Invitae Hereditary Motor Neuropathy Panel

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  • Test code: 03240
  • Turnaround time:
    10–21 calendar days (14 days on average)
  • Preferred specimen:
    3mL whole blood in a purple-top tube
  • Alternate specimens:
    DNA or saliva/assisted saliva
  • Sample requirements
  • Request a sample kit
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Test description

The Invitae Hereditary Motor Neuropathy Panel analyzes up to 24 genes associated with hereditary motor neuropathy (HMN), a heterogeneous group of peripheral nervous system disorders which cause progressive motor weakness and muscular atrophy, usually without sensory impairment. These genes were curated based on current available evidence to provide a comprehensive test for the genetic causes of hereditary motor neuropathy.

Given that distal and proximal hereditary motor neuropathy is a heterogeneous group of disorders, identification of the underlying genetic cause can help predict outcome for the individual, and inform recurrence risk.

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Primary panel (22 genes)

ATP7A BICD2 BSCL2 CHCHD10 DCTN1 DNAJB2 DYNC1H1 FBXO38 GARS HINT1 HSPB1 HSPB8 IGHMBP2 PLEKHG5 REEP1 SIGMAR1 SLC5A7 SMN1, SMN2 TRPV4 UBA1 VAPB

SMN1, SMN2: The SMN1 gene is identical to the SMN2 gene with the exception of exon 8 (typically referred to as exon 7). This assay unambiguously detects SMN1 exon 8 copy number and sequence variants. Sequence variants outside of exon 8 will also be detected, but this assay cannot determine whether the variant is located in SMN1 or SMN2. SMN2 exon 8 copy number will be reported for individuals with a positive result in SMN1. CNVs in exons 1-7 of SMN1 or SMN2 (typically referred to as exons 1-6 in the literature) will not be reported. This assay cannot detect silent carriers (individuals that have 2 functional copies of SMN1 on one chromosome and zero copies on the other). Therefore a negative result for carrier testing greatly reduces but does not eliminate the chance that a person is a carrier.

Add-on Preliminary-evidence Genes for Hereditary Motor Neuropathy (2 genes)

Preliminary-evidence genes currently have early evidence of a clinical association with the specific disease covered by this test. Some clinicians may wish to include genes which do not currently have a definitive clinical association, but which may prove to be clinically significant in the future. These genes can be added at no additional charge. Visit our Preliminary-evidence genes page to learn more.

HSPB3 VRK1

Alternative tests to consider

For a broader analysis of the genetics of hereditary neuropathy:

Hereditary motor neuropathies (HMNs), in some cases referred to as spinal muscular atrophies (SMAs), are a clinically and genetically heterogeneous group of disorders characterized by loss of motor neurons within the spinal cord, resulting in weakness and muscle wasting. The weakness and wasting is primarily distal, but in some cases can be proximal or combined proximal/distal. Typical clinical findings in individuals include slowly progressive muscle weakness and wasting. Onset of symptoms varies from the prenatal period to adulthood. Some forms of HMN also have minor involvement of the sensory neurons. Other features are variable depending on the causative gene, and may include vocal cord paralysis, facial weakness, pyramidal signs, and arthrogryposis. Many genes associated with HMN can also cause other forms of neuropathy with overlapping symptoms, such as Charcot Marie Tooth disease.

GeneInheritanceTypical age of onsetWeakness and wastingAssociated disorders
Autosomal dominantAutosomal recessiveX-linked
ATP7A early adulthood distal ATP7A-related HMN, Menkes disease, occipital horn syndrome
BICD2 childhood distal and proximal SMALED2
BSCL2 childhood to adulthood distal HMN5, CMT2, SPG17, CGL2
CHCHD10 adulthood distal and proximal SMAJ, FTDALS2, IMMD
DCTN1 childhood or young adulthood distal HMN7B, ALS, Perry Syndrome
DNAJB2 early adulthood distal DSMA5, CMT2T
DYNC1H1 variable (prenatal-onset to late adulthood) distal SMALED1, CMT2O
FBXO38 adolescence or adulthood distal HMN2D
GARS adolescence or early adulthood distal HMN5, CMT2D
HINT1 childhood or adolescence distal NMAN
HSPB1 adulthood distal HMN2B, CMT2F
HSPB3* adulthood distal HMN2C
HSPB8 adolescence to mid-adulthood distal HMN2A, CMT2L
IGHMBP2 infancy (HMN6), childhood (CMT2S) distal HMN6, CMT2S
PLEKHG5 childhood (DSM4A), adulthood (CMTRIC) distal CMTRIC, DSMA4
REEP1 childhood to early adulthood distal HMN5B, SPG31
SIGMAR1 childhood distal DSMA2
SLC5A7 adolescence distal HMN7A
SMN1 Variable (prenatal-onset to late adulthood) proximal SMA
SMN2 modifier of SMN1
TRPV4 childhood distal HMN8, SPSMA, CMT2C
UBA1 infancy proximal SMAX2
VAPB adulthood proximal SMAFK
VRK1* variable distal PCH1A

