Frontotemporal Dementia via the MAPT Gene
- Summary and Pricing
- Clinical Features and Genetics
|Test Code||Test||Individual Gene Price||CPT Code Copy CPT Codes|
Our most cost-effective testing approach is NextGen sequencing with Sanger sequencing supplemented as needed to ensure sufficient coverage and to confirm NextGen calls that are pathogenic, likely pathogenic or of uncertain significance. If, however, full gene Sanger sequencing only is desired (for purposes of insurance billing or STAT turnaround time for example), please see link below for Test Code, pricing, and turnaround time information.
For ordering targeted known variants, please proceed to our Targeted Variants landing page.
The great majority of tests are completed within 28 days.
Pathogenic variants in the MAPT gene account for up to 9% of patients with a clinical diagnosis of frontotemporal dementia (Pickering-Brown et al. 2008; Rohrer et al. 2009).
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).
FTD is inherited in about 40% of cases (Rosso et al. 2003). About 10% of these families have a history of dementia or a related condition that is inherited in an autosomal dominant manner. Because several symptoms of FTD overlap with symptoms of other psychiatric disorders, and because of incomplete family history, the mode of transmission of FTD could not be established in most families (Pickering-Brown et al. 2008; Rohrer et al. 2009).
FTD is genetically heterogeneous. Several genes have been implicated in the disorder: C9orf72, GRN, MAPT, CHMPEB, TARDBP, FUS and VCP.
Pathogenic variants in the MAPT gene account for up to 9% of patients with a clinical diagnosis of FTD (Pickering-Brown et al. 2008; Rohrer et al. 2009). About 70 different MAPT pathogenic variants have been reported in patients with the various forms of FTD. They include both missense and truncating variants and are usually classified in two categories. The first category includes missense variants and small deletions in the coding region of the gene; they affect the ability of the tau protein to associate with microtubules. The second category includes splicing variants, missense and silence variants, which affect the alternative splicing of exon 10. This results in the alteration of the isoform ratio and the development of FTD (Hutton et al. 1998; Spillantini et al. 1998). Large pathogenic copy number variations appear to be a rare cause of FTD. To date, only one large deletion has been reported (Human Gene Mutation Database; Rovelet-Lecrux et al. 2009).
In addition to FTD, MAPT pathogenic variants were reported in patients with progressive supranuclear palsy (Ros et al. 2005).
The MAPT gene encodes microtubule-associated protein tau. Through alternative splicing, the primary transcript produces six different isoforms that are differentially expressed during development and appear to have differential physiological roles (D’Souza et al. 2005).
For this NextGen test, the full coding regions plus ~20 bp of non-coding DNA flanking each exon are sequenced for the gene listed below. Sequencing is accomplished by capturing specific regions with an optimized solution-based hybridization kit, followed by massively parallel sequencing of the captured DNA fragments. Additional Sanger sequencing is performed for any regions not captured or with insufficient number of sequence reads. All pathogenic, likely pathogenic, or variants of uncertain significance are confirmed by Sanger sequencing.
Indications for Test
All patients with symptoms and MRI findings suggestive of FTD-bv or PPA (Neary et al. 1998; Snowden 2002; Rascovsky et al. 2011; Mesulam 2001).
|Official Gene Symbol||OMIM ID|
|Supranuclear Palsy, Progressive, 1||AD||601104|
|Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Sequencing Panel|
|Frontotemporal Dementia via the GRN Gene|
- Genetic Counselor Team - email@example.com
- Khemissa Bejaoui, PhD - firstname.lastname@example.org
- Bruni A.C. et al. 2007. Neurology. 69: 140-7. PubMed ID: 17620546
- Gustafson L. 1993. Dementia. 4: 143-8. PubMed ID: 8401782
- Human Gene Mutation Database (Bio-base).
- Hutton M. et al. 1998. Nature. 393: 702-5. PubMed ID: 9641683
- 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
- Pickering-Brown S.M. et al. 2008. Brain. 131: 721-31. PubMed ID: 18192287
- 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
- Rohrer J.D. et al. 2009. Neurology. 73: 1451-6. PubMed ID: 19884572
- Ros R. et al. 2005. Archives of Neurology. 62: 1444-50. PubMed ID: 16157753
- Rosso S.M. et al. 2003. Brain. 126: 2016-22. PubMed ID: 12876142
- Rovelet-Lecrux A. et al. 2009. Human Mutation. 30: E591-E602. PubMed ID: 19263483
- Snowden J.S. 2002. The British Journal of Psychiatry 180: 140-3. PubMed ID: 11823324
- Spillantini M.G. et al. 1998. Proceedings of the National Academy of Sciences of the United States of America. 95: 7737-41. PubMed ID: 9636220
We use a combination of Next Generation Sequencing (NGS) and Sanger sequencing technologies to cover the full coding regions of the listed genes plus ~20 bases of non-coding DNA flanking each exon. As required, genomic DNA is extracted from the patient specimen. For NGS, patient DNA corresponding to these regions is captured using an optimized set of DNA hybridization probes. Captured DNA is sequenced using Illumina’s Reversible Dye Terminator (RDT) platform (Illumina, San Diego, CA, USA). Regions with insufficient coverage by NGS are covered by Sanger sequencing. All pathogenic, likely pathogenic, or variants of uncertain significance are confirmed by Sanger sequencing.
