Genetic and phenotype analyses of primary lateral sclerosis datasets from international cohorts

Primary lateral sclerosis (PLS) is the rarest form of motor neurone disease (MND). It is characterized by upper motor neuron degeneration, leading to progressive weakness, spasticity and functional disability. Although PLS does not typically shorten life substantially, it gradually impacts quality of life as the diseases progresses. There is no established genetic cause of PLS. One of the biggest challenges faced by people with PLS is delayed diagnosis and misdiagnosis, since the initial symptoms can be similar to amyotrophic lateral sclerosis (ALS), the most common form of MND. In the absence of a concrete genetic test that differentiates PLS from other MNDs, this delay in diagnosis is inevitable. Understanding the genetic basis of PLS might help in reducing the time from the onset of symptoms to diagnosis, and it will improve our understanding of the disease biology favouring the development of a treatment. The aim of our study is to collect a large international PLS genetic and clinical dataset to investigate its genetic and phenotypic landscapes as well as to evaluate whether genetic testing should be advised in PLS. Through Project MinE and AnswerALS, we accessed whole-genome sequencing data of 120 PLS, 7405 ALS and 2444 controls. We identified variants in several MND genes such as FIG4, FUS, SPG7, SPG11 and SQSTM1 genes among others and repeat expansions in the ATXN1 (12.2%) and NIPA1 (7.3%) genes, but none in the C9orf72 and ATXN2 genes. Overall PLS patients harboured fewer clinically actionable MND-associated variants than ALS patients (p = 0.0001), however, depending on the panel, up to 11% of people with PLS might benefit from genetic testing. By looking at the clinical characteristics of these cohorts, the age of symptom onset was not younger for people with PLS than for those with ALS in both Project MinE and AnswerALS. On such bases, we advise that the current diagnostic criteria that discourage the use of genetic testing and rely on age of onset should be reconsidered.