A Very Rare Setx Gene Variant (C.2750T>C) In a 72-year-old Man with Amyotrophic Lateral Sclerosis and an Unremarkable Family History. Should Genetic Testing be Routinely Performed in all Patients?

Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative multisystem disease with loss of spinal, bulbar and cortical upper and lower motor neurons resulting in progressive and generalised paralysis. Unfortunately, many aspects of this disease remain unclear. In the age of next generation sequencing, numerous gene variants have been discovered that are associated with ALS. In this article, a 72-year-old male underwent a medical history interview, clinical neurological examinations, neuropsychological tests, electrophysiological examinations (electromyography, electroneurography, somatosensory evoked potentials), computed tomography scan of the head and the cervical spine, blood and cerebrospinal fluid tests and a genetic analysis. The results of these examinations provided the definitive diagnosis of ALS. Whole-exome sequencing revealed the very rare genetic finding of the SETX Class-4 variant c.2750T>C (p.Met917Thr). The case presented here discusses the role of the SETX gene as a possible pathogenetic variant of adult-onset ALS. It demonstrates the relevance of genetic screening for gene variants of ALS in routine diagnostics. The precise classification of disease-related gene variants is of great relevance for clinical practice. LEARNING POINTS: Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative multisystem disease with loss of spinal, bulbar and cortical upper and lower motor neurons resulting in progressive and generalised paralysis.The case presented here describes a very rare variant in the SETX gene (heterozygous Class-4 variant c.2750T>C, p.Met917Thr) in an adult man with sporadic rapidly progressive ALS, with an unremarkable family history.This case demonstrates the relevance of genetic screening for gene variants of ALS in routine diagnostics, both in sporadic and familial cases. This may add to the accuracy of diagnosis and may improve genetic counselling for rare diseases.