Limb Girdle Muscular Dystrophy Type 1F via the TNPO3 Gene

Limb girdle muscular dystrophy (LGMD) is a descriptive term for a group of disorders with atrophy and weakness of proximal girdle muscles and typical sparing of the heart and bulbar muscles. Clinical severity, age of onset, and disease progression are highly variable among the subtypes (Sáenz et al. 2005). Serum creatine kinase levels are typically elevated, and muscle biopsies demonstrate a dystrophic process. For comprehensive reviews, see Pegoraro and Hoffman (2012) and Nigro and Savarese (2014).

Limb girdle muscular dystrophy type 1F has been described in one large Spanish family of about 50 individuals (Melià et al. 2013; Torella et al. 2013). In this family, a presumed pathogenic TNPO3 variant was identified by whole genome sequencing and co-segregated with 29 affected individuals and was absent in 20 unaffected individuals. The individuals in this family presented with limb girdle and distal muscle weakness with variable distribution, severity, and rate of progression. Some individuals presented in infancy with mild delay in motor skills, whereas two of the most severe cases presented with an Emery-Dreifuss-like phenotype. Overall, the disorder typically presents in late childhood or early adolescence and less frequently in adulthood. About 40% of the cases had elevated creatine kinase levels. Muscle biopsy analysis revealed increased variability of fiber size and shape, increased endo- and peri-mysial connective tissue, occasional central nuclei, rimmed vacuoles and autophagic vacuoles.

Limb girdle muscular dystrophy type 1F is an autosomal dominant disorder caused by defects in the TNPO3 gene (Melià et al. 2013; Torella et al. 2013). In a very large Spanish family, a small deletion in the termination codon that leads to an extended protein product was reported to segregate with all affected individuals (c.2771del, p.*924Cysfs*16). Only one additional unrelated patient with a missense variant has been reported thus far. The TNPO3 gene encodes transportin 3, a protein involved in translocation of proteins from the cytoplasm to the nucleus. It is unknown if these dominant variants cause disease due to haploinsufficiency or to a dominant-negative mechanism.

Too few cases of LGMD1F have been reported to provide a numeric estimate of clinical or analytical sensitivity. However, pathogenic variants in TNPO3 appear to be a rare cause of LGMD. Analytical sensitivity could be high as the reported pathogenic variants are detectable by sequencing.

This test provides full coverage of all coding exons of the TNPO3 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).