Heat stress presenting with encephalopathy and MRI findings of diffuse cerebral injury and hemorrhage.

BACKGROUND: Heat stress results in multiorgan failure and CNS injury. There a few case reports in the literature on the neurological consequences of heat stress. CASE PRESENTATION: We describe a patient with heat stress presenting with encephalopathy and bilateral cerebral, cerebellar, and thalamic lesions and intraventricular hemorrhage on MRI. CONCLUSION: Heat stress should be in the differential diagnosis of patients presenting with encephalopathy and elevated serum inflammatory markers especially if the history suggests a preceding episode of hyperthermia.

Virus infection activates thyroid stimulating hormone synthesis in intestinal epithelial cells.

The small intestine has been shown to be an extra-pituitary site of thyroid stimulating hormone (TSH) production, and previous in vivo studies have shown that TSH synthesis localizes within areas of enteric virus infection within the small intestine; however, the cellular source of intestinal TSH has not been adequately determined. In the present study, we have used the murine MODE-K small intestinal epithelial cell line to demonstrate both at the transcriptional level and as a secreted hormone, as measured in a TSHbeta-specific enzyme-linked assay, that epithelial cells in fact respond to infection with reovirus serotype 3 Dearing strain by upregulating TSH synthesis. Moreover, sequence analysis of a PCR-amplified TSHbeta product from MODE-K cells revealed homology to mouse pituitary TSHbeta. These findings have direct functional implications for understanding a TSH immune-endocrine circuit in the small intestine.

Identification of novel candidate disease genes from de novo exonic copy number variants.

BACKGROUND: Exon-targeted microarrays can detect small (<1000 bp) intragenic copy number variants (CNVs), including those that affect only a single exon. This genome-wide high-sensitivity approach increases the molecular diagnosis for conditions with known disease-associated genes, enables better genotype-phenotype correlations, and facilitates variant allele detection allowing novel disease gene discovery. METHODS: We retrospectively analyzed data from 63,127 patients referred for clinical chromosomal microarray analysis (CMA) at Baylor Genetics laboratories, including 46,755 individuals tested using exon-targeted arrays, from 2007 to 2017. Small CNVs harboring a single gene or two to five non-disease-associated genes were identified; the genes involved were evaluated for a potential disease association. RESULTS: In this clinical population, among rare CNVs involving any single gene reported in 7200 patients (11%), we identified 145 de novo autosomal CNVs (117 losses and 28 intragenic gains), 257 X-linked deletion CNVs in males, and 1049 inherited autosomal CNVs (878 losses and 171 intragenic gains); 111 known disease genes were potentially disrupted by de novo autosomal or X-linked (in males) single-gene CNVs. Ninety-one genes, either recently proposed as candidate disease genes or not yet associated with diseases, were disrupted by 147 single-gene CNVs, including 37 de novo deletions and ten de novo intragenic duplications on autosomes and 100 X-linked CNVs in males. Clinical features in individuals with de novo or X-linked CNVs encompassing at most five genes (224 bp to 1.6 Mb in size) were compared to those in individuals with larger-sized deletions (up to 5 Mb in size) in the internal CMA database or loss-of-function single nucleotide variants (SNVs) detected by clinical or research whole-exome sequencing (WES). This enabled the identification of recently published genes (BPTF, NONO, PSMD12, TANGO2, and TRIP12), novel candidate disease genes (ARGLU1 and STK3), and further confirmation of disease association for two recently proposed disease genes (MEIS2 and PTCHD1). Notably, exon-targeted CMA detected several pathogenic single-exon CNVs missed by clinical WES analyses. CONCLUSIONS: Together, these data document the efficacy of exon-targeted CMA for detection of genic and exonic CNVs, complementing and extending WES in clinical diagnostics, and the potential for discovery of novel disease genes by genome-wide assay.