Complexities of Genetic Counseling for ALS: A Case of Two Siblings with Discordant Genetic Test Results

Abstract

Rapid advances in the genetics of amyotrophic lateral sclerosis (ALS) have dramatically changed the approach of clinicians and researchers to the motor neuron diseases. We report two siblings in whom the genetic study provided conflicting results, hence raising a number of issues which deserve to be considered by clinicians involved in genetic testing for ALS. The first patient died within 2 years of ALS onset, while her brother still manages to walk unaided, 7 years into onset. Genetic analyses, performed on the first patient as part of a research protocol, and as clinical genetic testing on the brother, provided different results. Results for Patient 1 were negative for all investigated genes, thus suggesting that her disease may be a phenocopy, while her brother carried an autosomal dominant TARDBP mutation (p.A382T). A multidisciplinary approach may help patients and clinicians face the emerging dilemmas in such a complex field. Sharing and updating of advances, not to mention uncertainties inherent to current knowledge, with patients and families may prove to be an effective way to support them and to make them aware of the present limits of our knowledge and of the blurred border between research and clinical practice.

Patient and Relative Experiences and Decision-making About Genetic Testing and Counseling for Familial ALS and FTD

“…The included population consisted of affected individuals, at-risk individuals, and other related or unrelated family members. Eleven studies included only a single person or family with, or at risk of, ALS/FTD 38–41,46,49–51,56–58. The total number of included patients, families and at-risk relatives was not calculated due to missing information or differences in defining familial and sporadic disease.…”

Predictive Genetic Counseling for Neurodegenerative Diseases: Past, Present, and Future

“…Much about the penetrance of these genes remains elusive, but some appear to be highly penetrant (MAPT, CHMP2B), whereas others have variable penetrance depending on the variation (SOD1). Moreover, several case reports and research findings raise the possibility of oligogenic inheritance and discordant family results due to sporadic ALS phenocopy (Mandich et al 2015;Giannoccaro et al 2017). Last, TMEM106B and possible other risk genes have been unveiled that influence the risk of sporadic disease as well as the presentation of familial disease when in combination with various pathogenic variants (e.g., C9orf72, PGRN) (Nicholson and Rademakers 2016).…”

Genetic Counseling Dilemmas for a Patient with Sporadic Amyotrophic Lateral Sclerosis, Frontotemporal Degeneration & Parkinson's Disease

“…Performing or offering genetic tests in patients with late-onset ALS and no family history is questionable, since the majority of ALS are sporadic. Nonetheless, patients wth ALS are increasingly aware of the importance of genetics, and probands and relatives frequently request genetic testing and seek to participate in international research programs (Mandich et al 2015). Moreover, clinical trials often require genetic tests for participating patients.…”