Amyotrophic Lateral Sclerosis/Motor Neuron Disease via the PFN1 Gene
Summary and Pricing 
Test Method
Sequencing and CNV Detection via NextGen Sequencing using PG-Select Capture Probes| Test Code | Test Copy Genes | Test CPT Code | Gene CPT Codes Copy CPT Code | Base Price | |
|---|---|---|---|---|---|
| 8947 | PFN1 | 81479 | 81479,81479 | $990 | Order Options and Pricing |
Pricing Comments
Testing run on PG-select capture probes includes CNV analysis for the gene(s) on the panel but does not permit the optional add on of exome-wide CNV analysis. Any of the NGS platforms allow reflex to other clinically relevant genes, up to whole exome or whole genome sequencing depending upon the base platform selected for the initial test.
An additional 25% charge will be applied to STAT orders. STAT orders are prioritized throughout the testing process.
This test is also offered via a custom panel (click here) on our exome or genome backbone which permits the optional add on of exome-wide CNV or genome-wide SV analysis.
Turnaround Time
3 weeks on average for standard orders or 2 weeks on average for STAT orders.
Please note: Once the testing process begins, an Estimated Report Date (ERD) range will be displayed in the portal. This is the most accurate prediction of when your report will be complete and may differ from the average TAT published on our website. About 85% of our tests will be reported within or before the ERD range. We will notify you of significant delays or holds which will impact the ERD. Learn more about turnaround times here.
Targeted Testing
For ordering sequencing of targeted known variants, go to our Targeted Variants page.
Clinical Features and Genetics
Clinical Features
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by a selective loss of motor neurons in the motor cortex, brain steam, and spinal cord (Tandan and Bradley 1985). The dysfunction and loss of these neurons results in rapid progressive muscle weakness, atrophy and ultimately paralysis of limb, bulbar and respiratory muscles. The mean age of onset of symptoms is about 55 years of age; most cases begin between 40 and 70 years of age. The annual incidence of ALS is 1-2 per 100,000 (Cleveland and Rothstein 2001).
The most common symptoms include twitching and cramping of muscles of the hands and feet, loss of motor control in the hands and arms, weakness and fatigue, tripping and falling. Symptoms usually begin with asymmetric involvement of the muscles. As the disease progresses, symptoms may include difficulty in talking, breathing and swallowing, shortness of breath, and paralysis.
Cognitive impairment has not been initially associated with ALS. However, frontotemporal dementia (FTD) has been reported in several cases. Dementia has been documented in patients with ALS from different ethnic groups and affects both males and females (Wikström et al. 1982; Lipton, et al. 2004; Mitsuyama and Inoue 2009).
Genetics
About 10% of ALS cases are familial (Emery and Holloway 1982). In most of these families, ALS is inherited in an autosomal dominant manner (AD-ALS) and is age-dependent with high penetrance. In rare families, the disease is transmitted in an autosomal recessive or dominant X-linked pattern.
About 90% of patients with ALS are sporadic cases (SALS) with no known affected relatives. It is unclear how many of the apparently sporadic cases are inherited with low penetrance. The clinical presentations of familial ALS (FALS) and sporadic ALS (SALS) are similar. However, the onset of symptoms in FALS is usually earlier compared to that of SALS (Kinsley and Siddique 2012).
Autosomal Dominant ALS (AD-ALS) is a clinically and genetically heterogeneous disorder that affects all ethnic groups. At least thirteen genetic loci have been reported. Several genes have been identified and include C9orf72, SOD1, FUS, TARDBP, ANG, OPTN, VCP, and VAPB.
Recently, pathogenic variants in the PFN1 gene have been reported in eight families with autosomal dominant ALS (AD-FALS). A total of four different variants, all missense, have been documented to segregate with the disease in families with a history of ALS (Wu et al. 2012; Ingre et al. 2013).
A small indel, defined as c.350_351delAAinsGT, and predicted to result in the amino acid substitution p.Glu117Gly was detected both in patients and healthy control individuals by several groups (Wu et al. 2012; Ingre et al. 2013; Chen et al. 2013; Tiloca et al. 2013). It was, therefore, suggested that the c.350_351delAAinsGT variant could be either a rare benign variant or a pathogenic variant resulting in a mild phenotype (Wu et al. 2012).
All patients with pathogenic PFN1 variants reported to date presented with the classic form of ALS, without apparent cognitive involvement.
The PFN1 gene encodes Profilin-1, an actin-binding protein, which is involved in cytoskeletal organization.
Clinical Sensitivity - Sequencing with CNV PG-Select
Pathogenic variants in the PFN1 gene were detected in about 2% of AD-ALS cases without pathogenic variants in C9orf72, SOD1, FUS, TARDBP, ANG, VCP, and VAPB (Wu et al. 2012).
Testing Strategy
This test provides full coverage of all coding exons of the PFN1 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.
Indications for Test
All patients with symptoms suggestive of ALS or Motor Neuron Disease, and no pathogenic variants in the C9orf72, SOD1, FUS, TARDBP, ANG, OPTN, VCP, and VAPB genes.
