Forms

Frontotemporal Dementia via the GRN Gene

  • Summary and Pricing
  • Clinical Features and Genetics
  • Citations
  • Methods
  • Ordering/Specimens
Order Kits
TEST METHODS

Sequencing

Test Code Test Copy GenesIndividual Gene PriceCPT Code Copy CPT Codes
1610 GRN$870.00 81406 Add to Order
Targeted Testing

For ordering targeted known variants, please proceed to our Targeted Variants landing page.

Turnaround Time

The great majority of tests are completed within 18 days.

Clinical Sensitivity
Pathogenic variants in the GRN gene account for up to 23 % of FTD familial cases and 5.8 % of simplex cases (Baker et al. 2006; Gass et al. 200; Chen-Plotkin et al. 2011).

See More

See Less

Clinical Features
Frontotemporal dementia (FTD), previously referred to as Pick’s disease, is a clinically heterogeneous syndrome due to the progressive degeneration and atrophy of various regions of the frontal and temporal lobes of the brain. Symptoms are insidious and begin usually during the fourth and sixth decades of life; although earlier and later onset have been documented (Snowden et al. 2002; Bruni et al. 2007 ). 

Two major forms, the behavioral-variant (FTD-bv) and the primary progressive aphasia (PPA), are recognized based on the site of onset of degeneration and the associated symptoms.

In FTD-bv the degenerative process begins in the frontal lobes and results in personality changes and deterioration of social conducts. Most common behavioral changes are: disinhibition, apathy, deterioration of executive function, obsessive thoughts, compulsive behavior, and neglect of personal hygiene.

In PPA the degenerative process begins in the temporal lobes. PPA is a language disorder that is further divided into two sub-forms: progressive non-fluent aphasia (PNFA) and semantic dementia (SD). PNFA is characterized by difficulty in verbal communications, word retrieval, and speech distortion. Reading, writing and spelling are also affected; while memory is relatively preserved. SD is characterized by the progressive impairment of word comprehension, object and face recognition, and loss of semantic memory. Reading and writing skills are relatively preserved (Gustafson et al. 1993). 

The clinical diagnosis of FTD is based on the combination of medical history, physical and neurological examination, brain imaging, and neuropsychological and psychiatric assessment (Neary et al. 1998; Snowden 2002; Rascovsky et al 2011; Mesulam 2001).

FTD affects people worldwide, with a prevalence of up to 15 per 100,000 (Ratnavalli et al. 2002).  It is the second most common dementia in people under the age of 65 years, after Alzheimer's disease, accounting for up to 20% of presenile dementia cases (Snowden et al. 2002).
Genetics
FTD is inherited in about 40% of cases (Rosso et al. 2003).  In these families, the disease is inherited in an autosomal dominant manner. The remaining cases appear to be simplex with no known affected relatives. It is, however, unclear how many of the apparently sporadic cases are inherited with low penetrance (Cruts et al. 2006;  Le Ber et al. 2007).

FTD is genetically heterogeneous. Several genes have been implicated in the disorder: C9orf72, GRN, MAPT, CHMPEB, TARDBP, FUS and VCP.

Pathogenic variants in the GRN gene account for up to 23 % of FTD familial cases and 5.8 % of simplex cases (Baker et al. 2006; Gass et al. 2006; Chen-Plotkin et al. 2011).

About 120 different GRN pathogenic variants, distributed along the entire coding region of the gene, have been reported in patients with the various forms of FTD.  Although the majority of variants are of the types that are expected to result in a truncated protein, missense variants that are predicted to result in amino acid substitutions have been documented (Human Gene Mutation Database; Cruts et al. 2006; van der Zee et al. 2007).

There are no clear genotype-phenotype correlations.  The same pathogenic variants result in various clinical presentations even within members of the same family, suggesting the involvement of genetic and environmental modifying factors (Hsiung and Feldman 2013).

