Genetic counseling for FTD/ALS caused by the C9ORF72 hexanucleotide expansion

Abstract

Frontotemporal degeneration (FTD) and amyotrophic lateral sclerosis (ALS) are related but distinct neurodegenerative diseases. The identification of a hexanucleotide repeat expansion in a noncoding region of the chromosome 9 open reading frame 72 (C9ORF72) gene as a common cause of FTD/ALS, familial FTD, and familial ALS marks the culmination of many years of investigation. This confirms the linkage of disease to chromosome 9 in large, multigenerational families with FTD and ALS, and it promotes deeper understanding of the diseases' shared molecular FTLD-TDP pathology. The discovery of the C9ORF72 repeat expansion has significant implications not only for familial FTD and ALS, but also for sporadic disease. Clinical and pathological correlates of the repeat expansion are being reported but remain to be refined, and a genetic test to detect the expansion has only recently become clinically available. Consequently, individuals and their families who are considering genetic testing for the C9ORF72 expansion should receive genetic counseling to discuss the risks, benefits, and limitations of testing. The following review aims to describe genetic counseling considerations for individuals at risk for a C9ORF72 repeat expansion.

Figure 1

Case example pedigree. The proband was referred for genetic counseling with a clinical diagnosis of probable frontotemporal degeneration (FTD). The proband's father died in his 40s in a motor vehicle accident. Her mother died in her 40s of uterine cancer. Neither had any known neurodegenerative or psychiatric disease. The proband's daughter had a history of attempted suicide in her 20s, but no known longstanding psychiatric illness. No information is known about the proband's grandparents. At the time of the initial visit, the remainder of the family history was noncontributory. Subsequent to the proband's visit, her brother was diagnosed with amyotrophic lateral sclerosis (ALS).