What are the clinical implications and management recommendations for an elderly male patient with a heterozygous SQSTM1 (Sequestosome 1) c.1294C>T (p.Gln432*) variant of uncertain significance?

SQSTM1 c.1294C>T (p.Gln432*) Heterozygous Variant of Uncertain Significance in an Elderly Male

Direct Recommendation

This heterozygous SQSTM1 nonsense variant should be managed as a likely pathogenic mutation for Paget's disease of bone, with clinical screening for bone disease, neurodegenerative conditions, and consideration of family cascade testing, while acknowledging the incomplete penetrance and variable expressivity of SQSTM1 mutations. 1

Understanding the Variant

• The p.Gln432* variant is a nonsense (stop-gain) mutation that truncates the SQSTM1/p62 protein, removing critical C-terminal domains including the ubiquitin-associated (UBA) domain 2, 3
• Nonsense and frameshift variants in SQSTM1 are typically classified as pathogenic or likely pathogenic, as they disrupt normal protein function through premature termination 1
• The variant of uncertain significance (VUS) classification likely reflects limited population frequency data or insufficient clinical correlation in databases, rather than true uncertainty about functional impact 1
• SQSTM1 mutations show incomplete penetrance, meaning not all carriers will develop clinical disease, particularly at younger ages 4

Clinical Conditions Associated with SQSTM1 Mutations

Paget's Disease of Bone (Primary Association)

• SQSTM1 mutations account for 25-50% of familial Paget's disease cases and are strongly disease-causing 5, 4
• The p.Pro392Leu mutation is the most common SQSTM1 variant, present in 63.5% of mutation carriers in one cohort 5
• Approximately 9% of SQSTM1 mutation carriers show evidence of Paget's disease by the fifth decade, with most being asymptomatic 5
• Disease onset in offspring with inherited mutations occurs later (mean age 45-48 years) compared to their affected parents, with less extensive skeletal involvement 4

Neurodegenerative Conditions (Secondary Associations)

• SQSTM1 mutations are associated with amyotrophic lateral sclerosis (ALS), particularly variants affecting the UBA domain 3
• Mutations can cause distal myopathy with rimmed vacuoles, characterized by late-onset distal lower extremity weakness 2
• Homozygous SQSTM1 mutations (not applicable to this heterozygous case) cause childhood-onset progressive cerebellar ataxia 6
• Frontotemporal dementia has been reported in association with SQSTM1 mutations 2, 3

Recommended Clinical Evaluation

Baseline Assessment for Paget's Disease

• Measure serum total alkaline phosphatase (ALP) as the primary screening test, though sensitivity for detecting early lesions is poor 5
• Obtain radionuclide bone scan to identify asymptomatic Paget's lesions, as 50% of early cases involve only a single skeletal site 5
• Consider bone-specific alkaline phosphatase and other bone turnover markers if total ALP is elevated 5
• Perform targeted skeletal radiographs of any abnormal areas identified on bone scan 5

Neurological Screening

• Conduct detailed neurological examination focusing on motor strength, particularly distal lower extremities 2
• Assess for signs of motor neuron disease including fasciculations, hyperreflexia, and muscle atrophy 3
• Evaluate for cognitive changes or behavioral symptoms suggestive of frontotemporal dementia 2, 3
• Consider EMG/nerve conduction studies if weakness or neurological symptoms are present 2

Ongoing Surveillance Strategy

• For asymptomatic elderly patients with normal baseline evaluation: repeat ALP and clinical assessment every 2-3 years 5, 4
• For patients with elevated ALP but no lesions: repeat bone scan in 1-2 years 5
• For patients with identified Paget's lesions: manage according to standard Paget's disease guidelines with bisphosphonate therapy 5
• Monitor for development of neurological symptoms annually through clinical history 2, 3

Genetic Counseling and Family Management

• Offer pre- and post-test genetic counseling to discuss autosomal dominant inheritance pattern with 50% transmission risk to offspring 1
• Recommend cascade genetic testing for first-degree relatives once the variant is confirmed as pathogenic/likely pathogenic 1
• Explain that SQSTM1 shows incomplete penetrance, so not all mutation carriers will develop clinical disease 4
• Advise that offspring inheriting the mutation typically develop disease later and with less severity than their parents, suggesting environmental factors play a role 4
• Do not use this VUS for predictive testing in family members until variant reclassification occurs 1, 7

Variant Reclassification Considerations

• Request serial reevaluation of the variant classification through the testing laboratory, as new evidence may lead to reclassification 1
• Family segregation studies showing the variant tracks with disease in multiple affected relatives would support pathogenic classification 1, 7
• Functional studies demonstrating loss of UBA domain function would support pathogenicity 2, 3
• Population frequency data showing the variant is absent or extremely rare in control populations supports pathogenicity 1

Critical Pitfalls to Avoid

• Do not dismiss this variant as benign based solely on the VUS classification—nonsense mutations truncating critical domains are typically pathogenic 1
• Do not delay clinical screening for Paget's disease while awaiting variant reclassification, as early asymptomatic disease is detectable and treatable 5
• Do not assume absence of symptoms means absence of disease—50% of early Paget's cases in SQSTM1 carriers are asymptomatic with single-site involvement 5
• Do not rely solely on ALP for screening—bone scan is necessary as ALP has poor sensitivity for detecting early lesions 5
• Do not overlook neurological manifestations—while Paget's disease is the primary phenotype, neurodegenerative conditions can occur with SQSTM1 mutations 2, 3
• Do not provide false reassurance about penetrance—while incomplete, approximately 9% show disease by age 50, and risk increases with age 5, 4

Management Based on Clinical Findings

• If Paget's disease is identified: Treat with bisphosphonates (zoledronic acid preferred) according to standard guidelines, monitor for complications including fracture, deformity, and rarely osteosarcoma 5
• If neurological disease develops: Refer to neurology for comprehensive evaluation and management of ALS, myopathy, or dementia as appropriate 2, 3
• If baseline evaluation is normal: Continue surveillance as outlined above, with lower threshold for repeat imaging if symptoms develop or ALP rises 5, 4