In addition to FTD, a homozygous truncating variant was reported to cause an adult form of neuronal ceroid lipofuscinosis (Smith et al. 2012). See also the description for Test #1909.

The progranulin protein, also known as granulin, is a growth factor involved in various cellular functions, including neuronal survival (He and Bateman 2003).  Its loss affects normal neurite outgrowth and branching (Gass et al. 2012).
Testing Strategy
 This test involves bidirectional DNA Sanger sequencing of all coding exons and splice sites of the GRN gene. The full coding sequence of each exon plus ~ 20 bp of flanking DNA on either side are sequenced. We will also sequence any single exon (Test #100) in family members of patients with a known mutation or to confirm research results.
Indications for Test
All patients with symptoms and MRI findings suggestive of FTD-bv or PPA, as described (Neary 1998; Snowden 2002; Rascovsky et al 2011; Mesulam 2001).

Gene

Official Gene Symbol OMIM ID
GRN 138945
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Disease

Name Inheritance OMIM ID
Frontotemporal Dementia, Ubiquitin-Positive 607485

Related Tests

Name
Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Sequencing Panel
Neuronal Ceroid Lipofuscinoses (Batten Disease) Sequencing Panel

CONTACTS

Genetic Counselors
Geneticist
Citations
  • Baker M, Mackenzie IR, Pickering-Brown SM, Gass J, Rademakers R, Lindholm C, Snowden J, Adamson J, Sadovnick AD, Rollinson S, Cannon A, Dwosh E, et al. 2006. Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17. Nature 442: 916–919. PubMed ID: 16862116
  • Bruni A.C. et al. 2007. Neurology. 69: 140-7. PubMed ID: 17620546
  • Chen-Plotkin AS, Martinez-Lage M, Sleiman PMA, Hu W, Greene R, Wood EM, Bing S, Grossman M, Schellenberg GD, Hatanpaa KJ, Weiner MF, White CL, et al. 2011. Genetic and Clinical Features of Progranulin-Associated Frontotemporal Lobar Degeneration. Archives of Neurology 68: 488. PubMed ID: 21482928
  • Cruts M, Gijselinck I, Zee J van der, Engelborghs S, Wils H, Pirici D, Rademakers R, Vandenberghe R, Dermaut B, Martin J-J, Duijn C van, Peeters K, Sciot R, Santens P, De Pooter T, Mattheijssens M, Van den Broeck M, Cuijt I, Vennekens K, De Deyn PP, Kumar-Singh S, Van Broeckhoven C. 2006. Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21. Nature 442: 920–924. PubMed ID: 16862115
  • Gass J, Cannon A, Mackenzie IR, Boeve B, Baker M, Adamson J, Crook R, Melquist S, Kuntz K, Petersen R, Josephs K, Pickering-Brown SM, et al. 2006. Mutations in progranulin are a major cause of ubiquitin-positive frontotemporal lobar degeneration. Hum. Mol. Genet. 15: 2988–3001. PubMed ID: 16950801
  • Gass J, Lee WC, Cook C, Finch N, Stetler C, Jansen-West K, Lewis J, Link CD, Rademakers R, Nykjær A, Petrucelli L. 2012. Progranulin regulates neuronal outgrowth independent of Sortilin. Molecular Neurodegeneration 7: 33. PubMed ID: 22781549
  • Gustafson L. 1993. Dementia. 4: 143-8. PubMed ID: 8401782
  • He Z, Bateman A. 2003. Progranulin (granulin-epithelin precursor, PC-cell-derived growth factor, acrogranin) mediates tissue repair and tumorigenesis. J. Mol. Med. 81: 600–612. PubMed ID: 12928786
  • Hsiung G-YR, Feldman HH. 2013. GRN-Related Frontotemporal Dementia. In: Pagon RA, Adam MP, Ardinger HH, Bird TD, Dolan CR, Fong C-T, Smith RJ, and Stephens K, editors. GeneReviews(®), Seattle (WA): University of Washington, Seattle. PubMed ID: 20301545
  • Human Gene Mutation Database (Bio-base).
  • Le Ber I, Zee J van der, Hannequin D, Gijselinck I, Campion D, Puel M, Laquerrière A, Pooter T De, Camuzat A, Broeck M Van den, Dubois B, Sellal F, Lacomblez L, Vercelletto M, Thomas-Antérion C, Michel BF, Golfier V, Didic M, Salachas F, Duyckaerts C, Cruts M, Verpillat P, Van Broeckhoven C, Brice A; French Research Network on FTD/FTD-MND. 2007. Progranulin null mutations in both sporadic and familial frontotemporal dementia. Human Mutation 28: 846–855. PubMed ID: 17436289
  • Mesulam M.M. 2001. Primary progressive aphasia. Ann. Neurol. 49: 425–432. PubMed ID: 11310619
  • Neary D. et al. 1998. Neurology. 51: 1546-54. PubMed ID: 9855500
  • Rascovsky K. et al. 2011. Brain : a Journal of Neurology. 134: 2456-77. PubMed ID: 21810890
  • Ratnavalli E. et al. 2002. Neurology. 58: 1615-21. PubMed ID: 12058088
  • Rosso S.M. et al. 2003. Brain : a Journal of Neurology. 126: 2016-22. PubMed ID: 12876142
  • Smith KR, Damiano J, Franceschetti S, Carpenter S, Canafoglia L, Morbin M, Rossi G, Pareyson D, Mole SE, Staropoli JF, Sims KB, Lewis J, et al. 2012. Strikingly Different Clinicopathological Phenotypes Determined by Progranulin-Mutation Dosage. Am J Hum Genet 90: 1102–1107. PubMed ID: 22608501
  • Snowden J.S. 2002. Frontotemporal dementia. The British Journal of Psychiatry 180: 140-3. PubMed ID: 11823324
  • van der Zee J, Ber I Le, Maurer-Stroh S, Engelborghs S, Gijselinck I, Camuzat A, Brouwers N, Vandenberghe R, Sleegers K, Hannequin D, Dermaut B, Schymkowitz J, et al. 2007. Mutations other than null mutations producing a pathogenic loss of progranulin in frontotemporal dementia. Human Mutation 28: 416–416. PubMed ID: 17345602
Order Kits
TEST METHODS

