An exome sequencing result on a child with atypical gait was reported as negative; follow-up biochemical evaluation and reanalysis led to diagnosis of treatable DOPA-responsive dystonia.Exome sequencing is phenotypic-driven analysis of coding genetic variants and is frequently used for the genetic diagnosis of nonspecific or clinically indistinguishable presentations. Clinical laboratories who provide exome sequencing filter variants based on phenotypic information provided by the ordering clinicians. This can lead to difficulties in reporting results that a laboratory does not believe are relevant to the testing indication. This is further complicated by common variants of uncertain significance and genes associated with wide spectrums of presentations. Here, we report a case of a 12-year-old boy who initially presented with gait disturbances. His whole exome sequencing, performed at a national reference laboratory, was initially reported as negative. Careful review of variants characterized by the laboratory as variants of uncertain significance “not associated with the patient’s phenotype,” along with the clinical context of the patient, suggested a possible diagnosis of guanosine triphosphate–cyclohydrolase 1 deficiency because of compound heterozygous variants of uncertain significance in this gene. Subsequent biochemical evaluations revealed a low urinary neopterin to biopterin ratio and normal baseline plasma phenylalanine. An elevated phenylalanine to tyrosine ratio after phenylalanine loading biochemically confirmed the diagnosis without invasive lumbar puncture. The patient subsequently responded with marked improvement in symptoms after initiation of levodopa therapy. This case highlights the importance of careful review of uncertain variants, in the context of phenotypic information, identified on exome sequencing.
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