GLT8D1

Inheritance Pattern: AD

Disease ID:MONDO:0004976

Submitter: ClinGen

*GLT8D1* was first reported in relation to autosomal dominant amyotrophic lateral sclerosis in 2019 (Cooper-Knock J et al., PMID:30811981). At least 14 unique variants, including missense, synonymous and frameshift variants, have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in 22 probands in 7 publications (PMID:30811981, 35525134, 34746377, 33714647, 31653410, 35873773, 33581933), but many were not scored in this curation due to a population frequency too high to be consistent with disease. This gene-disease relationship has been studied in at least two case-control studies (PMID:30811981). An aggregate variant analysis of the* GLT8D1* exon 4 burden showed that when exon 4 is excluded from burden analysis, no significant association with ALS is found. The test only included variants which were present in <1/10,000 of ExAC. A single variant analysis association study of the R29C variant showed an odds ratio of 54, although w​​hen looking at patients carrying R92C without an ARPP21 variant the OR drops to 20. This gene-disease relationship is also supported by an animal model and expression study. A zebrafish model demonstrated reduced movement of zebrafish after knockdown of endogenous *GLT8D1* and transfection of mutated version of *GLT8D1* (PMID:30811981). *GLT8D1* is expressed in central nervous system tissue (PMID:24309898), and a cellular model of GLT8D1 knock-down in neuronal stem cells which showed altered morphology of differentiated cells (PMID:29483533). This gene-disease pair was originally evaluated by the Amyotrophic Lateral Sclerosis Spectrum Disorders GCEP on November 8, 2022. It was reevaluated on November 12, 2024. As a result of this reevaluation, the classification did not change. New evidence was added to the curation, one new case and two case-control studies, but it was not strong enough to change the curation. 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 Amyotrophic Lateral Sclerosis Spectrum Disorders GCEP on the meeting date January 14, 2025 (SOP Version 11).