The Invitae Frontotemporal Dementia Panel analyzes up to 13 genes associated with frontotemporal dementia (FTD), a neurodegenerative disorder characterized by progressive behavioral and cognitive impairment. The genes on the Invitae Frontotemporal Dementia Panel were curated based on the available evidence to date in order to provide analysis for a number of newly characterized FTD genes along with well-known genetic causes of FTD, with the exception of the C9orf72 gene, which is not included in this panel and is thought to be the most common genetic cause of both FTD and ALS. C9orf72 hexanucleotide repeat expansion testing is considered first-line genetic testing for individuals with a personal and/or family history of FTD and/or ALS. The Invitae Frontotemporal Dementia Panel should only be considered in individuals who have previously had negative C9orf72 testing.
Individuals with a clinical diagnosis of FTD, especially those with a family history of FTD and/or ALS, may benefit from diagnostic genetic testing. Identification of the molecular basis of FTD in an affected individual may help to confirm a suspected diagnosis, provide anticipatory guidance, determine which relatives may be at risk, and/or promote enrollment in clinical trials.
CHCHD10 DCTN1 FUS GRN MAPT TARDBP TBK1 UBQLN2 VCP
CHMP2B HNRNPA2B1 PSEN1 SQSTM1
The CHMP2B, HNRNPA2B1, PSEN1, and SQSTM1 genes currently have early evidence of a clinical association with frontotemporal dementia. 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.
CHCHD10 DCTN1 FUS GRN MAPT TARDBP TBK1 UBQLN2 VCP
The CHMP2B, HNRNPA2B1, PSEN1, and SQSTM1 genes currently have early evidence of a clinical association with frontotemporal dementia. 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.
CHMP2B HNRNPA2B1 PSEN1 SQSTM1
For a broader analysis of the genetics of hereditary dementia and ALS:
Clinicians may also consider the Invitae Hereditary Parkinson’s Disease and Parkinsonism panel for individuals with a personal or family history of Parkinson’s disease or parkinsonian features.
Frontotemporal dementia (FTD) is a neurodegenerative disorder characterized by progressive behavioral and cognitive impairment due to atrophy of the frontal and/or anterior temporal lobes of the brain. Age of onset is variable but most commonly occurs between the 40s and 60s. It is one of the most common types of dementia in individuals under the age of 65. The most common form of FTD is behavioral variant FTD (bvFTD), which is characterized by degeneration that begins in the frontal lobes of the brain, resulting in behavioral and personality changes including apathy, restlessness, disinhibition, compulsive behaviors, and hyperorality. Individuals often display a marked lack of insight into their symptoms. A subset of individuals present with language impairment caused by degeneration in the temporal lobes of the brain, categorized broadly as primary progressive aphasia, which can be further delineated as progressive nonfluent variant aphasia (PNFA) or 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 remains relatively intact. SD is characterized by progressive impairment of word comprehension, object and face recognition, and loss of semantic memory. Reading and writing skills are typically preserved. Other features of FTD may include stereotypies, mutism, and dystonia. Some affected individuals also develop features of motor neuron disease such as ALS or a movement disorder such as parkinsonism. Approximately 40% of FTD has a hereditary cause.
Gene | Inheritance | Associated neurological disorders | Proportion of FTD | |
---|---|---|---|---|
Autosomal dominant | X-linked | |||
CHCHD10 | ✓ | FTDALS2; Spinal muscular atrophy; Mitochondrial myopathy | Rare | |
CHMP2B* | ✓ | FTD3; ALS17 | Unknown | |
DCTN1 | ✓ | Perry Syndrome, which may present with features of ALS and/or FTD | ~100% of Perry Syndrome, rare cause of isolated ALS/FTD | |
FUS | ✓ | ALS6 | ~4% of familial ALS and approximately 1% of sporadic ALS with or without FTD | |
GRN | ✓ | FTD with TDP43 inclusions | 13-25% | |
HNRNPA2B1* | ✓ | Inclusion body myopathy with early-onset Paget disease with or without FTD 2 (IBMPFD2) | Unknown | |
MAPT | ✓ | FTD with or without parkinsonism; Pick disease | 15-20% | |
PSEN1* | ✓ | Alzheimer’s disease 3 (AD3); Pick disease; FTD; Dilated cardiomyopathy | Unknown | |
SQSTM1* | ✓ | FTDALS3; Paget disease of bone | Unknown | |
TARDBP | ✓ | ALS10; FTD with TDP43 inclusions | ~4% of familial ALS and ~1% of sporadic ALS with or without FTD | |
TBK1 | ✓ | FTDALS4 | 1-4% of hereditary FTD and/or ALS | |
UBQLN2 | ✓ | ALS15 | Rare | |
VCP | ✓ | Inclusion Body Myopathy with Paget Disease of Bone and/or Frontotemporal Dementia (IBMPFD); ALS14 | ~100% of individuals who meet diagnostic criteria for IBMPFD, ~1-2% of familial ALS with or without FTD |
*Preliminary-evidence gene
The clinical sensitivity of this panel is dependent on the patient’s true clinical diagnosis, which can often only be accurately determined upon autopsy. For each gene, the table in the Clinical description section above shows the percentage of clinical cases in which a pathogenic variant is expected. For some genes, the incidence is rare and the clinical sensitivity is unknown. The sensitivity of this test also depends on age of onset and family history.