Bi-Directional Sanger Sequencing

Test Procedure

Nomenclature for sequence variants was from the Human Genome Variation Society (http://www.hgvs.org).  As required, DNA is extracted from the patient specimen.  PCR is used to amplify the indicated exons plus additional flanking non-coding sequence.  After cleaning of the PCR products, cycle sequencing is carried out using the ABI Big Dye Terminator v.3.0 kit.  Products are resolved by electrophoresis on an ABI 3730xl capillary sequencer.  In most cases, sequencing is performed in both forward and reverse directions; in some cases, sequencing is performed twice in either the forward or reverse directions.  In nearly all cases, the full coding region of each exon as well as 20 bases of non-coding DNA flanking the exon are sequenced.

Analytical Validity

As of March 2016, we compared 17.37 Mb of Sanger DNA sequence generated at PreventionGenetics to NextGen sequence generated in other labs. We detected only 4 errors in our Sanger sequences, and these were all due to allele dropout during PCR. For Proficiency Testing, both external and internal, in the 12 years of our lab operation we have Sanger sequenced roughly 8,800 PCR amplicons. Only one error has been identified, and this was due to sequence analysis error.

Our Sanger sequencing is capable of detecting virtually all nucleotide substitutions within the PCR amplicons. Similarly, we detect essentially all heterozygous or homozygous deletions within the amplicons. Homozygous deletions which overlap one or more PCR primer annealing sites are detectable as PCR failure. Heterozygous deletions which overlap one or more PCR primer annealing sites are usually not detected (see Analytical Limitations). All heterozygous insertions within the amplicons up to about 100 nucleotides in length appear to be detectable. Larger heterozygous insertions may not be detected. All homozygous insertions within the amplicons up to about 300 nucleotides in length appear to be detectable. Larger homozygous insertions may masquerade as homozygous deletions (PCR failure).

