Invitae Combined Hereditary Dementia and Amyotrophic Lateral Sclerosis Panel

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  • Test code: 03502
  • Turnaround time:
    10–21 calendar days (14 days on average)
  • Preferred specimen:
    3mL whole blood in a purple-top tube
  • Alternate specimens:
    DNA or saliva/assisted saliva
  • Sample requirements
  • Request a sample kit
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Test description

The Invitae Combined Hereditary Dementia and Amyotrophic Lateral Sclerosis Panel analyzes up to 27 genes associated with hereditary dementia and/or amyotrophic lateral sclerosis (ALS). The genes on the Invitae Combined Dementia and ALS Panel were curated based on the available evidence to date in order to provide analysis for a number of newly characterized dementia and ALS genes along with well-known genetic causes of dementia and ALS, 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 ALS and frontotemporal dementia (FTD). C9orf72 hexanucleotide repeat expansion testing is considered first-line genetic testing for individuals with a personal and/or family history of ALS and/or FTD. The Invitae Combined Hereditary Dementia and ALS Panel should only be considered in individuals who have previously had negative C9orf72 testing.

Individuals with clinical signs and symptoms of a hereditary form of dementia and/or ALS may benefit from diagnostic genetic testing. Given the clinical overlap between different neurodegenerative disorders, panel testing allows for more efficient evaluation of multiple conditions based on a single indication for testing. Identification of the molecular basis of disease 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.

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Primary panel (21 genes)

ALS2 APP CHCHD10 DCTN1 FUS GRN MAPT OPTN PFN1 PRNP PSEN1 PSEN2 SNCA SOD1 SPG11 TARDBP TBK1 TFG UBQLN2 VAPB VCP

Add-on Preliminary-evidence Genes for Hereditary Dementia and Amyotrophic Lateral Sclerosis (6 genes)

The CHMP2B, HNRNPA2B1, MATR3, SETX, SIGMAR1, and SQSTM1 genes currently have early evidence of a clinical association with hereditary dementia and/or ALS. 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 MATR3 SETX SIGMAR1 SQSTM1

Alternative tests to consider

Clinicians may 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.

Hereditary dementias are a clinically heterogenous group of disorders, including hereditary Alzheimer’s disease, frontotemporal dementia (FTD), and genetic prion disease.

Early-onset Alzheimer’s disease (EOAD) is a form of dementia characterized by progressive loss of episodic memory, executive functioning skills, and language, which may be accompanied by other features including hallucinations, seizures, and parkinsonism. EOAD presents before 60-65 years of age (and often presents before 55 years of age) with mild visuospatial deficits and memory loss. As the disorder progresses, executive dysfunction and language disturbances become more apparent, followed by features of motor stiffness, further impaired spatial skills, and psychiatric manifestations including apathy, depression, and agitation. In advanced stages of the disorder, individuals typically display severe cognitive, psychiatric/behavioral, and motor dysfunction. The hallmark pathological findings of Alzheimer’s disease identified upon autopsy are beta-amyloid neuritic plaques and intraneuronal neurofibrillary tangles. An estimated 25% of AD is familial, with two or more affected individuals in the same family, and 5% of individuals with familial AD have an early-onset form. Individuals with Alzheimer’s disease caused by pathogenic variants in PSEN2 typically show a later age of onset in the 50s or 60s, compared to onset in the 30s or 40s seen in individuals with Alzheimer’s disease caused by APP or PSEN1 variants. In addition, PSEN2-related Alzheimer’s disease has a higher frequency of behavioral and psychotic symptoms, such as hallucinations or delusions.

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.

Inherited prion diseases represent a spectrum of progressive neurodegenerative conditions associated with misfolding and aggregation of the prion protein within the brain. Historically labeled as distinct conditions such as genetic Creutzfeldt-Jakob disease, Gerstmann-Straussler-Scheinker syndrome, and fatal familial insomnia, they are now considered to represent a continuum of overlapping phenotypes that fall under the umbrella of prion diseases. The three major subtypes of hereditary prion disease may be categorized based on genotype, and can have variable clinical manifestations and age of onset, which ranges from early to late adulthood. The majority of affected individuals present with cognitive difficulties, ataxia, and dementia. The pathological hallmark of prion disease consists of the presence of spongiform changes and abnormal conformations of prion protein in the central nervous system (CNS) of affected individuals.

