Dynactin-Related Disorders via the DCTN1 Gene

Distal hereditary motor neuronopathy type VIIB (HMNVIIB; OMIM 607641) is one of several disorders with hallmark features of slowly progressive distal motor neuronopathy without sensory loss. Onset is in childhood or young adulthood, and initial signs often include weakness and wasting of extensor muscles of the lower extremities, followed by involvement of the upper limbs. Distal hereditary motor neuronopathy type VIIB is differentiated from other forms by findings of breathing difficulty due to vocal fold paralysis and progressive facial weakness. Use of sensory signs on physical examination to differentiate distal hereditary motor neuronopathy from Charcot-Marie-Tooth disease can be problematic because of variability in presentation of sensory loss. Therefore, electrophysiological studies are recommended (Irobi et al. Hum Mol Genet 13:195-202, 2004). Perry syndrome (OMIM 168605) is a neuropsychiatric disorder with onset in the 5th decade of life. The earliest sign is depression, which is not responsive to antidepressant drugs or electroconvulsive therapy (Perry et al. Arch Neurol 32:108-113, 1975). Other clinical presentations include sleep disturbances, exhaustion, and weight loss. Later in the course of disease parkinsonism and respiratory failure occur. Postmortem examination in a series of cases was remarkable for reduced taurine content and other neurochemical imbalances and severe neuronal loss (Perry et al. Neurology 40:1882-1887, 1990). In other cases, however, normal brain taurine content has been reported (Purdy et al. Ann Neurol 6:523-531, 1979; Roy et al. Neurology 38:637-639, 1988).

Distal hereditary motor neuronopathy, type VIIB and Perry syndrome are inherited as autosomal dominant disorders. Variants in the gene encoding dynactin 1 (DCTN1; OMIM 601143) are the cause of both disorders. In the cases thus far reported, all variants have resulted in amino acid substitutions.

DCTN1 variants have been found in fewer than ten families with either HMNVIIB or Perry syndrome; therefore, clinical sensitivity cannot be estimated. Analytical sensitivity should be high because all DCTN1 variants reported to date or of the type expected to be detected by DNA sequencing of genomic DNA.

This test provides full coverage of all coding exons of the DCTN1 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).