Congenital Muscular Dystrophy, Megaconial Type via the CHKB Gene

Congenital muscular dystrophy with mitochondrial structural abnormalities (MDCMC, OMIM 602541) is characterized by congenital-onset hypotonia, muscle wasting, mildly elevated serum CpK levels, mental retardation, and mitochondrial abnormalities. Muscle biopsies in these patients reveal dystrophic changes, fiber-size variation, increased endomysial connective tissue, and unusual distribution, size, and structure of mitochondria. Specifically, mitochondria are depleted in the center of the sarcoplasm, whereas the mitochondria at the periphery of muscle fibers are markedly enlarged and have abnormal cristae structure (Nishino et al. Muscle Nerve 21:40-47, 1998). Weakness is predominately proximal and slowly progressive and cardiomyopathy is often a cause of morbidity and mortality (Mitsuhashi et al. Am J Hum Genet 88:845-851, 2011). Among the first series of MDCMC patients described by Nishino et al. (1998), some individuals had delayed walking and others never achieved independent ambulation. Although most of the patients had microcephaly, none had structural brain abnormalities.

Congenital muscular dystrophy, megoconial type is inherited as an autosomal recessive disorder. The choline kinase beta enzyme, encoded by the CHKB gene (OMIM 612395), catalyzes the first step of phosphatidylcholine biosynthesis. Homozygous or compound heterozygous variants in the CHKB gene result in loss of choline kinase activity and decreased levels of phosphatidylcholine. Types of variants reported to date include nonsense, missense, splice site, and small deletions and duplications.

Only a small number of patients have thus far been described with this form of congenital muscular dystrophy. However, clinical sensitivity may be high in patients meeting clinical and histological criteria for this disorder. Analytical sensitivity may also be high because all CHKB variants reported to date will be detectable by direct sequencing of genomic DNA.

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