Distal Myopathy via the KLHL9 Gene

The hereditary distal myopathies are a genetically and clinically heterogeneous group of disorders characterized by prominent weakness beginning in the anterior or posterior compartment of either the distal upper or the distal lower limbs. Weakness of the wrists and ankles is a common pattern of muscle involvement. Age of onset, disease severity, rate of progression, and muscle pathology all vary among the many genetic subtypes of this disorder. For example, patients with Laing myopathy may present as early as 4 years of age (Meredith et. al. 2004. PubMed ID: 15322983), while patients affected by Udd myopathy or Welander myopathy may not become clinically affected until the 5th decade of life (Udd et al. 1993. PubMed ID: 8503797; Klar et al. 2013. PubMed ID: 23348830). Serum CpK levels are typically normal or slightly elevated; however, patients with Miyoshi myopathy, Miyoshi-like myopathy, and TCAP related myopathy have CpK levels 100-fold elevated over normal. Muscle pathology of the distal myopathies often reveal varied fiber size and abnormal vacuoles, and those subtypes with myofibrillar changes show accumulation of desmin. A diagnostic algorithm for the distal myopathies using clinical and laboratory data has been proposed (Udd. 2009. PubMed ID: 19477645). For a recent review of distal myopathies see Dimachkie and Barohn 2014 (Dimachkie and Barohn. 2014. PubMed ID: 25037092).

Distal myopathy due to a pathogenic KLHL9 variant was first described in a large 4 generation German family in which linkage analysis and candidate gene sequencing were used to discover the causative KLHL9 gene (Cirak et al. 2010. PubMed ID: 20554658). Onset was between the ages of 8 and 16 years. Typical symptoms included difficulty walking on heels followed by slow wasting of ankle extensors, high steppage gait, ankle contractures, and weakness in intrinsic hand muscles. The progression was slow and proximal muscle groups were spared.

Distal myopathy due to KLHL9 pathogenic variants is inherited in an autosomal dominant manner. The KLHL9 gene encodes Kelch-like homologue 9 (KLHL9) which binds to Cul3 to form an E3 ubiquitin ligase complex. The KLHL9-Cul3-Roc1 E3 ubiquitin ligase complex ubiqintinates substrate proteins for degradation by the proteasome. Thus far, the only established pathogenic variant reported in one large German family is a missense variant referred to as c.283C>T p.Leu95Phe, which was shown to result in reduced binding to Cul3 (Cirak et al. 2010. PubMed ID: 20554658; Human Gene Mutation Database).

Clinical sensitivity cannot be estimated because only a small number of patients have been reported. However, pathogenic variants in KLHL9 appear to be a rare cause of disease. Analytical sensitivity should be high because all reported pathogenic variants thus far are detectable by sequencing.

This test provides full coverage of all coding exons of the KLHL9 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).