Amyotrophic lateral sclerosis (ALS) disease is a rapidly progressive neurodegenerative disease involving the loss of motor neurons within the motor cortex, brainstem, and spinal cord. The majority of individuals with ALS present with twitching and cramping of muscles in the hands and feet, loss of motor control in the hands and arms, weakness and fatigue, and/or tripping and falling. Symptoms usually begin with asymmetric involvement of the muscles. As the disease progresses, symptoms may include difficulty talking, breathing, and swallowing, shortness of breath, and paralysis. However, some individuals have bulbar onset ALS, which presents with difficulty talking and/or swallowing. As the disorder progresses, additional components of the nervous system become involved, resulting in spasticity, weakness, muscle wasting, brisk deep tendon reflexes and eventually respiratory failure. Age of symptom onset is variable, but typically occurs in the 40s or 50s. An estimated 10% of individuals with ALS are classified as having familial ALS (FALS) based on the presence of two or more affected individuals in a family. An estimated 68% of familial ALS and 11% of sporadic ALS is thought to be hereditary. A number of genes associated with ALS can also cause FTD, and some individuals may develop features of both disorders. FTD may co-occur in up to 14% of individuals with ALS.

GeneInheritanceAssociated neurological disordersClinical sensitivity
Autosomal dominantAutosomal recessiveX-linked
ALS2 Juvenile ALS; Juvenile primary lateral sclerosis; Infantile-onset ascending hereditary spastic paraplegia Rare
APP Alzheimer’s disease type 1 (AD1); Cerebral amyloid angiopathy 10-15% of familial early-onset Alzheimer’s disease
CHCHD10 FTDALS2; Spinal muscular atrophy; Mitochondrial myopathy Rare
CHMP2B* ALS17; FTD3 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% of hereditary FTD
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% of hereditary FTD
MATR3* ALS21; Vocal cord and pharyngeal dysfunction with distal myopathy Unknown
OPTN ALS12 <1% of familial and sporadic ALS
PFN1 ALS18 Rare
PRNP Prion disease (Creutzfeldt-Jakob disease; Gerstmann-Straussler-Scheinker syndrome; Fatal familial insomnia) ~10-15% of all human prion disease
PSEN1 Alzheimer’s disease 3 (AD3); Pick disease; FTD; Dilated cardiomyopathy 30-70% of familial early-onset Alzheimer’s disease
PSEN2 Alzheimer’s disease 4 (AD4) <5% of familial early-onset Alzheimer’s disease
SETX* Motor neuropathy with pyramidal features (ALS4) Rare
SIGMAR1* ALS16; Distal spinal muscular atrophy (DSMA2) Unknown
SNCA Dementia with Lewy bodies; Parkinson’s disease (PD) Rare
SOD1 ALS1 ~12% of familial ALS and ~1-2% of sporadic ALS
SPG11 Hereditary spastic paraplegia with features of juvenile-onset ALS 21% of all recessive hereditary spastic paraplegia, unknown for isolated ALS
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
TFG Hereditary motor and sensory neuropathy, Okinawa type (HMSNO) Rare
UBQLN2 ALS15 Rare
VAPB Finkel type Spinal Muscular Atrophy 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. For example, the probability of identifying a genetic mutation in APP, PSEN1, or PSEN2 is <1% for individuals with a clinical diagnosis of Alzheimer’s and an age of onset >65 years of age who have two or more affected first-degree relatives; however, the probability climbs to 86% in individuals with a clinical diagnosis of Alzheimer’s disease who have an age of onset <60 years of age who have affected family members in three generations.

