Centronuclear Myopathy-4, Autosomal Dominant (CNM4) via the CCDC78 Gene

An apparently rare form of autosomal dominant centronuclear myopathy (CNM4; OMIM 614807) has been found to be caused by a mutation in the CCDC78 gene (Majczenko et al. Am J Hum Genet 91:365-371, 2012). CNM4 has been described in multiple members of a single family in which affected individuals display an early onset myopathy with distal weakness more pronounced than proximal weakness. Hypotonia was present at birth, as was fatigue and myalgias later in life. Ambulation is preserved, although patients experienced increased numbers of falls. Facial muscles, respiratory function, and cardiac muscles were not affected. Muscle biopsies revealed centralized nuclei, type 1 fiber predominance, fiber-size variability, and core-like areas in one patient. Internal aggregates stained positive for desmin.

Centronuclear myopathy is a genetically heterogeneous disorder. One X-linked form, one autosomal recessive form, and several autosomal dominant forms are known. CCDC78-related centronuclear myopathy (CNM-4) is inherited as an autosomal dominant disorder. Thus far, only one family has been reported with this form of CNM (Majczenko et al., 2012). A splice site mutation was found to cosegregate with an early onset myopathy in the reported family.

The ‘coiled-coil domain-containing’ protein is encoded by exons 1 - 14 of the CCDC78 gene (OMIM 614666) located on chr 16p13.3.

CCDC78-related centronuclear myopathy has been described in only one family, therefore, clinical and analytical sensitivity cannot be predicted. CNM4 may be rare because testing of 46 probands outside of the index family revealed no other patients with CCD78 mutations (Majczenko et al., 2012).

This test provides full coverage of all coding exons of the CCDC78 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).