Missense-depleted regions in population exomes implicate ras superfamily nucleotide-binding protein alteration in patients with brain malformation

2016 
A new prioritization strategy for analyzing clinical exome sequence data has identified a novel gene variantimportant in brain malformations. Gene variability in the population can make it difficult to identify key mutations in disease. Yet on a population level, mutations that trigger severe human disease typically have little variation. This suggests a place to focus the diagnostic hunt in patients with mysterious ailments. A team led by Joseph Shiehat UCSF Pediatrics/Human Genetics, developed a method for prioritizing gene regions that lack protein-altering mutations in population-level databases. They identified missense-depleted regions (MDRs) in the exome that are important for diseases. The researchers applied the technique to exome data from patients with neurological birth defects and found novel mutations in ARF1, a gene that encodes a protein important for intracellular transport. The MDR approach has broad utility for discovering disease-causing genes for undiagnosed diseases
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