Charcot-Marie-Tooth Type 4D via the NDRG1 Gene

Charcot Marie Tooth disease (CMT), also known as hereditary motor and sensory neuropathy (HMSN) is a large group of inherited disorders of the peripheral nerves. The progressive degeneration of motor nerves results in weakness and atrophy of the distal muscles; and the degeneration of sensory nerves leads to decreased sensation, tingling and numbness in the legs, feet, arms and hands and neuropathic pain. The age of onset varies from childhood to mid adulthood. Symptoms usually begin with weakness and atrophy in the muscle of the legs and feet. As the disease progresses, weakness and atrophy of the muscles of the arms and hands may occur. CMT is heterogeneous in regards to symptoms, severity and progression rate. Although the disease may lead to disability and respiratory difficulty, life expectancy is usually unaffected. Most common symptoms include foot deformity, loss of balance, hammertoes, foot drop, frequent tripping and falls, and reduced manual dexterity. Diagnosis is based on clinical features, family history, neurological examination, and electromyography (EMG) and nerve conduction velocity (NCV) findings (Pareyson and Marchesi 2009; Bird 2015). CMT affects approximately 1 in 3,300 people.

Charcot-Marie-Tooth type 4D (CMT4D) (also referred to as hereditary and sensory neuropathy-Lom- HMSNL) is an autosomal recessive from of CMT that presents with early-onset peripheral neuropathy that progresses to severe disability in adulthood (Kalaydjieva et al. 2000). Patients present with muscle weakness and wasting, tendon areflexia, skeletal and foot deformities, sensory loss, severe reduction in nerve conduction velocities, and hearing loss in the second or third decade (Kalaydjieva et al. 2000; Hunter et al. 2003, Okamota et al. 2014).

Charcot-Marie-Tooth type 4D (CMT4D) is inherited in an autosomal recessive manner due to pathogenic variants in NDRG1, located on chromosome 8q24.3. NDRG1 encodes the N-myc downstream-regulated 1 protein which has been shown to function in many pathways including tumor suppression, metastasis inhibition, stress response, differentiation, and N-myc developmental regulation (Echaniz-Laguna et al. 2007). CMT4D is almost exclusively found in individuals of Romani ancestry who carry a common founder mutation referred to as c.442C>T, p.Arg148* (Kalaydjieva et al. 2000; Hunter et al. 2003). A splice variant and large duplication have also been reported in the NDRG1 gene (Hunter et al. 2003; Okamota et al. 2014).

In a study of 104 patients with peripheral neuropathy in which common forms of CMT had been ruled out (negative for PMP22, MPZ, GJB1, and EGR2 variants), three were found to have a pathogenic variant in NDRG1 (2.9%) (Hunter et al. 2003).

Only one large duplication of the NRDG1 gene has been published to date; therefore, sensitivity of this test is uncertain (Okamoto et al. 2014).

This test provides full coverage of all coding exons of the NDRG1 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).