Heat Shock 22 kDa Protein-Related Disorders via the HSPB8 Gene

Charcot-Marie-Tooth disease type 2L (CMT2L; OMIM 608673) and distal hereditary motor neuronopathy type IIA (HMN2A; OMIM 158590) represent a phenotypic continuum of distal neuropathy with weakness and wasting starting in the distal limbs. In CMT2L distal sensory loss is evident while in HMN2A it is not, thus differentiating the two disorders (Irobi et al. Nat Genet 36:597-601, 2004). Among eighteen affected members of the first reported CMT2L family, clinical signs of lower limb weakness first appeared between 15 and 33 years of age (Tang et al. Hum Genet 114:527-533, 2004). Most affected individuals had symmetric muscle wasting and weakness of the distal lower limbs, absent or decreased deep tendon reflexes, and mild to moderate sensory loss. Upper limb weakness and wasting developed subsequent to lower limb involvement in one third of the patients. Most affected family members had high-arched feet. All affected elderly family members were severely affected, but none were wheelchair bound. Four families who displayed exclusively lower motor neuron disease with HSPB8 variants have also been described (Timmerman et al. J Neurol Sci 109:41-48, 1992; Timmerman et al. Hum Mol Genet 5:1065-1069, 1996; Irobi et al. 2004). Disease onset is between 15 and 25 years of age, and paresis of the great toe extensor muscles was found to be the presenting sign (Irobi et al. 2004). Foot extensor muscles are eventually affected and disease progression is rapid, culminating in paralysis of the distal muscles of the lower legs.

A family demonstrating autosomal dominant inheritance of axonal type Charcot-Marie-Tooth disease (Tang et al. Hum Genet 114:527-533, 2004) was later found to have a missense variant in the gene that encodes the heat shock 22 kDa protein (HSPB8, OMIM 608014; Tang et al. Hum Genet 116:222-224, 2005). Similarly, a small number of families with distal hereditary motor neuronopathy were also found to have HSPB8 variants (Timmerman et al. 1996; Irobi et al. 2004). HSPB8-related CMT and distal HMN are inherited as autosomal dominant disorders, and two missense variants affecting the same amino acid residue (p.Lys141Asn and p.Lys141Glu) have thus far been identified.

HSPB8 is probably a rare cause of the axonal form of CMT and distal HMN.

This test provides full coverage of all coding exons of the HSPB8 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).