For Sanger sequencing, Polymerase Chain Reaction (PCR) is used to amplify targeted regions. After purification of the PCR products, cycle sequencing is carried out using the ABI Big Dye Terminator v.3.0 kit. PCR products are resolved by electrophoresis on an ABI 3730xl capillary sequencer. In nearly all cases, cycle sequencing is performed separately in both the forward and reverse directions.
Patient DNA sequence is aligned to the genomic reference sequence for the indicated gene region(s). All differences from the reference sequences (sequence variants) are assigned to one of five interpretation categories, listed below, per ACMG Guidelines (Richards et al. 2015).
(1) Pathogenic Variants
(2) Likely Pathogenic Variants
(3) Variants of Uncertain Significance
(4) Likely Benign Variants
(5) Benign, Common Variants
Human Genome Variation Society (HGVS) recommendations are used to describe sequence variants (http://www.hgvs.org). Rare variants and undocumented variants are nearly always classified as likely benign if there is no indication that they alter protein sequence or disrupt splicing.
As of March 2016, 6.36 Mb of sequence (83 genes, 1557 exons) generated in our lab was compared between Sanger and NextGen methodologies. We detected no differences between the two methods. The comparison involved 6400 total sequence variants (differences from the reference sequences). Of these, 6144 were nucleotide substitutions and 256 were insertions or deletions. About 65% of the variants were heterozygous and 35% homozygous. The insertions and deletions ranged in length from 1 to over 100 nucleotides.
In silico validation of insertions and deletions in 20 replicates of 5 genes was also performed. The validation included insertions and deletions of lengths between 1 and 100 nucleotides. Insertions tested in silico: 2200 between 1 and 5 nucleotides, 625 between 6 and 10 nucleotides, 29 between 11 and 20 nucleotides, 25 between 21 and 49 nucleotides, and 23 at or greater than 50 nucleotides, with the largest at 98 nucleotides. All insertions were detected. Deletions tested in silico: 1813 between 1 and 5 nucleotides, 97 between 6 and 10 nucleotides, 32 between 11 and 20 nucleotides, 20 between 21 and 49 nucleotides, and 39 at or greater than 50 nucleotides, with the largest at 96 nucleotides. All deletions less than 50 nucleotides in length were detected, 13 greater than 50 nucleotides in length were missed. Our standard NextGen sequence variant calling algorithms are generally not capable of detecting insertions (duplications) or heterozygous deletions greater than 100 nucleotides. Large homozygous deletions appear to be detectable.
Interpretation of the test results is limited by the information that is currently available. Better interpretation should be possible in the future as more data and knowledge about human genetics and this specific disorder are accumulated.
When Sanger sequencing does not reveal any difference from the reference sequence, or when a sequence variant is homozygous, we cannot be certain that we were able to detect both patient alleles. Occasionally, a patient may carry an allele which does not amplify, due to a large deletion or insertion. In these cases, the report will contain no information about the second allele. Our Sanger and NGS Sequencing tests are generally not capable of detecting Copy Number Variants (CNVs).
We sequence all coding exons for each given transcript, plus ~20 bp of flanking non-coding DNA for each exon. Test reports contain no information about other portions of the gene, such as regulatory domains, deep intronic regions or any currently uncharacterized alternative exons.
In most 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 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.
Unless otherwise indicated, DNA sequence data is obtained from a specific cell-type (usually leukocytes from whole blood). Test reports contain no information about the DNA sequence in other cell-types.
We cannot be certain that the reference sequences are correct.
Rare, low probability interpretations of sequencing results, such as for example the occurrence of de novo mutations in recessive disorders, are generally not included in the reports.
We have confidence in our ability to track a specimen once it has been received by PreventionGenetics. However, we take no responsibility for any specimen labeling errors that occur before the sample arrives at PreventionGenetics.
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.
- The first four pages of the requisition form must accompany all specimens.
- Billing information is on the third and fourth pages.
- Specimen and shipping instructions are listed on the fifth and sixth pages.
- All testing must be ordered by a qualified healthcare provider.
(Delivery accepted Monday - Saturday)
- Collect 3-5 ml (5 ml preferred) of whole blood in EDTA (purple top tube) or ACD (yellow top tube). For Test #500-DNA Banking only, collect 10-20 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 good for up to 48 hours.
- If refrigerated, blood specimen is good for up to one week.
- Label the tube with the patient name, date of birth and/or ID number.
(Delivery accepted Monday - Saturday)
- NextGen Sequencing Tests: Send in screw cap tube at least 10 µg of purified DNA at a concentration of at least 50 µg/ml
- Sanger Sequencing Tests: Send in a screw cap tube at least 15 µg of purified DNA at a concentration of at least 20 µg/ml. For tests involving the sequencing of more than three genes, send an additional 5 µg DNA per gene. DNA may be shipped at room temperature.
- Deletion/Duplication via aCGH: Send in screw cap tube at least 1 µg of purified DNA at a concentration of at least 100 µg/ml.
- Whole-Genome Chromosomal Microarray: Collect at least 5 µg of DNA in TE (10 mM Tris-cl pH 8.0, 1mM EDTA), dissolved in 200 µl at a concentration of at least 100 ng/ul (indicate concentration on tube label). DNA extracted using a column-based method (Qiagen) or bead-based technology is preferred.
(Delivery accepted Monday - Thursday)
- PreventionGenetics should be notified in advance of arrival of a cell culture.
- Ship at least two T25 flasks of confluent cells.
- Label the flasks with the patient name, date of birth, and/or ID number.
- We do not culture cells.