Nemaline Myopathy With Cores (NEM6) via the KBTBD13 Gene

Variants in the gene encoding Kelch repeat and BTB/POZ domainscontaining protein-13 (KBTBD13; OMIM 613727) are one cause of autosomal dominant nemaline myopathy (NEM6; OMIM 609273). NEM is a genetically and clinically heterogeneous disorder characterized by muscle weakness, hypotonia, and the presence of nemaline bodies in skeletal muscle fibers. Muscle weakness is typically observed in affected neonates or infants, although later onset cases are reported (Ryan et al. Ann Neurol 50:312-320, 2001). The most severely-affected muscle groups are proximal limb, facial, bulbar, and respiratory muscles. Deep tendon reflexes are absent or depressed. Histologically, NEM is characterized by type 1 fiber predominance and the presence of rod-like structures called nemaline bodies upon Gomori trichrome staining of skeletal muscle (Ryan et al. Neurology 60:665-673, 2003). Six clinical types of NEM have been delineated based on age of onset, severity and distribution of weakness, and respiratory function (Ryan et al. 2001; North and Ryan. GeneReviews, 2009). KBTBD13-related nemaline myopathy has been described in a small number of patients with normal early motor development followed by childhood onset of slowly progressive proximal muscle weakness and exercise intolerance (Olive et al. Muscle Nerve 42:901-907, 2010; Sambuughin et al. Am J Hum Genet 87:842-847, 2010). Notable complaints from patients include feelings of muscle slowness or stiffness, and slow response times to falls (Gommans et al. Neuromusc Disord 12:13-18, 2002). Respiratory or cardiac muscles are not affected by NEM6. The disease is mildly progressive although there are no reports of wheelchair-bound patients. Histopathologic changes seen on skeletal muscle biopsy include nemaline rods, cores, loss of myofibrillar organization, and predominance of hypertrophic type 1 fibers.

Nemaline myopathy is a genetically heterogeneous disorder and variants in ACTA1 (NEM3) and NEB (NEM2) are the only relatively common causes (Ryan et al. 2001). Heterozygous variants in the KBTBD13 gene have been found in a small number of patients with a relatively constant clinical phenotype (Sambuughin et al. Am J Hum Genet 87:842-847, 2010). NEM6 is inherited as an autosomal dominant disorder secondary to KBTBD13 variants.

KBTBD13-related nemaline myopathy (NEM6) is likely a rare disorder. Thus far only a small number of patients have been reported.

This test provides full coverage of all coding exons of the KBTBD13 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).