α-Actin (Skeletal Muscle Form)-Related Myopathy via the ACTA1 Gene

Nemaline myopathy (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 rodlike structures called nemaline bodies with Gomori trichrome staining of skeletal muscle (Ryan et al. Neurol 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. 2010). Overlap among the six groups is significant, and adults are sometimes diagnosed only after a family member has presented with typical signs. Congenital fiber-type disproportion (CFTD) usually presents with hypotonia and varying degrees of skeletal muscle weakness affecting the limbs. Symptoms appear at birth or within the first year of life and, in the majority of cases, remain stable over time or improve with age. The diagnosis relies on histological observation of type 1 fibers that are at least 12% smaller than the mean diameter of type 2A or type 2B fibers in the absence of other significant pathologic findings, most notably nemaline bodies. Actinopathies are reviewed by Goebel and Laing (Brain Pathology 19:516-522, 2009).

Variants in the skeletal muscle form of α-actin (ACTA1; OMIM #102610) are one cause of nemaline myopathy (NEM3; OMIM #161800) and congenital fiber-type disproportion (CFTD1; OMIM #255310). Nearly 200 unique variants are known (Laing et al. Hum Mutat 30:1267-1277, 2009). NEM3 is most often inherited as an autosomal dominant condition, and most patients have de novo variants (Laing et al. 2009). Parental mosaicism for ACTA1 variants is documented (e.g. Nowak et al. Nat Genet 23:208-212, 1999). Recessive inheritance of NEM3 is rare and all such variants manifest as null alleles. Although CFTD is a genetically heterogeneous condition that can be inherited in an autosomal recessive, autosomal dominant, or X-linked manner, the three reported cases of ACTA1-related CFTD have been caused by autosomal dominant variants (Laing et al. Ann Neurol 56:689-694, 2004).

ACTA1 variants account for 15%-25% of all cases of nemaline myoapthy (e.g. Nowak et al. 1999; Ryan et al. 2001) and possibly up to 50% of the severe, congenital-onset form (Agrawal et al. Ann Neurol 56:86-96, 2004). Five other genes (NEB, TPM3, TNNT1, TPM2, and CFL2) are associated with NEM; however, the fraction of cases attributed by them is small. Laing et al. (2004) found heterozygous ACTA1 variants in 6% (three unrelated individuals) of a CFTD cohort from Japan and Australia.

This test provides full coverage of all coding exons of the ACTA1 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).