Nemaline myopathy and distal arthrogryposis associated with an autosomal recessive <italic>TNNT3</italic> splice variant.

Abstract: A male neonate presented with severe weakness, hypotonia, contractures and congenital scoliosis. Skeletal muscle specimens showed marked atrophy and degeneration of fast fibers with striking nemaline rods and hypertrophy of slow fibers that were ultrastructurally normal. A neuromuscular gene panel identified a homozygous essential splice variant in <italic>TNNT3</italic> (chr11:1956150G > A, NM_006757.3:c.681+1G > A). <italic>TNNT3</italic> encodes skeletal troponin‐T_fast and is associated with autosomal dominant distal arthrogryposis. <italic>TNNT3</italic> has not previously been associated with nemaline myopathy (NM), a rare congenital myopathy linked to defects in proteins associated with thin filament structure and regulation. cDNA studies confirmed pathogenic consequences of the splice variant, eliciting exon‐skipping and intron retention events leading to a frameshift. Western blot showed deficiency of troponin‐T_fast protein with secondary loss of troponin‐I_fast. We establish a homozygous splice variant in <italic>TNNT3</italic> as the likely cause of severe congenital NM with distal arthrogryposis, characterized by specific involvement of Type‐2 fibers and deficiency of troponin‐T_fast. [ABSTRACT FROM AUTHOR]