C9orf72 Repeat Expansion Discordance in 6 Multigenerational Kindreds

Marie Ryan; Mark A Doherty; Ahmad Al Khleifat; Emmet Costello; Jennifer C Hengeveld; Mark Heverin; Ammar Al-Chalabi; Russell L Mclaughlin; Orla Hardiman

doi:10.1212/NXG.0000000000200112

C9orf72 Repeat Expansion Discordance in 6 Multigenerational Kindreds

Neurol Genet. 2023 Dec 22;10(1):e200112. doi: 10.1212/NXG.0000000000200112. eCollection 2024 Feb.

Authors

Marie Ryan¹, Mark A Doherty¹, Ahmad Al Khleifat¹, Emmet Costello¹, Jennifer C Hengeveld¹, Mark Heverin¹, Ammar Al-Chalabi¹, Russell L Mclaughlin¹, Orla Hardiman¹

Affiliation

¹ From the Academic Unit of Neurology (M.R., E.C., M.H., O.H.) and Smurfit Institute of Genetics (M.A.D., J.C.H., R.L.M.), Trinity College Dublin, Ireland; Department of Basic and Clinical Neuroscience (A.A., A.A.-C.), Maurice Wohl Clinical Neuroscience Institute, King's College London, United Kingdom; Department of Psychology (E.C.), Beaumont Hospital, Dublin, Ireland; King's College Hospital (A.A.-C.), London, United Kingdom; and Department of Neurology (O.H.), Beaumont Hospital, Dublin, Ireland.

Abstract

Background and objectives: A hexanucleotide repeat expansion in the noncoding region of the C9orf72 gene is the most common genetically identifiable cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia in populations of European ancestry. Pedigrees associated with this expansion exhibit phenotypic heterogeneity and incomplete disease penetrance, the basis of which is poorly understood. Relatives of those carrying the C9orf72 repeat expansion exhibit a characteristic cognitive endophenotype independent of carrier status. To examine whether additional shared genetic or environmental risks within kindreds could compel this observation, we have conducted a detailed cross-sectional study of the inheritance within multigenerational Irish kindreds carrying the C9orf72 repeat expansion.

Methods: One hundred thirty-one familial ALS pedigrees, 59 of which carried the C9orf72 repeat expansion (45.0% [95% CI 36.7-53.5]), were identified through the Irish population-based ALS register. C9orf72 genotyping was performed using repeat-primed PCR with amplicon fragment length analysis. Pedigrees were further investigated using SNP, targeted sequencing data, whole-exome sequencing, and whole-genome sequencing.

Results: We identified 21 kindreds where at least 1 family member with ALS carried the C9orf72 repeat expansion and from whom DNA was available from multiple affected family members. Of these, 6 kindreds (28.6% [95% CI 11.8-48.3]) exhibited discordant segregation. The C9orf72 haplotype was studied in 2 families and was found to segregate with the C9orf72-positive affected relative but not the C9orf72-negative affected relative. No other ALS pathogenic variants were identified within these discordant kindreds.

Discussion: Family members of kindreds associated with the C9orf72 repeat expansion may carry an increased risk of developing ALS independent of their observed carrier status. This has implications for assessment and counseling of asymptomatic individuals regarding their genetic risk.