Amyotrophic Lateral Sclerosis/Frontotemporal Lobar Degeneration (C9orf72 repeat analysis, for patients 18 years and older)

Casandra

Casandra Test Code GE84914Version 1 (DRAFT)

Performing Lab

Lab GeneDxLab Test ID J805

Amyotrophic Lateral Sclerosis/Frontotemporal Lobar Degeneration (C9orf72 repeat analysis, for patients 18 years and older)

Clinical Use

Use

This test analyzes the hexanucleotide (GGGGCC) repeat expansion in the C9orf72 gene, which is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Normal alleles have 24 or fewer repeats, disease-associated expansions are 60 or greater, and 25–59 repeats are of uncertain clinical significance. Clinical sensitivity varies by phenotype: up to 50% of ALS, 29% of FTLD, and 88% of combined cases carry expansions. Penetrance is age‑dependent, approaching nearly 100% by age 80, but reduced penetrance has been observed. Southern blot is not performed for alleles larger than 145 repeats. Samples from individuals under age 18 are not accepted per professional guidelines.

Special Instructions

Repeat sizing is performed using Asuragen AmplideX PCR/CE kit with repeat‑primed PCR and fragment analysis. Alleles over 145 repeats require Southern blot for size determination, which is not completed as part of this test. Samples from individuals younger than 18 years are not accepted, in accordance with policies from ACMG, NSGC, ASHG, and AMA. Ordering requires use of GeneDx’s online portal or requisition form; kits may be requested. Testing is for germline variants only.

Limitations

This assay cannot size alleles larger than 145 repeats and does not include Southern blot confirmation for those larger expansions. Repeat‑primed PCR may fail in rare cases with indels downstream of the repeat region. Somatic mosaicism or lab artifacts such as blood transfusion or hematologic neoplasm may affect results. Reduced penetrance and lack of correlation between repeat size and age of onset limit prognostic interpretation. Negative result does not rule out mosaic expansion in untested tissues.

Test Details