All patients with symptoms suggestive of ALS or Motor Neuron Disease, and no pathogenic variants in the C9orf72, SOD1, FUS, TARDBP, ANG, OPTN, VCP, and VAPB genes.
Gene
| Official Gene Symbol | OMIM ID |
|---|---|
| PFN1 | 176610 |
| Inheritance | Abbreviation |
|---|---|
| Autosomal Dominant | AD |
| Autosomal Recessive | AR |
| X-Linked | XL |
| Mitochondrial | MT |
Disease
| Name | Inheritance | OMIM ID |
|---|---|---|
| Amyotrophic Lateral Sclerosis Type 18 | 614808 |
Related Tests
Citations
- Chen Y, Zheng ZZ, Huang R, Chen K, Song W, Zhao B, Chen X, Yang Y, Yuan L, Shang HF. 2013. PFN1 mutations are rare in Han Chinese populations with amyotrophic lateral sclerosis. Neurobiol Aging 34:1922.e1-5. PubMed ID: 23428184
- Cleveland D.W., Rothstein J.D. 2001. Nature Reviews. Neuroscience. 2: 806-19. PubMed ID: 11715057
- Emery A.E., Holloway S. 1982. Advances in Neurology. 36: 139-47. PubMed ID: 7180680
- Ingre C, Landers JE, Rizik N, Volk AE, Akimoto C, Birve A, Hübers A, Keagle PJ, Piotrowska K, Press R, Andersen PM, Ludolph AC, Weishaupt JH. 2013. A novel phosphorylation site mutation in profilin 1 revealed in a large screen of US, Nordic, and German amyotrophic lateral sclerosis/frontotemporal dementia cohorts. Neurobiol Aging 34:1708.e1-6. PubMed ID: 23141414
- Kinsley L, Siddique T. 2015 Amyotrophic Lateral Sclerosis Overview. In: Pagon RA, Adam MP, Bird TD, Dolan CR, Fong C-T, and Stephens K, editors. GeneReviews™, Seattle (WA): University of Washington, Seattle. PubMed ID: 20301623
- Lipton A.M. et al. 2004. Acta Neuropathologica. 108: 379-85. PubMed ID: 15351890
- Mitsuyama Y., Inoue T. 2009. Neuropathology : Official Journal of the Japanese Society of Neuropathology. 29: 649-54. PubMed ID: 19780984
- Tandan R., Bradley W.G. 1985. Annals of Neurology. 18: 271-80. PubMed ID: 4051456
- Tiloca C, Ticozzi N, Pensato V, Corrado L, Del Bo R, Bertolin C, Fenoglio C, Gagliardi S, Calini D, Lauria G, Castellotti B, Bagarotti A, Corti S, Galimberti D, Cagnin A, Gabelli C, Ranieri M, Ceroni M, Siciliano G, Mazzini L, Cereda C, Scarpini E, Sorarù G, Comi GP, D'Alfonso S, Gellera C, Ratti A, Landers JE, Silani V; SLAGEN Consortium. 2013. Screening of the PFN1 gene in sporadic amyotrophic lateral sclerosis and in frontotemporal dementia. Neurobiol Aging 34:1517.e9-10. PubMed ID: 23063648
- Wikström J. et al. 1982. Archives of Neurology. 39: 681-3. PubMed ID: 7125994
- Wu CH, Fallini C, Ticozzi N, Keagle PJ, Sapp PC, Piotrowska K, Lowe P, Koppers M, McKenna-Yasek D, Baron DM, Kost JE, Gonzalez-Perez P, Fox AD, Adams J, Taroni F, Tiloca C, Leclerc AL, Chafe SC, Mangroo D, Moore MJ, Zitzewitz JA, Xu ZS, van den Berg LH, Glass JD, Siciliano G, Cirulli ET, Goldstein DB, Salachas F, Meininger V, Rossoll W, Ratti A, Gellera C, Bosco DA, Bassell GJ, Silani V, Drory VE, Brown RH Jr, Landers JE. 2012. Mutations in the profilin 1 gene cause familial amyotrophic lateral sclerosis. Nature 488:499-503. PubMed ID: 22801503
Ordering/Specimens
Ordering Options
We offer several options when ordering sequencing tests. For more information on these options, see our Ordering Instructions page. To view available options, click on the Order Options button within the test description.
myPrevent - Online Ordering
- The test can be added to your online orders in the Summary and Pricing section.
- Once the test has been added log in to myPrevent to fill out an online requisition form.
- PGnome sequencing panels can be ordered via the myPrevent portal only at this time.
Requisition Form
- A completed requisition form must accompany all specimens.
- Billing information along with specimen and shipping instructions are within the requisition form.
- All testing must be ordered by a qualified healthcare provider.
For Requisition Forms, visit our Forms page
If ordering a Duo or Trio test, the proband and all comparator samples are required to initiate testing. If we do not receive all required samples for the test ordered within 21 days, we will convert the order to the most effective testing strategy with the samples available. Prior authorization and/or billing in place may be impacted by a change in test code.
Specimen Types
Specimen Requirements and Shipping Details
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