1. NGS panel - Genetic testing for frontotemporal dementia

Frontotemporal dementia

December 14, 2017

Clinical features

Frontotemporal dementia (FTD) is a clinically and pathologically heterogeneous group of non-Alzheimer dementias characterized by selective and progressive atrophy involving the frontal or temporal lobes1. It typically develops in the sixth decade of life 2, but some cases manifest at younger ages, where it may mimic psychiatric disorders such as schizophrenia, bipolar affective disorder, and major depression. The estimated prevalence of FTD ranges between 15 and 22 in 100,000, with 25% of all cases with late-life onset3. Population studies show nearly equal distribution by gender.

FTD has three main clinical manifestation groups based on the dominant symptoms at diagnosis:

  • The first is the frontal variant or behavioral variant, which may represent 70% of FTD 4. Frontal variant FTD results in alterations in interpersonal skills and behavior. Persons may show uninhibited behavior, disinhibition, apathy, or new obsessions or rituals, usually first noticed by a close contact of the patient 5, 6.
  • Progressive nonfluent aphasia variant is another manifestation group in which patients present with word-finding difficulty. Speech can become nonfluent, but comprehension remains intact5, 6. A semantic subtype of dementia is characterized by the loss of semantic memory. Patients may present with loss of word understanding and the inability to use or recall certain words. Instead, patients use less precise substitute terms and phrases 5, 6.
  • Movement disorder-related frontotemporal dementia: The following disorders, which are a part of the frontotemporal degeneration spectrum, produce changes in muscle functions with or without behavior or language problems:

    • Amyotrophic lateral sclerosis (ALS), which causes muscle weakness or wasting. ALS is a motor neuron disease also known as Lou Gehrig’s disease.
    • Corticobasal syndrome, which causes the arms and legs to become uncoordinated or stiff.
    • Progressive supranuclear palsy (PSP), which causes muscle stiffness, difficulty walking and changes in posture. It also affects eye movements.

In a small proportion of patients, extrapyramidal signs, such as rigidity or parkinsonian syndrome, may develop. These cases may overlap with Lewy body dementia, in which fluctuating mental status, early visual hallucinations, and sleep behavior disorder are characteristic, along with mild parkinsonian motor symptoms. Widespread muscle atrophy, bulbar signs, fasciculations, muscle weakness and hyperreflexia may ensue in patients with motor neuron disease.

Approximately 20–40% of FTD cases have a family history of disease, and 10% of FTD cases are inherited in an autosomal dominant fashion 8. The most notable variants are found in MAPT (microtubule-associated protein tau), C9ORF72, and PGRN (progranulin) 7. Genes associated with frontotemporal dementia are listed in the table.

Overview of genes associated with frontotemporal dementia

Locus Associated phenotypes (OMIM) Pathogenic variant frequency
9q34.2 Frontotemporal dementia and/or ALS1 (105550) 74-100% for GGGGCC hexanucleotide expansion17, 20, 22
22q11.23 Frontotemporal dementia and/or amyotrophic lateral sclerosis 2 (615911); Myopathy isolated mitochondrial (616209); Spinal muscular atrophy, Jokela type (615048) p.Gly66Val in 55 individuals from 17 Finnish families11
p.Arg15Leu in 6/213 ALS12
3p11.2 Amyotrophic lateral sclerosis 17 (614696); Dementia, familial, nonspecific (600795) Missense pathogenic variants reported in association with ALS and FTD
5q32 Leukoencephalopathy, diffuse hereditary, with spheroids (221820) 52/405 (13%) for ALSP13
2p13.1 Neuropathy, distal hereditary motor, type VIIB (607641); Perry syndrome (168605); ALS susceptibility (105400) 100% for Perry syndrome14
16p11.2 ALS6 with or without frontotemporal dementia (608030); Tremor, hereditary essential, 4 (614782) ~4% of FALS15
17q21.31 Frontotemporal lobar degeneration with ubiquitin-positive inclusions (607485); Ceroid lipofuscinosis neuronal 11 (614706) 23% for frontotemporal lobar degeneration16
5% of FTD 16
13q14.2 Dementia familial British (176500), Danish (117300); Retinal dystrophy (616079) <5%17
17q21.31 Dementia, frontotemporal, with or without parkinsonism (600274); Pick disease (172700); Supranuclear palsy progressive (601104) and atypical (260540); Parkinson disease susceptibility (168600) 13-30%18
20p13 Cerebral amyloid angiopathy (137440); Creutzfeldt-Jakob disease (123400); Gerstmann-Straussler disease (137440); Huntington disease-like 1 (603218); Insomnia, fatal familial (600072); Prion disease with protracted course (606688); Kuru susceptibility (245300) 5–10% of inherited forms of prion diseases 19
14q24.2 Alzheimer disease 3 (607822); Cardiomyopathy, dilated, 1U (613694), Dementia, frontotemporal (600274); Pick disease (172700) 20-70%20, 21
1q42.13 Alzheimer disease 4 (606889); Cardiomyopathy, dilated, 1V (613697) Rare20, 21
9p13.3 ALS 16 juvenile (614373); Spinal muscular atrophy 2 (605726) Rare22
1p36.22 Frontotemporal lobar degeneration, TARDBP-related (612069); ALS 10 (612069) 100% for TARDBP-related ALS23
6p21.1 Nasu-Hakola disease (221770) Rare20, 21
2q35 ALS22 with or without frontotemoral dementia (616208) Rare20, 21
Xp11.21 ALS 15 with or without frontotemporal dementia (300857) Rare24
9p13.3 ALS14 with or without frontotemporal dementia (613954); Charcot-Marie-Tooth disease type 2Y (616687); Inclusion body myopathy with Paget disease and frontotemporal dementia 1 (167320) 100% for Inclusion body myopathy25

