What are the clinical implications and management strategies for the SQSTM1 (Sequestosome 1) c.1294C>T variant?

SQSTM1 c.1294C>T Variant: Clinical Management

Direct Answer

The SQSTM1 c.1294C>T variant (p.Gln432) is a nonsense mutation creating a premature stop codon that should be managed as a likely pathogenic variant for Paget's disease of bone, requiring clinical screening for bone disease and neurodegenerative conditions, with consideration for family cascade testing.* 1

Variant Classification and Pathogenicity

The c.1294C>T variant results in a premature termination codon (p.Gln432*), which disrupts normal SQSTM1/p62 protein function. Nonsense and frameshift variants in SQSTM1 are typically classified as pathogenic or likely pathogenic because they cause premature protein termination. 1 This specific variant truncates the protein before the critical ubiquitin-associated (UBA) domain, which is essential for selective autophagy function. 2, 3

The variant may be listed as a VUS (variant of uncertain significance) in some databases due to limited population frequency data rather than true uncertainty about functional impact. 1 However, the molecular mechanism—premature termination disrupting the UBA domain—strongly supports pathogenicity. 1

Clinical Phenotypes Associated with SQSTM1 Mutations

Paget's Disease of Bone (Primary Association)

SQSTM1 mutations are the most established genetic cause of familial Paget's disease of bone, with mutation frequencies of approximately 20% in hereditary cases. 3, 4 Key clinical features include:

• Highly variable expressivity within families: Some mutation carriers develop early-onset disease with extensive bone involvement and markedly elevated alkaline phosphatase, while siblings with the same mutation may have limited bone involvement detectable only by technetium-99m MDP bone scan. 3
• Incomplete penetrance: Multiple asymptomatic mutation carriers exist in affected families, with at least one unaffected carrier identified in each of five studied kindreds. 3
• The mutation acts as a predisposition gene rather than a deterministic cause, indicating that nongenetic factors play important roles in disease manifestation. 3

Neurodegenerative Conditions

SQSTM1 mutations are increasingly recognized in neurological disorders:

• Progressive childhood-onset cerebellar ataxia with vertical supranuclear gaze palsy can result from homozygous SQSTM1 mutations. 5
• SQSTM1 mutations may act as genetic modifiers in CADASIL, potentially worsening disease aggressiveness when co-occurring with NOTCH3 mutations, particularly in patients with early-onset stroke, severe white matter burden, and early dementia. 6
• Frontotemporal dementia and amyotrophic lateral sclerosis are associated with SQSTM1 mutations. 5

The mechanistic link involves impaired autophagy-lysosomal pathway function, as SQSTM1/p62 serves as a selective autophagy receptor linking ubiquitinated proteins to LC3. 2, 6

Molecular Mechanisms

SQSTM1/p62 functions as a selective autophagy receptor that links ubiquitinated proteins to LC3 via its WXXL/LIR motif, and simultaneously regulates KEAP1 degradation to control NFE2L2/NRF2 antioxidant responses. 2 The protein also:

• Mediates SLC40A1/ferroportin degradation, affecting cellular iron homeostasis. 2
• Accumulates when macroautophagy is inhibited, interacting with HDAC6 to regulate microtubule acetylation and autophagosome turnover. 2
• Maintains protein folding capacity under endoplasmic reticulum stress, with p62 deficiency enhancing both basal and chemically induced ER stress. 7

Truncation mutations like c.1294C>T eliminate the UBA domain, preventing normal ubiquitin binding and autophagy function. 3

Clinical Management Algorithm

Initial Evaluation

1. Obtain baseline serum alkaline phosphatase to screen for Paget's disease activity. 3
2. Perform technetium-99m MDP bone scan to identify affected skeletal sites, as clinical symptoms may be absent despite bone involvement. 3
3. Conduct neurological assessment including evaluation for ataxia, gaze abnormalities, cognitive function, and signs of frontotemporal dementia or motor neuron disease. 5, 6
4. Order brain MRI if neurological symptoms are present to assess for white matter changes or cerebellar atrophy. 5, 6

Genetic Counseling and Family Testing

Provide pre- and post-test genetic counseling to discuss the autosomal dominant inheritance pattern with 50% transmission risk to offspring. 1 Key counseling points include:

• Incomplete penetrance means not all mutation carriers will develop disease. 3
• Variable expressivity means disease severity cannot be predicted from genotype alone. 3
• Cascade genetic testing should be offered to first-degree relatives once the variant is confirmed as pathogenic/likely pathogenic. 1
• Do not use this variant for predictive testing in family members if it remains classified as a VUS until reclassification occurs. 1

Ongoing Monitoring

For mutation carriers (symptomatic or asymptomatic):

• Annual serum alkaline phosphatase monitoring to detect subclinical Paget's disease. 3
• Periodic bone scans (every 2-5 years) for asymptomatic carriers to identify early bone involvement. 3
• Annual neurological screening for cognitive changes, gait disturbances, or motor symptoms. 5, 6

Treatment Considerations

• Bisphosphonate therapy for active Paget's disease based on standard treatment guidelines. 3
• Symptomatic management for neurological manifestations as no disease-modifying therapies currently exist for SQSTM1-related neurodegeneration. 5, 6

Variant Reclassification Strategies

To support pathogenic classification:

• Family segregation studies demonstrating the variant tracks with disease in multiple affected relatives would strengthen pathogenicity evidence. 1
• Functional studies showing loss of UBA domain function would provide definitive pathogenicity evidence. 1
• Population frequency data showing the variant is absent or extremely rare in control populations supports pathogenicity. 1

Critical Pitfalls to Avoid

• Do not assume all mutation carriers will develop disease—incomplete penetrance is well-documented. 3
• Do not rely solely on clinical symptoms to identify affected family members—bone scans may reveal subclinical disease. 3
• Do not overlook neurological screening—SQSTM1 mutations have broader phenotypic spectrum beyond Paget's disease. 5, 6
• Do not dismiss the variant as benign based on VUS classification—nonsense mutations disrupting the UBA domain are functionally deleterious. 1, 3