Limb Girdle Muscular Dystrophy Type 1G via the HNRNPDL 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).

A large Brazilian family and Uraguayan family have been reported with limb girdle muscular dystrophy type 1G (Starling et al. 2004; Vieira et al. 2014). The Brazilian family had 12 members with mild adult-onset LGMD which age of onset ranging from 30-47 years of age with proximal lower limb weakness in most patients. A unique finding was limitation in finger and toe flexion in almost all individuals (Starling et al. 2004). The Uraguayan family with 18 affected members also presented with a similar late-onset LGMD, with the same finger and toe flexion limitation. In addition, 6 of 11 clinically affected individuals also presented with cataracts with onset before age 50 (Vieira et al. 2014).

Limb girdle muscular dystrophy type 1G is an autosomal dominant disorder caused by defects in the HNRNPDL gene, located on chromosome 4q21.22 (Vieira et al 2014). The HNRNPDL gene encodes for a heterogenous ribonucleoprotein family member, which participates in mRNA biogenesis and metabolism. To date, only two missense variants that alter the same amino acid (p.Asp378Asn and p.Asp378His) have been reported in two large families with limb girdle muscular dystrophy type 1G. A few asymptomatic carriers were also observed, suggesting there is reduced penetrance for this disorder.

Too few cases of LGMD1G have been reported to provide a numeric estimate of clinical or analytical sensitivity. However, pathogenic variants in HNRNPDL appear to be a rare cause of limb girdle muscular dystrophy. Analytical sensitivity could be high as all reported pathogenic variants are detectable by sequencing.

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