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

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.

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.

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.

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.