Familial visceral myopathy diagnosed by exome sequencing of a patient with chronic intestinal pseudo-obstruction.

A 55-year-old woman with a history of bowel dysmotility presented with abdominal distension and peritonitis. Family history included premature deaths with intestinal symptomatology, suggesting autosomal dominant inheritance. Computed tomography showed a distended small bowel. Symptoms were alleviated by enterocutaneous stomas. Initial ileal biopsy suggested neuropathy; however, exome sequencing revealed an Arg148Ser mutation in the enteric smooth muscle actin gamma 2 (ACTG2) gene. Histological reassessment showed abnormal muscularis propria and smooth muscle actin, with the same findings in sibling, confirming familial visceral myopathy. Thus, noninvasive genomic analysis can provide early and specific diagnosis of familial visceral myopathy, which may help to avoid inappropriate surgery.

Association between cigarette smoking, APC mutations and the risk of developing sporadic colorectal adenomas and carcinomas.

BACKGROUND: The association between colorectal cancer (CRC) and smoking has not been consistent. Incomplete smoking history and association to a specific subset of CRC tumors have been proposed as explanations. The adenomatous polyposis coli (APC) gene has been reported to have a "gatekeeper" function in the colonic mucosa. METHODS: To evaluate the hypothesis that cigarette smoking is associated with adenoma and carcinoma development and further to investigate whether this association is due to mutations in the APC gene, we used a study population consisting of 133 cases (45 adenomas and 88 carcinomas) and 334 controls. All tumors were sequenced in the mutation cluster region (MCR) of the APC gene. Cases and controls were drawn from a homogeneous cohort of Norwegian origin. RESULTS: The mutational spectra of the APC gene revealed no difference in frequencies of mutations in cases based on ever and never smoking status. An overall case-control association was detected for adenomas and "ever smoking" OR = 1.73 (95% CI 0.83-3.58). For CRC cases several smoking parameters for dose and duration were used. We detected an association for all smoking parameters and "duration of smoking > 30 years", yielded a statistically significant OR = 2.86 (1.06-7.7). When cases were divided based on APC truncation mutation status, an association was detected in adenomas without APC mutation in relation to "ever smoking", with an OR = 3.97 (1.26-12.51). For CRC cases without APC mutation "duration of smoking > 30 years", yielded a statistically significant OR = 4.06 (1.20-13.7). The smoking parameter "starting smoking > or = 40 years ago" was only associated with CRC cases with APC mutations, OR = 2.0 (0.34-11.95). A case-case comparison revealed similar findings for this parameter, OR = 2.24 (0.73-6.86). CONCLUSION: Our data suggest an association between smoking and adenoma and CRC development. This association was strongest for cases without APC truncation mutation. This may implicate other factors in development of these tumors. The association detected between smoking and CRC cases with APC mutation was in relationship to the smoking parameter "starting smoking > or = 40 years ago", a time period long enough to proceed CRC initiation.

Boundary-layer mantle flow under the Dead Sea transform fault inferred from seismic anisotropy.

Lithospheric-scale transform faults play an important role in the dynamics of global plate motion. Near-surface deformation fields for such faults are relatively well documented by satellite geodesy, strain measurements and earthquake source studies, and deeper crustal structure has been imaged by seismic profiling. Relatively little is known, however, about deformation taking place in the subcrustal lithosphere--that is, the width and depth of the region associated with the deformation, the transition between deformed and undeformed lithosphere and the interaction between lithospheric and asthenospheric mantle flow at the plate boundary. Here we present evidence for a narrow, approximately 20-km-wide, subcrustal anisotropic zone of fault-parallel mineral alignment beneath the Dead Sea transform, obtained from an inversion of shear-wave splitting observations along a dense receiver profile. The geometry of this zone and the contrast between distinct anisotropic domains suggest subhorizontal mantle flow within a vertical boundary layer that extends through the entire lithosphere and accommodates the transform motion between the African and Arabian plates within this relatively narrow zone.