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Delayed development of Paget's disease in offspring inheriting SQSTM1 mutations
Mark J Bolland1, Pak Cheung Tong, Dorit Naot
1Department of Medicine, University of Auckland, New Zealand. m.bolland@auckland.ac.nz
Insights
Offspring inheriting SQSTM1 mutations for familial Paget's disease are diagnosed later and have less severe symptoms than their parents. This suggests environmental factors influence disease development, indicating incomplete penetrance of the SQSTM1 mutation.
Area of Science:
- Genetics
- Bone Metabolism
- Disease Pathogenesis
Background:
- Familial Paget's disease is linked to mutations in the sequestosome 1 (SQSTM1) gene.
- SQSTM1 mutations are found in 25-50% of familial Paget's disease cases.
- Understanding genetic predisposition and environmental influences is key to Paget's disease research.
Purpose of the Study:
- To compare the age of diagnosis and disease severity in parents and offspring with shared SQSTM1 mutations.
- To investigate the penetrance of SQSTM1 mutations in familial Paget's disease.
- To explore potential environmental factors contributing to Paget's disease.
Main Methods:
- Sequencing of the SQSTM1 gene in 58 offspring from 10 families.
- Bone scintigraphy and serum alkaline phosphatase (ALP) levels to assess Paget's disease presence and severity.
- Comparison of clinical data between affected parents and their offspring with inherited SQSTM1 mutations.
Main Results:
- 23 out of 58 offspring inherited an SQSTM1 mutation.
- Offspring with mutations showed a 63% reduced risk of diagnosis compared to parents (p=0.028).
- Paget's disease in affected offspring was diagnosed later and was less severe than in their parents.
Conclusions:
- SQSTM1 mutations exhibit incomplete penetrance in familial Paget's disease.
- Environmental factors likely play a significant role in the pathogenesis and clinical presentation of the disease.
- Decreasing exposure to environmental factors may be contributing to the observed differences between generations.
Unlabelled:
Familial Paget's disease is associated with mutations in SQSTM1. We compared the age at diagnosis and severity of Paget's disease in parents with SQSTM1 mutations to their offspring who inherited a mutation. At any given age, the offspring were less likely to be diagnosed with Paget's disease and had less severe disease than their parents.
Introduction:
Mutations in sequestosome 1 (SQSTM1) occur in 25-50% of cases of familial Paget's disease and are thought to be disease-causing. We sought to determine whether there are differences in age at diagnosis and severity of disease in parents and their offspring who share the same genetic predisposition to Paget's disease.
Materials And Methods:
Eighty-four offspring from 10 families (29 index patients with Paget's disease) with mutations in SQSTM1 were approached, and 58 agreed to participate. The ubiquitin-binding domain region of SQSTM1 was sequenced, and the presence or absence of the known mutation was established. The presence of Paget's disease in offspring who had inherited an SQSTM1 mutation was determined by bone scintigraphy and measurement of serum alkaline phosphatase (ALP).
Results:
Twenty-three of 58 offspring had inherited a germline mutation in SQSTM1. The mean ALP was 77 U/liter in offspring with mutations and 72 U/liter in those without mutations (p=0.84). Scintiscans from four offspring (mean age, 45 years; mean ALP, 139 U/liter; mean skeletal involvement, 6%) showed evidence of Paget's disease but were normal in the other 19 (mean age, 44 years; mean ALP, 64 U/liter). In comparison, in the 15 parents of the 23 offspring, the mean age of diagnosis was 48 years, the mean ALP was 850 U/liter, and the mean skeletal involvement was 30%. There was a 63% reduction in the risk of being diagnosed with Paget's disease at a comparable age in the offspring compared with the parents (p=0.028).
Conclusions:
Only 17% of offspring inheriting an SQSTM1 mutation had evidence of Paget's disease on scintigraphy, and this was diagnosed at a later age and was less extensive than in their affected parents. SQSTM1 thus shows incomplete penetrance. The data are consistent with the hypothesis that an environmental factor is important in the pathogenesis and clinical phenotype of familial Paget's disease and that exposure to this factor may be falling.
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