Clinical exome sequencing identifies a novel TUBB4A mutation in a child with static hypomyelinating leukodystrophy.

BACKGROUND: Leukodystrophies are a large group of inherited diseases of central nervous system myelin. There are few treatments, and most patients do not receive a final genetic diagnosis. PATIENT: We report a novel presentation of a female child with hypotonia, global developmental delay, and rotatory nystagmus. Brain MRI demonstrated profound hypomyelination and minimal or no atrophy in the brain stem or cerebellum.
RESULTS: Extensive testing failed to yield a diagnosis until clinical whole-exome sequencing revealed a novel pathogenic mutation in the β-tubulin gene TUBB4A. TUBB4A is a cause of hereditary dystonia type 4 and has recently been reported to cause hypomyelination with atrophy of the basal ganglia and cerebellum.
CONCLUSIONS: This report expands the phenotypic spectrum of TUBB4A-associated neurological diseases to include static hypomyelinating leukodystrophy and supports the clinical relevance of next-generation sequencing diagnosis approaches.