Comprehensive Neuropathy Panel

This comprehensive panel includes genes that are causative for Charcot-Marie-Tooth disease (CMT), hereditary motor neuropathies and hereditary sensory and autonomic neuropathies (HSAN). These inherited neuropathies of the peripheral nervous system are genetically and phenotypically heterogeneous.

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. 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 muscles 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 (Bird and Bird. 2015. PubMed ID: 20301532). Diagnosis is based on clinical features, family history, neurological examination, and electromyography (EMG) and nerve conduction velocity (NCV) findings. CMT affects approximately 1 in 3,300 people (Bird and Bird. 2015. PubMed ID: 20301532; Saporta et al. 2011. PubMed ID: 21280073). Demyelinating forms of CMT primarily affect the myelin sheath of the peripheral nerve and are characterized by slow nerve conduction velocities (NCV) of less than 38 m/s in upper limbs. Axonal forms of CMT primarily affect the axons of the peripheral nerves and are characterized by normal or almost normal NCV of greater than 38 m/s. Intermediate NCV of 25-45 m/s can be difficult to classify as axonal or demyelinating.

Hereditary sensory and autonomic neuropathy (HSAN) is a heterogeneous group of slowly-progressing neurological diseases characterized by progressive dysfunction of peripheral sensory nerves (Auer-Grumbach. 2013. PubMed ID: 23931820; Auer-Grumbach. 2008. PubMed ID: 18348718). Many patients with HSAN manifest loss of pain and temperature sensation which can lead to chronic skin ulcers, and even osteomyelitis and necrosis (Auer-Grumbach. 2013. PubMed ID: 23931820). HSAN affects approximately 1 in 25,000 people (Auer-Grumbach. 2013. PubMed ID: 23931820, Davidson et al. 2012. PubMed ID: 22302274).

Distal hereditary motor neuropathy (dHMN) is a clinically and genetically heterogeneous group of disorders characterized by progressive distal motor weakness and atrophy. The distribution of 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 Rossor et al. 2012. PubMed ID: 22028385 and Drew et al. 2011. PubMed ID: 21902652.

Charcot-Marie-Tooth can be inherited in an autosomal dominant, autosomal recessive or an X-linked manner. The MPZ, LITAF, NEFL, PMP22, FBLN5, MFN2, YARS1/YARS, RAB7, TRPV4, GARS1/GARS, HSPB1, HSPB8, INF2, GNB4, AARS1/AARS, DYNC1H1, LRSAM1, DHTKD1, MARS1/MARS, KIF5A genes are involved in autosomal dominant CMT. Autosomal recessive forms of CMT involve the LMNA, MED25, HINT1, HK1, TRIM2, MTMR2, SBF2, SBF1, SH3TC2, PRX, FGD4, FIG4, NDRG1, KARS1/KARS, CTDP1, PLEKHG5, IGHMBP2 and COX6A1 genes. Pathogenic variants in the EGR2, GDAP1, and DNM2 genes can exhibit both dominant and recessive inheritance. In cases of Dejerine-Sottas syndrome, the PMP22, MPZ, EGR2, and PRX genes can exhibit both dominant and recessive inheritance as well. Pathogenic variants in the GJB1, AIFM1, PRPS1, and PDK3 genes are inherited in an X-linked manner. Approximately 70% of CMT1 is caused by the recurrent 1.5 Mb duplication of chromosome 17p11.2 which includes the PMP22 gene (Bird and Bird. 2015. PubMed ID: 20301532; Li et al. 2013. PubMed ID: 23224996).

HSAN 1 is inherited in an autosomal dominant manner and can be caused by pathogenic variants in multiple genes including SPTLC1, SPTLC2, ATL1, and DNMT1. HSAN 2-5 typically exhibit an autosomal recessive form of inheritance. HSAN 2 is associated with FAM13B, KIF1A, SCN9A, and WNK1. HSAN 3-5 are caused by pathogenic variants in ELP1/IKBKAP, NTRK1, and NGFB, respectively. CCT5 pathogenic variants can cause another autosomal recessive type of HSNA which does not fit into the current five classifications.

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 HSPB1, HSPB8, SETX, GARS1, BSCL2, SLC5A7, DCTN1, TRPV4, and REEP1. Recessively inherited forms of dHMN are caused by pathogenic variants in the IGHMBP2, GAN, and HINT1 genes. Two X-linked forms are also known (ATP7A and LAS1L).

See individual gene test descriptions for information on molecular biology of gene products and spectra of pathogenic variants.

A genetic etiology can be identified in approximately 50-70% of individuals with Charcot-Marie-Tooth Disease (CMT) (Saporta et al. 2011. PubMed ID: 21280073; Rossor et al. 2013. PubMed ID: 24018473). Specifically, a molecular diagnosis can be identified in approximately 80-85% of individuals with demyelinating neuropathy (CMT1), and a molecular diagnosis can be identified in approximately 25-35% of individuals with axonal neuropathy (CMT2) (Bird and Bird. 2015. PubMed ID: 20301532; Rossor et al. 2013. PubMed ID: 24018473). It is estimated that ~70% of all Charcot Marie Tooth Type 1 (CMT1) is due to the PMP22 1.5 Mb duplication, while only around 5% of CMT1 cases are due to point pathogenic variants (Bird and Bird. 2015. PubMed ID: 20301532). Only about 20% of patients with distal hereditary motor neuropathy or hereditary sensory and autonomic neuropathy will obtain a genetic diagnosis (Rossor et al. 2012. PubMed ID: 22028385; Rotthier et al. 2009. PubMed ID: 19651702). The sensitivity of this panel will vary based on the clinical phenotype of the patient.

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

This panel typically provides 99.8% 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).

Please note that for technical reasons, exon 8 of the INF2 gene is not currently included in this panel. Thus far, only exons 2 to 6, especially exons 2 to 4 that encode the diaphanous inhibitory domain (DID), have been reported to harbor pathogenic INF2 variants (Boyer et al. 2011. PubMed ID: 21258034; Barua et al. 2013. PubMed ID: 23014460; Human Gene Mutation Database).

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).