Analytical Limitations

In exons where our sequencing did not reveal any variation between the two alleles, we cannot be certain that we were able to PCR amplify both of the patient’s alleles. Occasionally, a patient may carry an allele which does not amplify, due for example to a deletion or a large insertion. In these cases, the report contains no information about the second allele.

Similarly, our sequencing tests have almost no power to detect duplications, triplications, etc. of the gene sequences.

In most cases, only the indicated exons and roughly 20 bp of flanking non-coding sequence on each side are analyzed. Test reports contain little or no information about other portions of the gene, including many regulatory regions.

In nearly all cases, we are unable to determine the phase of sequence variants. In particular, when we find two likely causative mutations for recessive disorders, we cannot be certain that the mutations are on different alleles.

Our ability to detect minor sequence variants, due for example to somatic mosaicism is limited. Sequence variants that are present in less than 50% of the patient’s nucleated cells may not be detected.

Runs of mononucleotide repeats (eg (A)n or (T)n) with n >8 in the reference sequence are generally not analyzed because of strand slippage during PCR and cycle sequencing.

Unless otherwise indicated, the sequence data that we report are based on DNA isolated from a specific tissue (usually leukocytes). Test reports contain no information about gene sequences in other tissues.

Order Kits

Ordering Options


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.
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.

SPECIMEN TYPES
WHOLE BLOOD

(Delivery accepted Monday - Saturday)

  • Collect 3 ml -5 ml (5 ml preferred) of whole blood in EDTA (purple top tube) or ACD (yellow top tube). For Test #500-DNA Banking only, collect 10 ml -20 ml of whole blood.
  • For small babies, we require a minimum of 1 ml of blood.
  • Only one blood tube is required for multiple tests.
  • Ship blood tubes at room temperature in an insulated container. Do not freeze blood.
  • During hot weather, include a frozen ice pack in the shipping container. Place a paper towel or other thin material between the ice pack and the blood tube.
  • In cold weather, include an unfrozen ice pack in the shipping container as insulation.
  • At room temperature, blood specimen is stable for up to 48 hours.
  • If refrigerated, blood specimen is stable for up to one week.
  • Label the tube with the patient name, date of birth and/or ID number.

DNA

(Delivery accepted Monday - Saturday)

  • Send in screw cap tube at least 5 µg -10 µg of purified DNA at a concentration of at least 20 µg/ml for NGS and Sanger tests and at least 5 µg of purified DNA at a concentration of at least 100 µg/ml for gene-centric aCGH, MLPA, and CMA tests, minimum 2 µg for limited specimens.
  • For requests requiring more than one test, send an additional 5 µg DNA per test ordered when possible.
  • DNA may be shipped at room temperature.
  • Label the tube with the composition of the solute, DNA concentration as well as the patient’s name, date of birth, and/or ID number.
  • We only accept genomic DNA for testing. We do NOT accept products of whole genome amplification reactions or other amplification reactions.

CELL CULTURE

(Delivery preferred Monday - Thursday)

  • PreventionGenetics should be notified in advance of arrival of a cell culture.
  • Culture and send at least two T25 flasks of confluent cells.
  • Some panels may require additional flasks (dependent on size of genes, amount of Sanger sequencing required, etc.). Multiple test requests may also require additional flasks. Please contact us for details.
  • Send specimens in insulated, shatterproof container overnight.
  • Cell cultures may be shipped at room temperature or refrigerated.
  • Label the flasks with the patient name, date of birth, and/or ID number.
  • We strongly recommend maintaining a local back-up culture. We do not culture cells.
loading Loading... ×