Diagnostic utility of transcriptome sequencing for rare Mendelian diseases.

PURPOSE: We investigated the value of transcriptome sequencing (RNAseq) in ascertaining the consequence of DNA variants on RNA transcripts to improve the diagnostic rate from exome or genome sequencing for undiagnosed Mendelian diseases spanning a wide spectrum of clinical indications. METHODS: From 234 subjects referred to the Undiagnosed Diseases Network, University of California-Los Angeles clinical site between July 2014 and August 2018, 113 were enrolled for high likelihood of having rare undiagnosed, suspected genetic conditions despite thorough prior clinical evaluation. Exome or genome sequencing and RNAseq were performed, and RNAseq data was integrated with genome sequencing data for DNA variant interpretation genome-wide. RESULTS: The molecular diagnostic rate by exome or genome sequencing was 31%. Integration of RNAseq with genome sequencing resulted in an additional seven cases with clear diagnosis of a known genetic disease. Thus, the overall molecular diagnostic rate was 38%, and 18% of all genetic diagnoses returned required RNAseq to determine variant causality. CONCLUSION: In this rare disease cohort with a wide spectrum of undiagnosed, suspected genetic conditions, RNAseq analysis increased the molecular diagnostic rate above that possible with genome sequencing analysis alone even without availability of the most appropriate tissue type to assess.

Molecular bases and clinical spectrum of early infantile epileptic encephalopathies.

Epilepsy can be a challenging diagnosis to make in the neonatal and infantile periods. Seizures in this age group may be due to a serious underlying cause that results in an epileptic encephalopathy. Early infantile epileptic encephalopathy (EIEE) is a progressive neurologic condition that exhibits concomitant cognitive and motor impairment, and is often associated with severe intellectual disability. This condition belongs to the group of age-dependent epileptic encephalopathies, and thus the clinical and electro-encephalographic features change with age as the central nervous system evolves. The molecular bases and the clinical spectrum associated with the early infantile epileptic encephalopathies continue to expand as new genetic discoveries are made. This review will highlight the molecular etiologies of early infantile epileptic encephalopathy, and the clinical and electro-encephalographic changes that take place in these epileptic phenotypes as the brain develops.