Charcot-Marie-Tooth disease, axonal, type 20, Spinal muscular atrophy with lower extremity predominance and Mental retardation, autosomal dominant type 13 via the DYNC1H1 Gene

In a large four generation pedigree affected with type 2 Charcot-Marie-Tooth disease (OMIM 614228) a heterozygous DYNC1H1 missense mutation was found to cosegregate with disease (Weedon et al. Am J Hum Genet 89:308-312, 2011). Some patients presented at birth with club foot or pes cavus and others were reported to require multiple surgeries to correct foot and ankle problems. Other individuals presented early in the second decade of life with abnormal gait, difficulty running, and frequent falls. Still others presented with delayed motor milestones, developmental delays, or speech delays. Common clinical features include proximal and distal lower limb weakness and wasting. Reflexes were reduced in some, but not all affected individuals.

Two cases of autosomal dominant mental retardation have been attributed to de novo mutations in the DYNC1H1 gene (OMIM 614563). Both cases were discovered by family-based exome sequencing. The first affected individual had, in addition to severe intellectual disability, hypotonia, hyporeflexia, mild dysmorphic facial features, and broad-based waddling gait with toe-walking (Vissers et al. Nat Genet 42:1109-1112, 2010). The patient was also found to have deficient gyration of the frontal lobes by brain MRI studies. The second case was ascertained at the age of 51years (Willemsen et al. J Med Genet 49:179-183, 2012). This patient also had severe intellectual impairment since infancy and was unable to walk or speak. Additionally, she was mildly dysmorphic and had abnormal cortex structure with deficient gyration.

In a large six generation pedigree affected with spinal muscular atrophy with lower extremity predominance (SMALED, OMIM 158600) a heterozygous DYNC1H1 missense mutation was found to cosegregate with disease (Harms et al. Neurology 78:1714-1720, 2012). In affected individuals from this pedigree muscle atrophy and weakness was confined to the lower limbs and there was little progression. Early clinical signs included a waddling gait and awkward running. Deep tendon reflexes were reduced at the knees and nerve conduction studies were consistent with motor neuron disease without sensory involvement. Thirty-two other patients with SMALED were tested by DYNC1H1 sequencing and two were found to have missense mutations. Notably, all three SMALED-causing mutations are located in the tail domain of the DYNC1H1 protein.

DYNC1H1-related disorders are inherited in an autosomal dominant mode. Individuals with Charcot-Marie-Tooth disease type 20 spinal muscular atrophy with lower extremity predominance inherit a DYNC1H1 mutation from an affected parent. Mutations resulting in autosomal dominant mental retardation type 13 have been shown to be de novo (Vissers et al. Nature Genet 42: 1109-1112, 2010; Willemsen et al. J Med Genet 49:179-183, 2012). Missense mutations are the only form of pathogenic gene variant thus far reported for the DYNC1H1 gene.

Analytical sensitivity may be high because all DYNC1H1 mutations reported to date are expected to be detectable by direct sequencing of genomic DNA. Clinical sensitivity is problematic to predict due to genetic heterogeneity of these disorders and the death of documented cases. Vissers et al. (Nat Genet 42: 1109-1112, 2010) tested exomes of ten patients with unexplained severe intellectual impairment and found one to have a de novo DYNC1H1 mutation. Harms et al. (Neurology 78: 1714-1720, 2012) found two patients with DYNC1H1 mutations among 32 probands with spinal muscular atrophy with lower extremity predominance.

This test provides full coverage of all coding exons of the DYNC1H1 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).