*Preliminary-evidence gene

BSCL2 is one of the most common causes of distal HMN, and accounts for 7-12% of affected individuals. The HSPB1 and HSPB8 genes each account for less than 5% of individuals with distal HMN. SMN1 accounts for the majority of cases diagnosed with spinal muscular atrophy. This panel also includes other genes that have been identified as causes of HMN, although the exact contribution of these genes to the overall detection rate is not known and is dependent on the clinical presentation of the individual.

Hereditary motor neuropathies can be inherited in an autosomal dominant, autosomal recessive, or X-linked pattern. The inheritance of SMN1-related spinal muscular atrophy is complicated by the modifying effects of SMN2.

Distal hereditary motor neuropathy associated with the ATP7A gene is a completely penetrant disorder, and the penetrance of DNAJB6- and PLEKHG5-associated distal HMN is thought to be high. Penetrance of BSCL2-associated disorders is incomplete, with more than 20% of individuals showing no symptoms. Disorders associated with TRPV4 are associated with clinical variability and incomplete penetrance. Penetrance of SMN1-related SMA is high, but is complicated by modifying effects of SMN2 copy number. Most other forms of HMN are rare, and penetrance estimates are not known. Some forms of HMN may not present until late in adulthood, which makes determination of penetrance difficult.

Hereditary motor neuropathies are a rare group of disorders, and the overall prevalence of these conditions is unknown. The prevalence of SMN1-related SMA is estimated to be <2 per 100,000 of the general population (PMID: 745211)

The clinical spectrum of hereditary motor neuropathy is broad. Genetic testing may confirm a suspected diagnosis or rule out disorders with similar symptoms. A genetic diagnosis may also help predict disease progression and inform recurrence risk.

