Background: Epilepsy, hypotonia, and developmental delay are common signs and symptoms of neurogenetic disorders with or without recognizable metabolic abnormalities. Neuroimaging and “candidate” metabolic studies often fail to identify a specific etiology. Next generation sequencing (NGS) is now recognized as an established robust and reliable method for molecular diagnosis.

Objective: To identify the underlying molecular etiology in a group of 125 patients presenting with various neurogenetic/neurometabolic phenotypes.

Methods: Neuroimaging, and metabolic studies (MS/MS based acylcarnitines, very long chain fatty acids, urine organic acids, quantitative plasma amino acids, creatine and transferrin glycosylation profiles) were performed followed by molecular analysis of gDNA using an Ion AmpliSeq based “753 gene” panel.

Results: A pathogenic or likely pathogenic mutation was identified in 62% (77/125) of these individuals who had normal metabolic profiling. Six novel variants (FOLR1, SUOX, SPAST, ALDH5A1, MUSK, SPTAN1) were found. In particular, the MUSK mutation was found in a newborn with vocal cord paralysis, a very rare and treatable presentation of congenital myasthenia syndrome.

Conclusion: Mutation analysis using NGS based neurogenetic panel is superior to targeted metabolic screening of common metabolic disorders.