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Neurometabolic disorders are markedly heterogeneous, both clinically and genetically, and are characterized by variable neurological dysfunction accompanied by suggestive neuroimaging or biochemical abnormalities. Despite early specialist input, delays in diagnosis and appropriate treatment initiation are common. Next-generation sequencing approaches still have limitations but are already enabling earlier and more efficient diagnoses in these patients. We designed a gene panel targeting 614 genes causing inborn errors of metabolism and tested its diagnostic efficacy in a paediatric cohort of 30 undiagnosed patients presenting with variable neurometabolic phenotypes. Genetic defects that could, at least partially, explain observed phenotypes were identified in 53% of cases. Where biochemical abnormalities pointing towards a particular gene defect were present, our panel identified diagnoses in 89% of patients. Phenotypes attributable to defects in more than one gene were seen in 13% of cases. The ability of in silico tools, including structure-guided prediction programmes to characterize novel missense variants were also interrogated. Our study expands the genetic, clinical and biochemical phenotypes of well-characterized (POMGNT1, TPP1) and recently identified disorders (PGAP2, ACSF3, SERAC1, AFG3L2, DPYS). Overall, our panel was accurate and efficient, demonstrating good potential for applying similar approaches to clinically and biochemically diverse neurometabolic disease cohorts.

Original publication

DOI

10.1093/brain/aww221

Type

Journal article

Journal

Brain

Publication Date

01/11/2016

Volume

139

Pages

2844 - 2854

Keywords

gene panel, heterogeneity, inborn errors of metabolism, neurometabolic disorders, next-generation sequencing, Adolescent, Brain Diseases, Metabolic, Child, Child, Preschool, Cohort Studies, Female, Genetic Predisposition to Disease, Genetic Testing, Genotype, Humans, Imaging, Three-Dimensional, Infant, Magnetic Resonance Imaging, Male, Metabolism, Inborn Errors, Phenotype, Young Adult