Germline MBD4 deficiency causes a multi-tumor predisposition syndrome

We report an autosomal recessive, multi-organ tumor predisposition syndrome, caused by bi-allelic loss-of-function germline variants in the base excision repair (BER) gene MBD4. We identified five individuals with bi-allelic MBD4 variants within four families and these individuals had a personal and/or family history of adenomatous colorectal polyposis, acute myeloid leukemia, and uveal melanoma. MBD4 encodes a glycosylase involved in repair of G:T mismatches resulting from deamination of 5′-methylcytosine. The colorectal adenomas from MBD4-deficient individuals showed a mutator phenotype attributable to mutational signature SBS1, consistent with the function of MBD4. MBD4-deficient polyps harbored somatic mutations in similar driver genes to sporadic colorectal tumors, although AMER1 mutations were more common and KRAS mutations less frequent. Our findings expand the role of BER deficiencies in tumor predisposition. Inclusion of MBD4 in genetic testing for polyposis and multi-tumor phenotypes is warranted to improve disease management

Germline MBD4-deficiency causes a multi-tumor predisposition syndrome

We report an autosomal recessive, multi-organ tumor predisposition syndrome, caused by bi-allelic loss-of-function germline variants in the base excision repair (BER) gene MBD4. We identified five individuals with bi-allelic MBD4 variants within four families and these individuals had a personal and/or family history of adenomatous colorectal polyposis, acute myeloid leukemia, and uveal melanoma. MBD4 encodes a glycosylase involved in repair of G:T mismatches resulting from deamination of 5′-methylcytosine. The colorectal adenomas from MBD4-deficient individuals showed a mutator phenotype attributable to mutational signature SBS1, consistent with the function of MBD4. MBD4-deficient polyps harbored somatic mutations in similar driver genes to sporadic colorectal tumors, although AMER1 mutations were more common and KRAS mutations less frequent. Our findings expand the role of BER deficiencies in tumor predisposition. Inclusion of MBD4 in genetic testing for polyposis and multi-tumor phenotypes is warranted to improve disease management

An illustrated comparison of processing methods for MR phase imaging and QSM: combining array coil signals and phase unwrapping

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A method for the dynamic correction of B0-related distortions in single-echo EPI at 7T

We propose a method to calculate field maps from the phase of each EPI in an fMRI time series. These field maps can be used to correct the corresponding magnitude images for distortion caused by inhomogeneity in the static magnetic field. In contrast to conventional static distortion correction, in which one 'snapshot' field map is applied to all subsequent fMRI time points, our method also captures dynamic changes to B-0 which arise due to motion and respiration. The approach is based on the assumption that the non-B-0-related contribution to the phase measured by each radio-frequency coil, which is dominated by the coil sensitivity, is stable over time and can therefore be removed to yield a field map from EPI. Our solution addresses imaging with multi-channel coils at ultra-high field (7T), where phase offsets vary rapidly in space, phase processing is non-trivial and distortions are comparatively large. We propose using dual-echo gradient echo reference scan for the phase offset calculation, which yields estimates with high signal-to-noise ratio. An extrapolation method is proposed which yields reliable estimates for phase offsets even where motion is large and a tailored phase unwrapping procedure for EPI is suggested which gives robust results in regions with disconnected tissue or strong signal decay. Phase offsets are shown to be stable during long measurements (40min) and for large head motions. The dynamic distortion correction proposed here is found to work accurately in the presence of large motion (up to 8.1 degrees), whereas a conventional method based on single field map fails to correct or even introduces distortions (up to 11.2mm). Finally, we show that dynamic unwarping increases the temporal stability of EPI in the presence of motion. Our approach can be applied to any EPI measurements without the need for sequence modification. (C) 2018 The Authors. Published by Elsevier Inc