associated with increased risk of diffuse gastric cancer and lobular breast cancer. Risk reduction strategies include consideration of prophylactic surgery, thereby making accurate interpretation of germline CDH1 variants critical for physicians deciding on these procedures. The Clinical Genome Resource (ClinGen) CDH1 Variant Curation Expert Panel (VCEP) developed specifications for CDH1 variant curation with a goal to resolve variants of uncertain significance (VUS) and with ClinVar conflicting interpretations and continues to update these specifications.MethodsCDH1 variant classification specifications were modified based on updated genetic testing clinical criteria, new recommendations from ClinGen and expert knowledge from ongoing CDH1 variant curations. The CDH1 VCEP reviewed 273 variants using updated CDH1 specifications and incorporated published and unpublished data provided by diagnostic laboratories.ResultsUpdated CDH1-specific interpretation guidelines include 11 major modifications since the initial specifications from 2018. Using the refined guidelines, 97% (36 of 37) of variants with ClinVar conflicting interpretations were resolved to benign, likely benign, likely pathogenic or pathogenic, and 35% (15 of 43) of VUS were resolved to benign or likely benign. Overall, 88% (239 of 273) of curated variants had non-VUS classifications. To date, variants classified as pathogenic are either nonsense, frameshift, splicing, or affecting the translation initiation codon, and the only missense variants classified as pathogenic or likely pathogenic have been shown to affect splicing.ConclusionsThe development and evolution of CDH1-specific criteria by the expert panel resulted in decreased uncertain and conflicting interpretations of variants in this clinically actionable gene, which can ultimately lead to more effective clinical management recommendations

Discordant results between conventional newborn screening and genomic sequencing in the BabySeq Project

Abstract Purpose Newborn screening (NBS) is performed to identify neonates at risk for actionable, severe, early-onset disorders, many of which are genetic. The BabySeq Project randomized neonates to receive conventional NBS or NBS plus exome sequencing (ES) capable of detecting sequence variants that may also diagnose monogenic disease or indicate genetic disease risk. We therefore evaluated how ES and conventional NBS results differ in this population. Methods We compared results of NBS (including hearing screens) and ES for 159 infants in the BabySeq Project. Infants were considered "NBS positive" if any abnormal result was found indicating disease risk and "ES positive" if ES identified a monogenic disease risk or a genetic diagnosis. Results Most infants (132/159, 84%) were NBS and ES negative. Only one infant was positive for the same disorder by both modalities. Nine infants were NBS positive/ES negative, though seven of these were subsequently determined to be false positives. Fifteen infants were ES positive/NBS negative, all of which represented risk of genetic conditions that are not included in NBS programs. No genetic explanation was identified for eight infants referred on the hearing screen. Conclusion These differences highlight the complementarity of information that may be gleaned from NBS and ES in the newborn period