Nemaline Myopathy 10 via the LMOD3 Gene

Nemaline myopathy (NM) 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 have been reported (Ryan et al. 2001). The most severely affected muscle groups are proximal limb, facial, bulbar, and respiratory muscles. Deep tendon reflexes are absent or depressed. Histologically, NM 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. 2003). Six clinical types of NM have been delineated based on age of onset, severity and distribution of weakness, and respiratory function (Ryan et al. 2001; North and Ryan. 2015). Overlap among the six clinical groups is significant and adults are sometimes diagnosed only after another family member has presented with typical signs.

Nemaline myopathy 10 is caused by pathogenic variants in the LMOD3 gene. A severe congenital phenotype was observed in 13 of 14 families (Yuen et al. 2014). Polyhydramnios (62% of patients), decreased or absent fetal movements (48% of patients), and joint contractures (48% of patients) were also observed in this cohort of patients. All patients had severe generalized hypotonia, respiratory insufficiency, feeding difficulties, and bulbar weakness.

Nemaline myopathy 10 is inherited in an autosomal recessive manner due to pathogenic variants in LMOD3, located on chromosome 3p14.1. The LMOD3 gene encodes for the leiomodin-3 (LMOD3) protein which has been identified as a binding partner for KLHL40 and is necessary for stability of the sarcomere thin filament. Absence of LMOD3 results in shortening and disorganization of thin filaments (Yuen et al. 2014). Pathogenic variants reported include missense, nonsense, small deletions/duplications that result in a frame-shift and premature protein truncation, and a small in-frame deletion of a single amino acid (Yuen et al. 2014).

NEB gene pathogenic variants are most common cause of nemaline myopathy, accounting for up to 50% of cases (Ryan et al. 2001; North and Ryan 2015). ACTA1 pathogenic variants account for 15%-25% of all individuals with nemaline myopathy (Laing et al. 2009). Eight other genes (TPM3, TNNT1, TPM2, CFL2, LMOD3, KBTBD13, KLHL40, KLHL41) are involved with nemaline myopathy; however, the fraction of cases attributed to each of them is small (North and Ryan 2015).

This test provides full coverage of all coding exons of the LMOD3 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).