Congenital Myopathy via the MYO18B Gene

Congenital myopathy (CM) refers to a genetically and clinically heterogeneous group of disorders characterized by muscle weakness and hypotonia at birth or in infancy. Five forms of congenital myopathy are recognized by the International Standards of Care Committee for Congenital Myopathies (North et al. 2014. PubMed ID: 24456932): nemaline myopathy, core myopathy, centronuclear myopathy, myosin storage myopathy, and congenital fiber type disproportion. The clinical course of congenital myopathy is typically static or slowly progressive. Lower facial weakness leading to an open mouth is often the first sign of congenital myopathy in the newborn. Ptosis and ophthalmoplegia are also common. See North et al. (2014) for diagnostic strategies and a comprehensive review of the congenital myopathies.

MYO18B-related congenital myopathies have been reported in at least 6 individuals to date, with 4 of these 6 also presenting with Klippel-Feil anomaly. All cases have been homozygous or compound heterozygous for loss of function variants in MYO18B (Alazami et al. 2015. PubMed ID: 25748484; Malfatti et al. 2015. PubMed ID: 27858739; Schieffer et al. 2019. PubMed ID: 31195167; Brunet et al. 2020. PubMed ID: 32184166; Mihaylova et al. 2020. PubMed ID: 32637634). Klippel-Feil syndrome is characterized by fusion of the cervical spine which can result in scoliosis but can also include limited neck mobility and low posterior hairline. All reported patients presented with congenital myopathy and dysmorphic features; however, Klippel-Feil anomaly was not present in all cases (See Table in Mihaylova et al. 2020. PubMed ID: 32637634; Malfatti et al. 2015. PubMed ID: 27858739). Clinical features include generalized muscle weakness, hypotonia, feeding problems, delayed motor milestones, facial weakness, dysmorphic features, and, in some cases, cardiac findings. One case presented on prenatal ultrasound with micrognathia, cleft palate, and bilateral clinodactyly (Brunet et al. 2020. PubMed ID: 32184166).

Genetic testing may aid in establishing a differential diagnosis and may assist reproductive planning.

Pathogenic variants in the MYO18B gene are associated with autosomal recessive congenital myopathy with or without Klippel-Feil anomaly. Established pathogenic variants include nonsense and small, frameshifting deletions and duplications. Missense variants have been reported; however, evidence for pathogenicity of these variants is limited at this time. All reported variants have been inherited from a carrier parent. No structural variants have been reported. Of note, a frameshift variant in the last exon that results in a truncated protein has been reported in a patient with nemaline myopathy and cardiomyopathy while other reported patients do not present with cardiac findings (Malfatti et al. 2015. PubMed ID: 27858739). 

MYO18B encodes a non-conventional myosin that is predominantly expressed in skeletal and cardiac muscle. MYO18B protein localizes at the sacromeric Z-line and implies a possibly role in muscle contractile function. Knockout of MYO18B in zebrafish results in disrupted sarcomeric assembly in skeletal muscles (Gurung et al. 2017. PubMed ID: 27879346). MYO18B has been cited as a non-essential gene for growth of human tissue culture cells (Online Gene Essentiality).

The clinical sensitivity is difficult to estimate, as to date, a limited number of cases have been described in the literature. Analytical sensitivity should be high as all pathogenic variants reported to date are detectable by sequencing and NGS copy number variant analysis.

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This test provides full coverage of all coding exons of the MYO18B gene plus 10 bases flanking noncoding DNA in all available transcripts in addition to 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).