SS18L1

Inheritance Pattern: AD

Disease ID:MONDO:0004976

Submitter: ClinGen

*SS18L1* (HGNC:15592) was first reported in relation to autosomal dominant amyotrophic lateral sclerosis in 2013 (Chesi A et al., PMID: 23708140). *SS18L1* encodes a calcium-responsive transactivator (CREST) that is an essential subunit of a neuron-specific chromatin-remodeling complex (nBAF). *SS18L1* is expressed only in postmitotic neurons and regulates dendritic length. There are 5 variants (one nonsense, three missense, and one in-frame del) that have been reported in 5 probands in 3 publications (PMIDs: 23708140, 24360741, 31522742) that are included in this curation, one of which was not scored due to the patient harboring a variant in another ALS-causing gene and a high minor allele frequency in population databases. ALS-associated *SS18L1* variants are suggested to dysregulate neuronal function by inhibiting dendrite outgrowth and microglial activation through a dominant-negative mechanism, however there is an absence of functional data from primary tissue of *SS18L1* mutation carriers. This gene-disease relationship is also supported by experimental evidence (mouse models, expression, and protein interactions; PMIDs: 30976389, 14716005, 23708140). CREST knockout (Crest +/− ) and Q394X knock-in mice generated through CRISPR/Cas9 system displayed deficits in motor coordination and partially recapitulated ALS phenotypes (PMID: 30976389). 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 the meeting date May 25, 2023 (SOP Version 9).

Inheritance Pattern: AD

Disease ID:MONDO:0004976

Submitter: Genomics England PanelApp

Inheritance Pattern: AR

Disease ID:MONDO:0100038

Submitter: LiferaOmics

Genetic evidence – Published (AR scope) No scorable published cases of biallelic (autosomal recessive) SS18L1 variants causing a defined neurodevelopmental disorder were identified in the literature. Published genetic evidence total = 0 / 12 Published (AD context; not scored for AR) PMID: 37500730 – Large-scale neurodevelopmental disorder sequencing study of mSWI/SNF (BAF) complex genes reporting de novo (monoallelic) SS18L1 variants in individuals with neurodevelopmental phenotypes. Because this represents a dominant/de novo context, it is not scorable under the autosomal recessive model. ClinGen Gene–Disease Validity curation – SS18L1 is classified in association with amyotrophic lateral sclerosis under a dominant context. No autosomal recessive neurodevelopmental disorder has been curated. AD-context evidence total (not scored for AR) = 0 Genetic evidence – Our case Family 1 – One proband. Case-level (biallelic predicted null in AR model; homozygous frameshift; consanguinity −0.5 applied) = (1.5 − 0.5) = 1.0; Segregation = 0; Case-control = 0 Family 1 total = 1.0 Total genetic evidence (published AR + our case) 1.0 / 12 Experimental evidence – Published (conservative and phenotype-aligned) No experimental evidence found at this time. Experimental evidence total = 0 / 6 Overall score Genetic evidence = 1.0 Experimental evidence = 0