Amyotrophic lateral sclerosis and frontotemporal dementia

Recent, rapid advancements in the understanding of genetic causes of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) paved the way for the development of gene-targeted therapies tailored toward individual patients.¹ Genetic testing to confirm a molecular diagnosis is an essential component in the management of affected individuals, including establishing eligibility for targeted therapeutics.

Our FTD and ALS evaluations include both targeted panels and single gene evaluations to confirm and clarify diagnosis. Our assays provide improved coverage, offering increased sensitivity at above 99% for single nucleotide variants, above 94% for deletions/insertions less than 40 base pairs (bp), and above 95% for deletions up to 75 bp and insertions up to 47 bp. Both evaluations include repeat expansion testing for C9orf72, the most common cause of familial ALS and FTD.

Key testing

• AFTDP | Inherited Frontotemporal Dementia and Amyotrophic Lateral Sclerosis Gene Panel, Varies
  • Evaluates 50 genes associated with frontotemporal dementia and/or ALS and repeat expansion analysis for C9orf72.
• C9ORF | C9orf72 Hexanucleotide Repeat, Molecular Analysis, Varies
  • Provides molecular confirmation of clinically suspected cases of c9FTD/ALS, FTD, or ALS.
• SOD1Z | SOD1 Gene, Full Gene Analysis, Varies
  • Identifies variants within SOD1 known to be associated with ALS, allowing for predictive testing of at-risk family members.
  • Establishes a molecular diagnosis for patients with ALS.

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Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy

CADASIL is caused by pathogenic variants in the NOTCH3 gene. CADASIL can lead to cognitive problems and dementia, and testing may be indicated particularly in individuals with a personal or family history of stroke and migraine. Diagnosis of the condition enables physicians and families to develop the most appropriate care plan for patients.

Key testing

• NTC3Z | NOTCH3 Gene, Full Gene Analysis, Varies
  • Molecular diagnosis in patients with features of CADASIL and NOTCH3-related disorders.

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Hereditary Alzheimer’s disease

Genetic testing for Alzheimer’s disease may be beneficial in specific clinical cases, especially for patients with symptoms of early-onset Alzheimer’s disease or for individuals with a strong family history of the condition. In these cases, testing for genes such as APP, PSEN1, PSEN2, and othersmay be considered.²

Key testing

• APOEG | Apolipoprotein E Genotyping, Blood
  • Determines the specific apolipoprotein E (APOE) genotypes in patients. A form of the gene, APOE e4, increases the risk of Alzheimer's disease, though not everyone with this form of the gene will develop the disease.
  • Determining the specific apolipoprotein E (APOE) genotypes that may increase risk for amyloid-related imaging abnormalities (ARIA) in individuals being treated for Alzheimer's disease with β-amyloid-targeting antibodies.
  • *The use of APOE analysis for predictive testing for Alzheimer's disease is not currently recommended by the American College of Medical Genetics due to limited clinical utility and poor predictive value.^3,4
  • Additionally, according to the U.S. Food and Drug Administration label, the APOE e4 allele in the context of amyloid-targeting antibody treatments for Alzheimer's disease has been associated with a higher incidence of amyloid-related imaging abnormalities.⁵
• CGPH | Custom Gene Panel, Hereditary, Next-Generation Sequencing, Varies
  • Can be used to analyze single genes that may be linked to hereditary Alzheimer’s disease, such as APP, PSEN1, and PSEN2.
• FMTT | Familial Variant, Targeted Testing, Varies
  • Can be used for diagnosis and predictive testing when a specific familial variant is known.

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References

1. Roggenbuck J, Fong JC. Genetic testing for amyotrophic lateral sclerosis and frontotemporal dementia: impact on clinical management. Clin Lab Med. 2020;40(3):271-287. doi:10.1016/j.cll.2020.05.002
2. National Institutes of Health. Alzheimer’s Disease Genetics Fact Sheet. https://www.nia.nih.gov/health/genetics-and-family-history/alzheimers-disease-genetics-fact-sheet
3. Goldman JS. Hahn S, Williamson Catania J, et al. Genetic counseling and testing for Alzheimer disease: Joint practice guidelines of the American College of Medical Genetics and the National Society of Genetic Counselors. Genet Med. 2011;13(6):597-605. https://doi.org/10.1097/GIM.0b013e31821d69b8
4. Goldman JS, Hahn SE, Williamson Catania J, et al. ADDENDUM: Genetic counseling and testing for Alzheimer disease: joint practice guidelines of the American College of Medical Genetics and the National Society of Genetic Counselors. Genet Med. 2019;21:2404. doi.org/10.1038/s41436-019-0559-1
5. Ritchie M, Sajjadi SA, Grill JD. Apolipoprotein E Genetic Testing in a New Age of Alzheimer Disease Clinical Practice. Neurol Clin Pract. 2024 Apr;14(2):e200230. doi: 10.1212/CPJ.0000000000200230. Epub 2024 Jan 5.