Assessment of risk of ALS conferred by the GGGGCC hexanucleotide repeat expansion in C9orf72 among first-degree relatives of patients with ALS carrying the repeat expansion

• Published in: Amyotrophic lateral sclerosis and frontotemporal degeneration Vol. 25; no. 1-2; pp. 188 - 196
• Main Authors: Van Wijk, Iris F, Van Eijk, Ruben P A, Van Boxmeer, Loes, Westeneng, Henk-Jan, Van Es, Michael A, Van Rheenen, Wouter, Van Den Berg, Leonard H, Eijkemans, Marinus J C, Veldink, Jan H
• Format: Journal Article
• Language: English
• Published: England 01-02-2024
• Subjects: Aged, 80 and over; Amyotrophic Lateral Sclerosis - epidemiology; Amyotrophic Lateral Sclerosis - genetics; C9orf72 Protein - genetics; DNA Repeat Expansion - genetics; Frontotemporal Dementia - genetics; Humans; Proteins - genetics; c9orf72; penetrance
• ISSN: 2167-8421; 2167-9223
• DOI: 10.1080/21678421.2023.2272187

We aimed to estimate the age-related risk of ALS in first-degree relatives of patients with ALS carrying the
repeat expansion.
We included all patients with ALS carrying a
repeat expansion in The Netherlands. Using structured questionnaires, we determined the number of first-degree relatives, their age at death due to ALS or another cause, or age at time of questionnaire. The cumulative incidence of ALS among first-degree relatives was estimated, while accounting for death from other causes. Variability in ALS risk between families was evaluated using a random effects hazards model. We used a second, distinct approach to estimate the risk of ALS and FTD in the general population, using previously published data.
In total, 214 of the 2,486 (9.2%) patients with ALS carried the
repeat expansion. The mean risk of ALS at age 80 for first-degree relatives carrying the repeat expansion was 24.1%, but ranged between individual families from 16.0 to 60.6%. Using the second approach, we found the risk of ALS and FTD combined was 28.7% (95% CI 17.8%-54.3%) for carriers in the general population.
On average, our estimated risk of ALS in the
repeat expansion was lower compared to historical estimates. We showed, however, that the risk of ALS likely varies between families and one overall penetrance estimate may not be sufficient to describe ALS risk. This warrants a tailor-made, patient-specific approach in testing. Further studies are needed to assess the risk of FTD in the
repeat expansion.