Early Onset Alzheimer's NGS Diagnostic Test

CPT: 81405; 81406(x2); 81479
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Test Includes

This test includes: APP, PSEN1, PSEN2.


Special Instructions

This assay currently is not available in New York state.

Contact an Integrated Genetics laboratory genetic coordinator at 800-255-7357 with any questions.


Expected Turnaround Time

28 days


Specimen Requirements


Specimen

Whole blood, buccal swab or extracted DNA (from blood or buccal only)


Volume

4 mL, 1 swab, or 200 ng of DNA


Container

Whole blood: lavender-top (EDTA) tube; oral swab: OCD-100 DNA Genotek device only; or extracted DNA: sterile screw-capped vial


Stability Requirements

Room temperature: Blood: 5 days; Swab: 60 days; DNA: 30 days

Refrigerated: Blood: 5 days; Swab: 60 days; DNA: 30 days

Frozen: Blood: Do not freeze; Swab: 60 days; DNA: Indefinitely


Causes for Rejection

Frozen blood EDTA tube; insufficient swab cell collection or incorrect oral swab device use; extracted DNA A260:A280 ratio outside of 1.8-2.0 range


Test Details


Use

Diagnostic testing. This test is to detect pathogenic variants in the amyloid protein precursor (APP), presenilin 1 (PSEN1) and presenilin 2 (PSEN2) genes that cause autosomal dominant early onset Alzheimer's disease. Testing may be considered to confirm a diagnosis of early onset Alzheimer's disease in symptomatic individuals and for presymptomatic testing in individuals with a family history of early onset AD or a relative with a known APP, PSEN1 or PSEN2 pathogenic variant. This testing is not appropriate for individuals under the age of 18. Alzheimer's disease (AD) is the most common form of progressive dementia and currently affects more than 5 million Americans. It is a neurodegenerative disorder with brain findings of neurofibrillary tangles and amyloid plaques. AD is a complex and heterogeneous disease, influenced by many genetic and environmental factors. Early onset AD (presenting before age 65, with cases as young as 25 and most cases between 45-60) occurs in ~5% of AD cases. Early onset familial AD comprises <2% if AD cases. Of early onset familial AD, PSEN1 contributes to the most cases (20% to 70%), followed by APP (10% to 15%) and PSEN2 (~5%). Penetrance is considered to be ~100% for APP and PSEN1 by age 60-65 and slightly reduced for PSEN2.


Limitations

This assay will not consistently detect germline mosaicism below 50% or rule out the presence of large chromosomal aberrations, including rearrangements and inversions that do not change copy number of genomic regions. The assay does not detect repeat expansions. Possible intergenic variant interactions are not commented on. False positive or false negative results may occur for reasons that include: insufficient information available about rare genetic variants, sex chromosome abnormalities, pseudogene interference, homologous regions, blood transfusions, bone marrow transplantation, somatic or tissue-specific mosaicism, mislabeled samples, or erroneous representation of family relationships. Variants that do not alter an amino acid composition of a protein may be difficult to assess for pathogenicity since they may produce abnormalities in structures not assessed by conventional analysis paradigms, eg, mRNA expression and processing.1 For mitochondrial DNA variants, low levels of heteroplasmy (<1%) may not be reliably detected by this technique. Mitochondrial variants may be tissue-specific. Interpretation of the clinical significance of gene variations is limited by information about the variant that is available at the time of reporting, and by the quality and quantity of clinical information provided with the sample. As the understanding of human genetic diversity improves, the interpretation of the clinical significance of variants may change.


Methodology

Nuclear Gene Single Nucleotide Variant and Small Indel Sequencing Assessment: Genomic regions of interest are selected using a custom capture reagent for target enrichment (Twist Bioscience) and sequenced via the Illumina® Novaseq 6000 next generation sequencing platform. Sequencing reads are aligned with the human genome reference GRCh37/hg19 build. Regions of interest include all exons and intron/exon junctions (+/-20 nucleotides) for each gene analyzed. A minimum of 99% of bases in targeted regions are covered at >15X. Analytical sensitivity is estimated to be >99% for single nucleotide variants, >97% for insertions/deletions less than six base pairs, and >95% for insertions/deletions between six and 15 base pairs. Uncovered regions with known pathogenic variants are sequenced in a targeted manner (List based on ClinVar Database: July 22, 2019, release).

Nuclear Gene Copy Number Variant Assessment: Next Generation Sequencing data used to call SNPs and small indels are assessed with Illumina’s DRAGEN (Dynamic Read Analysis for GENomics) Bio-IT Platform. Genes listed in ClinVar with intragenic pathogenic deletions are padded with additional intronic probes to allow single exon resolution CNV detection (List based on ClinVar Deletion Database: January 2019 release). For other genes, large deletions (>10 exons) can be detected. The resolution of this analysis can vary depending on region-specific features. Analytical sensitivity is estimated to be >95%.

Results Interpretation: Results should be used in the context of available clinical information and should not be used as the sole basis for patient management or treatment. Genetic counseling is recommended. Variants are assessed according to ACMG criteria.2 This report contains interpretation of pathogenic and likely pathogenic variants (by ACMG Criteria) as well as variants of uncertain significance (VUS) with pathogenic predictions related to the clinical information provided. Variants not reported: (1) Variants classified as benign or likely benign by ACMG Criteria; (2) variants of uncertain significance (VUS) with benign or likely benign predictions; (3) Variants related to carrier status; (4) Polymorphisms with implications in drug response (pharmacogenomics variants). We will reanalyze the data periodically at the clinician’s request to allow potential reinterpretation based on new research or evidence. GnomAD abbreviations for population frequency data: African/African American (AFR), Latino (AMR), Ashkenazi Jewish (ASJ), East Asian (EAS), Finnish (FIN), Non-Finnish European (NFE), South Asian (SAS), Other (OTH).


Footnotes

1. Nackley AG, Shabalina SA, Tchivileva IE, et al. Human catechol-O-methyltransferase haplotypes modulate protein expression by altering mRNA secondary structure. Science. 2006 Dec 22;314(5807):1930-1933.17185601
2. Richards S, Nazneen A, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015 May;17(5):405-424.25741868

References

Bird TD. Alzheimer disease overview. Adam MP, Ardinger HH, Pagon RA, et al, eds. In: GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2021.1998 Oct 23 [updated 2018 Dec 20].20301340
Cacace R, Sleegers K, Van Broeckhoven C. Molecular genetics of early-onset Alzheimer's disease revisited. Alzheimers Dement. 2016 Jun;12(6):733-748.27016693
D'Argenio V, Sarnataro D. New insights into the molecular bases of familial Alzheimer's disease. J Pers Med. 2020 Apr 19;10(2):26.32325882
Schellenberg GD, Montine TJ. The genetics and neuropathology of Alzheimer's disease. Acta Neuropathol. 2012 Sep;124(3):305-323.22618995

LOINC® Map

Order Code Order Code Name Order Loinc Result Code Result Code Name UofM Result LOINC
630557 Early Onset Alzheimer's Panel 630559 Result 51969-4
630557 Early Onset Alzheimer's Panel 630560 Interpretation 50398-7
630557 Early Onset Alzheimer's Panel 630575 Footnotes N/A
630557 Early Onset Alzheimer's Panel 630576 PDF 51969-4

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