Submission Details

TIA1 was first reported in relation to autosomal dominant amyotrophic lateral sclerosis (ALS) type 26 with or without FTD in 2017 (Mackenzie et al., PMID: 28817800). TIA1 is an RNA-binding protein involved in the regulation of alternative pre-RNA splicing and mRNA translation by binding to uridine-rich RNA sequences. It also participates in the cellular response to environmental stress by promoting the recruitment of untranslated mRNAs to cytoplasmic stress granules. TIA1 has also been associated with autosomal dominant Welander distal myopathy. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found difference in phenotypic variability and in molecular mechanism. Despite both diseases being caused by missense mutations in the low complexity domain of TIA1, Welander distal myopathy is caused by a founder mutation E384K. There have been no reports of patients with this variant developing ALS. Therefore, the following disease entities have been split into separate disease entities, ALS26 with or without FTD (OMIM:619133) and Welander distal myopathy (OMIM:604454). Five missense variants that have been reported in six probands in four publications (PMIDs: 28817800, 29370934, 29699721, 29773329) are included in this curation. Six other reported missense variants have relatively high minor allele frequencies in population databases (>0.00001 in gnomAD) and were not scored as genetic-level evidence (PMIDs: 28817800 and 29886022). This gene-disease relationship is also supported by experimental evidence. TIA1 is a component of stress granules and since stress granules play a role in ALS, points were given for biochemical function. Expression studies via immunohistochemistry on lumbar spinal cord of a SOD1G86S patient revealed an abundance of TIA1 positive puncta granules in neuronal and non-neuronal cells; in contrast, TIA1 immunoreactivity was restricted to the nucleus of motor neurons in controls (PMID: 33025330). In vitro experiments show that ALS associated variants, particularly those that affect proline residues, affect stress granule dynamics by decreasing their mobility and delaying their clearance (PMIDs: 28817800, 34310938). In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the ClinGen ALS GCEP on October 11, 2022 (SOP Version 9).