A multi-institutional study has discovered spontaneous mutations in RNF2 (RING2) gene as the underlying cause of a novel neurological disorder. This Undiagnosed Diseases Network (UDN) study was led by Dr. Shinya Yamamoto, investigator at the Jan and Dan Duncan Neurological Research Institute (NRI) at Texas Children's Hospital and assistant professor at Baylor College of Medicine, and Dr. Vandana Shashi at Duke University Medical Center. Using a combination of comprehensive clinical tests, trio genome sequencing and functional studies in the fruit flies, and global gene matchmaking efforts, the teams found loss-of-function variants in RNF2 gene disrupt normal neuronal development and function that likely resulted in a wide gamut of symptoms from severe intellectual disabilities, hypotonia, impaired motor skills, epilepsy, growth retardation, seizures and feeding difficulties in two affected individuals. The UDN is a National Institutes of Health-funded research study that brings together clinical and research experts from across the United States to solve the most challenging medical mysteries using advanced technologies. This often involves severely affected patients who, despite years of testing, are unable to get a definitive diagnosis for their medical problems—the crucial first step towards receiving appropriate treatment, support and clinical care.

This study was initiated with the enrollment of an adolescent female patient with the above-mentioned symptoms at one of the UDN's Clinical sites at Duke University. Initially, researchers at Dr. Shashi's lab at Duke performed a whole slew of genetic tests, all of which came back negative. Next, they performed trio whole-exome sequencing, a relatively newer sequencing technology that compares the DNA sequences of the parents and the affected individuals to identify a potential genetic alteration that might explain these symptoms. Using this method, they found this patient carried a rare mis-sense variant in the RNF2 gene, which was not present in genomes of either parent, indicating that the mutation arose spontaneously in the patient's genome.

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John
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Immunogenetics Open Access