The majority of hereditary forms of dementia and ALS are inherited in an autosomal dominant manner. The ALS2, SIGMAR1, and SPG11 genes are associated with autosomal recessive disease, and the SETX and SOD1 genes may be associated with both autosomal dominant and recessive disorders. The OPTN gene is most commonly associated with autosomal recessive disease, although an autosomal dominant form of OPTN-associated ALS has also been suggested. The UBQLN2 gene is associated with X-linked disease.

As most forms of hereditary dementia and ALS are late-onset conditions with variable expressivity and age of onset, penetrance is typically age-dependent and can be difficult to calculate.

An estimated 90% of individuals with either a SOD1 or FUS mutation will have symptoms of ALS by 70 years of age. GRN-related FTD has an estimated penetrance of 90% by 75 years of age. Reduced penetrance has been described in MAPT-related FTD. PNRP-associated prion disease typically has complete penetrance. The penetrance of pathogenic variants in APP is estimated to be 100% by the early 60s. The majority of pathogenic variants in PSEN1 have complete penetrance by 65 years of age, while pathogenic variants in PSEN2 have an estimated 95% penetrance.

Alzheimer’s disease is the most common form of dementia, and affects an estimated 5% of individuals over age 70, with 25% of all cases being familial (two or more affected individuals within a family). Early-onset AD makes up approximately 1-5% of all cases of Alzheimer’s disease, with a prevalence of 41.2 per 100,000 individuals aged 40-59 years. Approximately 1% of all individuals with Alzheimer’s disease have a genetic form.

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.

The annual incidence of ALS is estimated to be 4-8 per 100,000 individuals, and an estimated 10% of all cases are hereditary.

Prion diseases are very rare, with a yearly incidence of 1-1.5 cases per million people. Genetic forms of prion disease account for an estimated 10% of all cases.

A genetic cause for dementia or ALS 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 dementia (onset before 60 years of age), especially in those with a family history of dementia or related conditions
  • A clinical diagnosis of early-onset ALS (onset before 50 years of age), especially in those with a family history of ALS or related conditions.
  • No personal history of disease (unaffected individuals) but who are known to be at risk for a hereditary form of dementia and/or ALS because of family history

In addition to meeting one of the above criteria, individuals considering genetic testing for hereditary forms of dementia and/or ALS 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.

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Clinical management guidelines for dementia and ALS can be found at www.aan.com.

Assay and technical information

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, +/- 10 base pairs of adjacent intronic sequence, and select noncoding variants. Our assay provides a Q30 quality-adjusted mean coverage depth of 350x (50x minimum, or supplemented with additional analysis). Variants classified as pathogenic or likely pathogenic are confirmed with orthogonal methods, except individual variants that have high quality scores and previously validated in at least ten unrelated samples.

Our analysis detects most intragenic deletions and duplications at single exon resolution. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. If you are requesting the detection of a specific single-exon copy number variation, please contact Client Services before placing your order.

Gene Transcript reference Sequencing analysis Deletion/Duplication analysis
ALS2 NM_020919.3
APP NM_000484.3
CHCHD10 NM_213720.2; NM_001301339.1
CHMP2B NM_014043.3
DCTN1 NM_004082.4
FUS NM_004960.3
GRN NM_002087.3
HNRNPA2B1 NM_031243.2
MAPT NM_005910.5; NM_001123066.3
MATR3 NM_199189.2; NM_001194956.1
OPTN NM_021980.4
PFN1 NM_005022.3
PRNP* NM_000311.3
PSEN1 NM_000021.3
PSEN2 NM_000447.2
SETX NM_015046.5
SIGMAR1 NM_005866.3
SNCA NM_000345.3
SOD1 NM_000454.4
SPG11 NM_025137.3
SQSTM1 NM_003900.4
TARDBP NM_007375.3
TBK1 NM_013254.3
TFG NM_006070.5
UBQLN2 NM_013444.3
VAPB NM_004738.4
VCP NM_007126.3

PRNP: Analysis does not include the octapeptide repeat region. Codon 129 status will only be reported in the presence of a pathogenic variant.