The C9orf72 hexanucleotide repeat expansion presents a challenge for testing laboratories and genetic counseling

Abstract

C9orf72 hexanucleotide repeat expansions are the most common known cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Genetic testing for C9orf72 expansions in patients with ALS and/or FTD and their relatives has become increasingly available since hexanucleotide repeat expansions were first reported in 2011. The repeat number is highly variable and the threshold at which repeat size leads to neurodegeneration remains unknown. We present the case of an ALS patient who underwent genetic testing through our Motor Neurone Disease Clinic. We highlight current limitations to analysing and interpreting C9orf72 expansion test results and describe how this resulted in discordant reports of pathogenicity between testing laboratories that confounded the genetic counselling process. We conclude that patients with ALS or FTD and their at-risk family members, need to be adequately counselled about the limitations of current knowledge to ensure they are making informed decisions about genetic testing for C9orf72. Greater collaboration between clinicians, testing laboratories and researchers is required to ensure risks to patients and their families are minimised.

Keywords:

• Genetic testing
• genetic counseling
• C9orf72
• repeat expansions
• intermediate expansions
• laboratory methods
• genetics

Acknowledgements

The authors would like to thank the patient and her family. Biospecimens used in this research were obtained from the Macquarie University Neurodegenerative Disease Biobank, Macquarie University, New South Wales, Australia. Sarah Furlong provided further clarification on the biobank processes, and Rebecca Dickson and Rosie Fell provided feedback on the manuscript. We appreciate their assistance.

Disclosure statement

The authors declare no conflict of interest.

Additional information

Funding

This work was supported by a grant from the National Health and Medical Research Council of Australia [NHMRC, APP1095215]. GMH is an NHMRC Senior Principal Research Fellow and receives NHMRC funding.