There is no specific treatment for frontotemporal dementia. There are medications which can reduce agitation and other behavioral problems and/or depression. These treatments should be used to help improve the quality of life.

CENTOGENE offers full gene sequencing and deletion/duplication analysis of the genes in the Frontotemporal dementia panel (C9orf72, CHCHD10, CHMP2B, CSF1R, DCTN1, FUS, GRN, ITM2B, MAPT, PRNP, PSEN1, PSEN2, SIGMAR1, TARDBP, TREM2, TUBA4A, UBQLN2, VCP) and repeat expansion analysis for the C9orf72 gene.

Differential diagnosis

The differential diagnosis of Alzheimer disease-related disorders includes the following diseases - depending on the major presenting symptoms:

Other causes of dementia, especially treatable forms of cognitive decline including:

  • Depression
  • Chronic drug intoxication
  • Chronic CNS infection
  • Thyroid disease
  • Vitamin B12 and thiamine deficiencies

Other degenerative disorders associated with dementia, such as:

  • Amyotrophic lateral sclerosis
  • Alzheimer´s disease
  • Picks disease
  • Parkinson disease
  • Diffuse Lewy body disease
  • Creutzfeldt-Jakob disease

Testing strategy

CENTOGENE offers an advanced, fast and cost-effective strategy to test large NGS panels and diagnose complex phenotypes based on PCR-free whole genome sequencing and NGS technology. This approach offers an unparalleled advantage by reducing amplification/capture biases and providing sequencing of the entire gene with more uniform coverage.

To confirm/establish the diagnosis, CENTOGENE offers the following testing strategy for frontotemporal dementia using NGS Panel Genomic targeted towards this specific phenotype:

Step 1: Whole genome sequencing from a single filter card. The sequencing covers the entire gene region (coding region, exon/intron boundaries, intronic and promoter) for all the genes included in the Frontotemporal dementia panel. Repeat expansion analysis for the C9orf72 gene and deletion/duplication analysis are performed separately.

Step 2: If no pathogenic variant is identified after analysis of the Frontotemporal dementia panel, we further recommend continuing the bioinformatics analysis of the data using whole genome sequencing to cover those genes which are either implicated in an overlapping phenotype or could be involved in a similar pathway but are not strongly clinically implicated based on the current information in literature.

Referral reasons

The following individuals are candidates for Frontotemporal dementia gene panel testing:

  • Individuals with a family history of frontotemporal dementia and presentation of the most common symptoms
  • Individuals without a positive family history, but with symptoms resembling frontotemporal dementia
  • Individuals with a negative but suspected family history, in order to perform proper genetic counseling (prenatal analyses are recommended in families with affected individuals).

Test utility

Sequencing, deletion/duplication of frontotemporal dementia related genes should be performed in all individuals suspected of having this condition. In parallel, other genes reported to be related with this clinical phenotype should also be analyzed for the presence of pathogenic variants, due to the overlap in many clinical features caused by those particular genes.

Confirmation of a clinical diagnosis through genetic testing can allow for genetic counseling and may direct medical management. Genetic counseling can provide a patient and/or family with the natural history of frontotemporal dementia, identify at-risk family members, provide information on reproductive risks as well as preconception/prenatal options, and allow for appropriate referral for patient support and/or resources.

More information on CENTOGENE´s Frontotemporal dementia panel can be found in our genetic test catalogue.