Distal Hereditary Motor Neuropathy Panel

Distal hereditary motor neuropathy (dHMN) is a clinically and genetically heterogeneous group of disorders characterized by progressive distal motor weakness and atrophy. The weakness is usually greater in the distal lower limbs than the upper limbs, and weakness of the toe extensor muscles is often the presenting sign. Nerve conduction velocities are generally normal in dHMN, and sensory impairment is not a feature of this disorder. Subtypes of dHMN can be differentiated to some extent based on age of onset, pattern of weakness, rate of progression, and appearance of additional complicating features. For discussions on classification, pathophysiology, and molecular genetics of dHMN see Irobi et al. (2004. PubMed ID: 15358725) and Drew et al. (2011. PubMed ID: 21902652).

Distal hereditary motor neuropathies can be inherited as autosomal dominant, autosomal recessive, or X-linked conditions. Genes that are involved in dominantly inherited dHMN include AARS1/AARS, BICD2, DYNC1H1, FBXO38, HSPB1, HSPB3, HSPB8, SETX, GARS1/GARS, BSCL2, SLC5A7, SYT2, DCTN1, TRPV4, and REEP1. Recessively inherited forms of dHMN are caused by pathogenic variants in the DNAJB2, IGHMBP2, GAN, HINT1 and SIGMAR1 genes. Two X-linked forms are also known (ATP7A and LAS1L).

See individual gene test descriptions for information on molecular biology of gene products.

Clinical sensitivity cannot be estimated as data do not yet exist. Analytical sensitivity is expected to be high as nearly all pathogenic variants for this disorder are detectable by sequencing. Analytical sensitivity specifically for the IGHMBP2 gene may be lower as gross deletions have been reported.

Clinical sensitivity is expected to be low for these genes because relatively few copy number variations have been reported.

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel provides 100% coverage of all coding exons of the genes 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 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).