Polyglucosan Body Myopathy Type I, with or without Immunodeficiency, via the RBCK1 Gene

Polyglucosan body myopathy type I is caused by a genetic deficiency of the ubiquitin ligase RBCK1. The majority of patients that have been described to date have presented with progressive muscle weakness that typically begins with leg weakness, dilated cardiomyopathy, and polyglucosan accumulation in the skeletal muscle, heart, and/or liver. Some of these patients have also presented with ptosis, scoliosis, hepatomegaly, elevated liver transaminases, and growth retardation. Onset is typically during childhood or adolescence (Nilsson et al. 2013; Wang et al. 2013).

A small number of more severely affected patients have been reported. These patients have presented with severe immune dysfunction, including B-cell memory deficiency and hyper-IgA syndrome. As a result, they suffered frequent bacteriological infections from infancy and throughout childhood, chronic systemic inflammation, gastrointestinal symptoms (including vomiting, diarrhea, abdominal pain, and blood and mucous in stools), and dermatological abnormalities. RBCK1 deficiency was fatal in all three of the patients described with this more severe presentation (Boisson et al. 2012).

Polyglucosan body myopathy type I is an autosomal recessive disorder caused by pathogenic variants in the RBCK1 gene. Over 10 pathogenic variants have been described in this gene. The majority of reported variants are expected to lead to premature protein termination, and include nonsense variants, small frameshift deletions and insertions, and splice variants. A small number of missense variants have been reported, as well as one multi-exonic deletion (Human Gene Mutation Database). It has been proposed that the severity of the phenotype may be related to the type and location of sequence variant within RBCK1. For example, patients with a missense variant tend to have a mild form of disease with either no cardiomyopathy, or later-onset cardiomyopathy. The small number of patients with immunological symptoms have had loss-of-function variants that reside within the N-terminal region of RBCK1, whereas the patients without immunological symptoms have had at least one variant located in the middle or C-terminal region of RBCK1 (Nilsson et al. 2013).

The RBCK1 gene encodes an E3 ubiquitin ligase. It interacts with a variety of different proteins, including EYA1 (involved in myogenesis) and IRP2 (involved in control of iron homeostasis). It is also part of the linear ubiquitin assembly complex (LUBAC), which is important for regulation of the NFkB pathway that plays an important role in regulation of the immune system (Nilsson et al. 2013).

Based on cumulative totals of patients reported in the literature, 29 small sequence variants were detected in a total of 16 patients, for an estimated sensitivity of ~91% (29 of 32 alleles). The remaining 3 alleles were multi-exonic deletions that would not be expected to be detected via direct sequencing (Boisson et al. 2012; Nilsson et al. 2013; Wang et al. 2013).

This test provides full coverage of all coding exons of the RBCK1 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).