Submission Details

SQSTM1 was first reported in relation to autosomal dominant frontotemporal dementia (FTD) and/or amyotrophic lateral sclerosis (ALS) 3 (OMIM: 616437) in 2011 (Fecto et al., PMID: 22084127). SQSTM1 encodes Sequestosome 1 (sqstm1/p62) and is a scaffolding protein that regulates multiple biological processes, including NFKB1 signaling, apoptosis, transcription regulation, ubiquitin-mediated autophagy. SQSTM1 has also been associated with autosomal dominant distal myopathy/myositis (OMIM: 617158), autosomal dominant Paget disease of bone 3 (OMIM: 167250), and autosomal recessive, childhood-onset neurodegeneration with ataxia, dystonia, and gaze palsy (OMIM: 617145). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we did not find a distinct difference between the molecular mechanism, phenotypic variability, or inheritance pattern of distal myopathy/myositis and FTD/ALS 3, nor a distinct difference between the molecular mechanism or inheritance pattern of Paget disease of bone 3 and FTD/ALS 3; therefore, these diseases were lumped for the purposes of gene curation. However, we found a difference in molecular mechanism, inheritance pattern, and phenotypic variability between childhood-onset neurodegeneration with ataxia, dystonia, and gaze palsy and FTD/ALS 3, and these disease entities were split. This split curation for autosomal recessive, childhood-onset neurodegeneration with ataxia, dystonia, and gaze palsy will be curated separately.

The association between SQSTM1 and ALS was first established in an aggregate variant case-control analysis that identified an association between non-synonymous rare variants in the gene and ALS based on the Sanger sequencing of SQSTM1 in 1092 ALS cases and 1448 controls (Fecto et al., PMID: 22084127). This curation also includes one other case-control analysis from 1 publication that was scored (PMIDs: 24899140). Additionally, 28 variants, including missense, nonsense, and splicing variants, reported in 28 probands from 14 publications were scored in this curation. Based on the curation, a genetic evidence score of 5.6 was reached. The majority of variants identified in SQSTM1 appear to be missense variants.

The gene-disease association is also supported by experimental evidence describing physical interaction with other known ALS associated genes (PMIDs: 30022074, 30290707, and 19765191); aberrant expression in patient cells (PMID: 14762676); functional alterations in patient and non-patient cells (PMIDs: 31362587, 28490746, 27554286, and 27158844); and establishment of model organisms and rescues (PMIDs: 33557921 and 25410659). An experimental evidence score of 5.5 was reached.

Although the final score of 11.1 is typically rounded to the next highest whole number based on SOPv9, the ALS GCEP has chosen to apply standard rounding guidelines resulting in a score of 11 and a classification of moderate association with FTD/ALS 3. Notably, the current literature lacks evidence of variant segregation in SQSTM1 , which is needed to gain a greater understanding of the involvement of SQSTM1 in ALS. It is important to understand that in the clinical diagnostic setting, the identification of missense variants of uncertain significance will be common in this gene, and variant interpretation must be completed with caution.

In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged.This classification was approved by the ClinGen ALS GCEP on the meeting date Decemeber 13, 2022 (SOP Version 9).