It is important to note that pathogenic variants in the C9orf72 gene account for an estimated 25% of familial ALS, and this panel should only be considered in those who have already been tested for C9orf72 at an alternate laboratory.
The majority of hereditary forms of FTD are inherited in an autosomal dominant manner. The UBQLN2 gene is associated with X-linked ALS with or without FTD.
Hereditary FTD is associated with variable expressivity and age of onset, and penetrance is typically age-dependent and difficult to calculate for the majority of genes. Symptom expressivity varies even within families for the majority of genetic forms of FTD. Penetrance of GRN-related FTD has an estimated penetrance of 90% by 75 years of age. Reduced penetrance has been described for MAPT-related FTD.
The overall annual incidence of FTD has been estimated at 3.5 cases per 100,000 individuals aged 45-64 years. It is estimated that approximately 40% of all people with FTD have a hereditary form of the condition.
A genetic cause for FTD may be suspected in individuals who have:
In addition to meeting one of the above criteria, individuals considering genetic testing for hereditary forms of FTD should first receive thorough pre-test genetic counseling from a professional qualified to provide such counseling regarding the implications of testing for neurodegenerative disorders that have no known treatment or cure at this time.
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 and 10 to 20 base pairs of adjacent intronic sequence on either side of the coding exons in the transcript listed below. In addition, the analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any limitations in the analysis of these genes will be listed on the report. Contact client services with any questions.
Based on validation study results, this assay achieves >99% analytical sensitivity and specificity for single nucleotide variants, insertions and deletions <15bp in length, and exon-level deletions and duplications. Invitae's methods also detect insertions and deletions larger than 15bp but smaller than a full exon but sensitivity for these may be marginally reduced. Invitae’s deletion/duplication analysis determines copy number at a single exon resolution at virtually all targeted exons. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. Certain types of variants, such as structural rearrangements (e.g. inversions, gene conversion events, translocations, etc.) or variants embedded in sequence with complex architecture (e.g. short tandem repeats or segmental duplications), may not be detected. Additionally, it may not be possible to fully resolve certain details about variants, such as mosaicism, phasing, or mapping ambiguity. Unless explicitly guaranteed, sequence changes in the promoter, non-coding exons, and other non-coding regions are not covered by this assay. Please consult the test definition on our website for details regarding regions or types of variants that are covered or excluded for this test. This report reflects the analysis of an extracted genomic DNA sample. In very rare cases, (circulating hematolymphoid neoplasm, bone marrow transplant, recent blood transfusion) the analyzed DNA may not represent the patient's constitutional genome.
Gene | Transcript reference | Sequencing analysis | Deletion/Duplication analysis |
---|---|---|---|
CHCHD10 | NM_213720.2 | ||
CHMP2B | NM_014043.3 | ||
DCTN1 | NM_004082.4 | ||
FUS | NM_004960.3 | ||
GRN | NM_002087.3 | ||
HNRNPA2B1 | NM_031243.2 | ||
MAPT | NM_005910.5 | ||
PSEN1 | NM_000021.3 | ||
SQSTM1 | NM_003900.4 | ||
TARDBP | NM_007375.3 | ||
TBK1 | NM_013254.3 | ||
UBQLN2 | NM_013444.3 | ||
VCP | NM_007126.3 |