Alzheimer’s disease and other Dementia comprehensive panel

Alzheimer’s disease and other Dementia comprehensive panel

[28 genes]

TOURNAROUND TIME: 6 WEEKS

APOE APP ATP13A2 CSF1R CHCHD10 CHMP2B FUS GBA GRN HNRNPA1
HNRNPA2B1 ITM2B LRRK2 MAPT PINK1 PLA2G6 PRNP PSEN1 PSEN2 SNCA
SNCB SQSTM1 TARDBP TBK1 TIMM8A TREM2 UBQLN2 VCP
APOE APP ATP13A2 CSF1R
CHCHD10 CHMP2B FUS GBA
GRN HNRNPA1 HNRNPA2B1 ITM2B
LRRK2 MAPT PINK1 PLA2G6
PRNP PSEN1 PSEN2 SNCA
SNCB SQSTM1 TARDBP TBK1
TIMM8A TREM2 UBQLN2 VCP
RELATED PHENOTYPES
Primary progressive aphasia GRN
Cerebral amyloid angiopathy APP, PRNP
Lewy body dementia SNCA, SNCB
Dementia associated with inclusion body myopathy and Paget disease HRNPA2B1, VCP
Frontotemporal dementia-Parkinson ATP13A2, GRN, LRRK2, MAPT, PINK2, PLA2G6, SNCA, SNCB
Frontotemporal dementia with/without amyotrophic lateral sclerosis CHCHD10, SQSTM1, TBK1
Dementia associated with prion disease PRNP
Gaucher disease GBA
Nasu-Hakola disease TREM2
Pick disease MAPT
Amyotrophic lateral sclerosis with frontotemporal dementia FUS, TARDBP, UBQLN, VCP
Hereditary diffuse leukoencephalopathy with spheroids CSF1R
Progressive supranuclear palsy/ Corticobasal degeneration MAPT, GRN, CHMP2B, DCTN1, TREM2
Mohr-Tranebjaerg syndrome TIMM8A

Dementia constitutes an important social, health, and economic problem. Twenty five percent of people over age 55 have a family history of dementia. In 2016, it affected 46.8 million people worldwide. With an exponential growth, this number is estimated to reach 131.5 million by 2050 (World Alzheimer Report 2016).

Alzheimer’s disease (AD) is the most common type of primary neurodegenerative dementia (60%-80% of cases). Approximately 25% of patients with AD have two or more affected relatives. Among familial forms, only 5% have an early onset (age <65 years). In these cases, transmission is autosomal dominant and is caused by pathogenic variants in genes PSEN1 (30%-70%), PSEN2 (<5%), and APP (10%-15%) (Loy et al., 2014). Allele 4 of the APOE gene represents a risk factor for AD (OR=2-3 in heterozygosis, OR=14.9 in homozygosis; Farrer et al., 1997),

although the presence of the allele 4 of APOE is not necessary or sufficient to develop disease. Therefore, although genotyping of APOE can be clinically useful to support diagnosis in the context of other data suggesting AD, particularly in late-onset forms (age >65), its use is not indicated in asymptomatic individuals.

Between 5% and 15% of pre-senile dementia cases (<65 years) are frontotemporal type, with a prevalence of 10-15/100 000 in the age group between 45 and 65 years. 25%-50% of patients with frontotemporal dementia have a family history of dementia or psychiatric disease, and 10%-30% are compatible with an autosomal dominant inheritance pattern (Rohrer et al., 2009). Pathogenic variants in C9orf72, GRN, and MAPT are involved in 80% of families with autosomal dominant forms. A single genetic alteration in the C9orf72 gene has been identified, consisting in a GGGGCC hexanucleotide expansion, not detectable by next-generation-sequencing.

REFERENCES
  1. World Alzheimer Report 2016; https://www.alz.co.uk/research/world-report-2016
  2. Loy CT, Schofield PR, Turner AM, Kwok JB. Genetics of dementia. Lancet. 2014 Mar 1;383(9919):828-40. doi: 10.1016/S0140-6736(13)60630-3.
  3. Farrer LA, Cupples LA, Haines JL, Hyman B, Kukull WA, Mayeux R, Myers RH, Pericak-Vance MA, Risch N, van Duijn CM. Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium. JAMA. 1997 Oct 22-29;278(16):1349-56.
  4. Rohrer JD, Guerreiro R, Vandrovcova J, Uphill J, Reiman D, Beck J, Isaacs AM, Authier A, Ferrari R, Fox NC, Mackenzie IR, Warren JD, de Silva R, Holton J, Revesz T, Hardy J, Mead S, Rossor MN. The heritability and genetics of frontotemporal lobar degeneration. Neurology. 2009 Nov 3;73(18):1451-6.

 

NEUROLOGY PORTFOLIO


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INFORMED CONSENT
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VARIANT CLASSIFICATION
Variant classification and clinical usefulness criteria

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