Frontotemporal Dementia via the MAPT Gene

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).

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).

This test provides full coverage of all coding exons of the MAPT gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.