  1. Azzedine, H, et al. PLEKHG5 deficiency leads to an intermediate form of autosomal-recessive Charcot-Marie-Tooth disease. Hum. Mol. Genet. 2013; 22(20):4224-32. PMID: 23777631
  2. Barwick, KE, et al. Defective presynaptic choline transport underlies hereditary motor neuropathy. Am. J. Hum. Genet. 2012; 91(6):1103-7. PMID: 23141292
  3. Beetz, C, et al. Exome sequencing identifies a REEP1 mutation involved in distal hereditary motor neuropathy type V. Am. J. Hum. Genet. 2012; 91(1):139-45. doi: 10.1016/j.ajhg.2012.05.007. PMID: 22703882
  4. Berciano, J, et al. Reduced penetrance in hereditary motor neuropathy caused by TRPV4 Arg269Cys mutation. J. Neurol. 2011; 258(8):1413-21. PMID: 21336783
  5. Dierick, I, et al. Relative contribution of mutations in genes for autosomal dominant distal hereditary motor neuropathies: a genotype-phenotype correlation study. Brain. 2008; 131(Pt 5):1217-27. PMID: 18325928
  6. Gess, B, et al. HSJ1-related hereditary neuropathies: novel mutations and extended clinical spectrum. Neurology. 2014; 83(19):1726-32. PMID: 25274842
  7. Grohmann, K, et al. Characterization of Ighmbp2 in motor neurons and implications for the pathomechanism in a mouse model of human spinal muscular atrophy with respiratory distress type 1 (SMARD1). Hum. Mol. Genet. 2004; 13(18):2031-42. PMID: 15269181
  8. Kaler, SG. ATP7A-Related Copper Transport Disorders. 2003 May 09. In: Pagon, RA, et al, editors. GeneReviews(®) (Internet). University of Washington, Seattle. PMID: 20301586
  9. Kolb, SJ, Kissel, JT. Spinal Muscular Atrophy. Neurol Clin. 2015; 33(4):831-46. PMID: 26515624
  10. Kolb, SJ, et al. Mutant small heat shock protein B3 causes motor neuropathy: utility of a candidate gene approach. Neurology. 2010; 74(6):502-6. PMID: 20142617
  11. Pearn, J. Incidence, prevalence, and gene frequency studies of chronic childhood spinal muscular atrophy. J. Med. Genet. 1978; 15(6):409-13. PMID: 745211
  12. Prior, TW, Russman, BS. Spinal Muscular Atrophy. 2000 Feb 24. In: Pagon, RA, et al, editors. GeneReviews(®) (Internet). University of Washington, Seattle. PMID: 20301526
  13. Prior, TW, et al. Homozygous SMN1 deletions in unaffected family members and modification of the phenotype by SMN2. Am. J. Med. Genet. A. 2004; 130A(3):307-10. PMID: 15378550
  14. Puls, I, et al. Mutant dynactin in motor neuron disease. Nat. Genet. 2003; 33(4):455-6. PMID: 12627231
  15. Reilly, MM, Shy, ME. Diagnosis and new treatments in genetic neuropathies. J. Neurol. Neurosurg. Psychiatr. 2009; 80(12):1304-14. PMID: 19917815
  16. Rossor, AM, et al. The distal hereditary motor neuropathies. J. Neurol. Neurosurg. Psychiatr. 2012; 83(1):6-14. PMID: 22028385
  17. Scoto, M, et al. Novel mutations expand the clinical spectrum of DYNC1H1-associated spinal muscular atrophy. Neurology. 2015; 84(7):668-79. PMID: 25609763
  18. Sumner, CJ, et al. A dominant mutation in FBXO38 causes distal spinal muscular atrophy with calf predominance. Am. J. Hum. Genet. 2013; 93(5):976-83. PMID: 24207122
  19. Zimoń, M, et al. Loss-of-function mutations in HINT1 cause axonal neuropathy with neuromyotonia. Nat. Genet. 2012; 44(10):1080-3. PMID: 22961002

Assay and technical information

Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).

Our sequence analysis covers clinically important regions of each gene, including coding exons, +/- 10 base pairs of adjacent intronic sequence, and select noncoding variants. Our assay provides a Q30 quality-adjusted mean coverage depth of 350x (50x minimum, or supplemented with additional analysis). Variants classified as pathogenic or likely pathogenic are confirmed with orthogonal methods, except individual variants that have high quality scores and previously validated in at least ten unrelated samples.

Our analysis detects most intragenic deletions and duplications at single exon resolution. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. If you are requesting the detection of a specific single-exon copy number variation, please contact Client Services before placing your order.

Gene Transcript reference Sequencing analysis Deletion/Duplication analysis
ATP7A NM_000052.6
BICD2 NM_001003800.1
BSCL2 NM_032667.6; NM_001122955.3
CHCHD10 NM_213720.2; NM_001301339.1
DCTN1 NM_004082.4
DNAJB2 NM_001039550.1
DYNC1H1 NM_001376.4
FBXO38 NM_030793.4
GARS NM_002047.2
HINT1 NM_005340.6
HSPB1 NM_001540.3
HSPB3 NM_006308.2
HSPB8 NM_014365.2
IGHMBP2 NM_002180.2
PLEKHG5 NM_020631.4
REEP1 NM_022912.2
SIGMAR1 NM_005866.3
SLC5A7 NM_021815.2
SMN1, SMN2* SMN1: NM_000344.3, SMN2: NM_017411.3
TRPV4 NM_021625.4
UBA1 NM_003334.3
VAPB NM_004738.4
VRK1 NM_003384.2

SMN1, SMN2: The SMN1 gene is identical to the SMN2 gene with the exception of exon 8 (typically referred to as exon 7). This assay unambiguously detects SMN1 exon 8 copy number and sequence variants. Sequence variants outside of exon 8 will also be detected, but this assay cannot determine whether the variant is located in SMN1 or SMN2. SMN2 exon 8 copy number will be reported for individuals with a positive result in SMN1. CNVs in exons 1-7 of SMN1 or SMN2 (typically referred to as exons 1-6 in the literature) will not be reported. This assay cannot detect silent carriers (individuals that have 2 functional copies of SMN1 on one chromosome and zero copies on the other). Therefore a negative result for carrier testing greatly reduces but does not eliminate the chance that a person is a carrier.