Nemaline Myopathy 5 (Amish Nemaline Myopathy) via the TNNT1 Gene

Variants in the troponin T1 gene (TNNT1; OMIM 191041) are one cause of autosomal recessive nemaline myopathy (NEM5; OMIM 605355). 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. 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 2009). Troponin T1-associated NEM is a lethal form of nemaline myopathy described only in the Old Order Amish community of Pennsylvania (Johnston et al. Am J Hum Genet 67:814-821, 2000). Newborns affected with TNNT1-associated nemaline myopathy are hypotonic and have shoulder and hip contractures along with tremors. Contractures and muscle weakness progressively worsen and patients develop pectus carinatum before life-threatening respiratory symptoms develop in the second year of life (Johnston et al. 2000).

To date, variants in six genes have been shown to cause nemaline myopathy. Variants in ACTA1 (NEM3) and NEB (NEM2) are the only relatively common causes (Ryan et al. 2001). Among Old Order Amish of Lancaster County, Pennsylvania, a p.Glu180* founder variant in exon 11 of the TNNT1 gene was found to account for the autosomal recessive nemaline myopathy in this community (Johnston et al. 2000; Jin et al. J Biol Chem 278:26159-26165, 2003). The incidence of NEM5 among this population is ~1/500 (Johnston et al. 2000).

Clinical and analytical sensitivity for testing symptomatic individuals of the Old Order Amish is expected to be high. Clinical sensitivity among other populations is not known.

This test provides full coverage of all coding exons of the TNNT1 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).