Invitae Frontotemporal Dementia Panel

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.

^*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:

• A clinical diagnosis of frontotemporal dementia and/or ALS, and who have previously tested negative for repeat expansion of the C9orf72 gene
• A clinical diagnosis of early-onset frontotemporal dementia (onset before 60 years of age), especially in those with a family history of dementia or ALS
• No personal history of disease (unaffected individuals), but who are known to be at risk for a hereditary form of FTD because of family history

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.