Dynamin-2 Related Disorders via the DNM2 Gene

Centronuclear myopathy-1 (CNM1, OMIM 160150) and axonal Charcot-Marie-Tooth disease, intermediate type B (CMTDIB, OMIM 606482) are allelic disorders caused by heterozygous variants of the DNM2 gene. Patients with centronuclear myopathy-1 exhibit variable age of onset ranging from congenital to early childhood to as late as the third decade of life (Bitoun et al. Nat Genet 37:1207-1209, 2005). Generalized muscle weakness especially in the distal lower limbs is a constant finding. Congenital-onset cases have been described as having a more severe disease course requiring ventilation and NG tube feeding (Bitoun et al. Ann Neurol 62:666-670, 2007). Two patients with childhood-onset disease were described as having normal motor development and restrictive respiratory syndrome (Bitoun et al. 2007). Other findings from this published series of patients include open mouth; high, arched palate; high, arched foot; ptosis; scoliosis; contractures; and hyperlaxity. Another patient with onset in early childhood was described as having difficulty walking and running as a child with progression to requiring a wheelchair by age 30 (Bitoun et al. Neurology 72:93-95, 2009). This patient also had a progressive restrictive respiratory syndrome, facial weakness, and ptosis. Histopathology of affected muscles in CNM1 show hypotrophy of type 1 fibers and centrally placed nuclei. CMTDIB patients present in the first decade of life with progressive gait unsteadiness and foot deformities, including pes cavus (Fabrizi et al. Neurology 69:291-295, 2007; Zuchner et al. Nat Genet 37:289-294, 2005). Additional findings include peripheral sensory neuropathy, painful paresthesias, distal muscle weakness, atrophy of the lower limbs, and variable hand weakness and atrophy (Gallardo et al. J Neurol 255:986-992, 2008). Histology in CMTDIB is consistent with an axonal neuropathy without demyelination.

Centronuclear myopathy and axonal Charcot-Marie-Tooth diseases are genetically heterogeneous disorders. Numerous axonal forms of CMT are known (Bird, GeneReviews, 2012). One X-linked form and several other autosomal dominant forms of centronuclear myopathy are also known. DNM2-related centronuclear myopathy and Charcot-Marie-Tooth disease are inherited as autosomal dominant disorders. Missense variants are the most common form of pathogenic gene variant. Small deletions, mostly in-frame, have also been reported.

Analytical sensitivity may be high because all DNM2 variants reported to date will be detectable by direct sequencing of genomic DNA. Clinical sensitivity is difficult to predict due to genetic heterogeneity of these disorders.

This test provides full coverage of all coding exons of the DNM2 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).