A screen for deeply conserved non-coding GWAS SNPs uncovers a MIR-9-2 functional mutation associated to retinal vasculature defects in human.

Thousands of human disease-associated single nucleotide polymorphisms (SNPs) lie in the non-coding genome, but only a handful have been demonstrated to affect gene expression and human biology. We computationally identified risk-associated SNPs in deeply conserved non-exonic elements (CNEs) potentially contributing to 45 human diseases. We further demonstrated that human CNE1/rs17421627 associated with retinal vasculature defects showed transcriptional activity in the zebrafish retina, while introducing the risk-associated allele completely abolished CNE1 enhancer activity. Furthermore, deletion of CNE1 led to retinal vasculature defects and to a specific downregulation of microRNA-9, rather than MEF2C as predicted by the original genome-wide association studies. Consistent with these results, miR-9 depletion affects retinal vasculature formation, demonstrating MIR-9-2 as a critical gene underpinning the associated trait. Importantly, we validated that other CNEs act as transcriptional enhancers that can be disrupted by conserved non-coding SNPs. This study uncovers disease-associated non-coding mutations that are deeply conserved, providing a path for in vivo testing to reveal their cis-regulated genes and biological roles.

Sphincter of Oddi dysfunction in children with recurrent abdominal pain: 5-year follow-up after endoscopic sphincterotomy.

BACKGROUND: Sphincter of Oddi (SO) dysfunction has not been reported as a cause of recurrent abdominal pain (RAP) in children. We present a 5-year follow-up of a group of children with RAP and manometry proven SO dysfunction. METHODS: Retrospective chart review of children who underwent SO manometry and endoscopic sphincterotomy (ES) for recurrent abdominal pain. Long-term follow-up was obtained by telephone survey. RESULTS: Eleven of the 12 children had abdominal pain; one had reproducible postprandial discomfort. Five children localized the pain to the upper abdomen. The same number of children had associated nausea or vomiting. On hepatobiliary scintigraphy study, three children had SO dysfunction type curve, four had low ejection fraction and nine had reproduction of symptoms on cholecystokinin (CCK) infusion. SO manometry revealed elevated pressure in 11 children. The remaining child had paradoxical contraction of the SO. On short-term follow-up, eight children had resolution of symptoms after ES, three did not respond and one had recurrence of symptom in 6 months. Children symptomatic for less than 1 year were more likely to respond to ES (P < 0.01). All children with upper abdominal pain with nausea and/or vomiting, postprandial pain and SO type scintiscan curve responded to ES. On long-term follow-up, seven of the eight responders to ES remained symptom free, one recurred with irritable bowel syndrome-like symptoms. One child with recurrent symptoms had resolution after cholecystectomy and another non-responder improved after an appendectomy. CONCLUSION: SO dysfunction is an uncommon but treatable cause of RAP in children. Awareness of this condition may help a segment of children with RAP.

Bilateral occipital lobe hyperperfusion demonstrated by single photon emission computed tomography during seizure-related cortical blindness.

An 81-year-old woman with chronic dementia developed lethargy, confusion, binocular blindness, and episodic left-beating nystagmus. Diffusion magnetic resonance imaging (MRI) revealed high signal in the right occipital region suggesting recent ischemia. A concurrent electroencephalogram (EEG) showed a right occipital seizure focus that spread to the opposite occipital lobe. A single photon emission computed tomography (SPECT) performed during the seizure epoch showed bilateral occipital lobe hyperperfusion. This is the second report to document SPECT bi-occipital hyperperfusion in seizure-related cortical blindness.