Publicação
Family genetics of Paget’s disease of bone
| Resumo: | Paget's disease of bone (PDB) is a systemic disease characterized by increased bone resorption and formation, causing gradual destruction of parts of the skeleton and subsequent reconstruction of a more fragile bone. PDB has an overall incidence of 2% in the population over 55 years. PDB is a complex disease with multiple genes implicated in its pathogenesis, but in its monogenic form, only one gene (SQSTM1) has been linked to PDB. To identify novel genes causing familial PDB, we performed whole exome sequencing (WES) in six individuals from a Portuguese multiplex family composed of five PDB cases, two unaffected individuals and one individual with unclear diagnosis. Given the uncertain diagnosis for one family member, we conducted two analyses: model 1, in which this individual is considered affected and model 2 where he is unaffected. DNA was captured using the SureSelect Target Enrichment System kit and sequenced using Hiseq2000 (Illumina’s Solexa). We identified three variants (c.C4786T (KIAA1875), c.C53T (NLRC3) and c.T566C (SRL)) in model 1 and one variant (c.G180A (SERINC2)) in model 2 that were present in all affected and absent from the unaffected in next-generation sequencing (NGS) data. Validation of these mutations by Sanger sequencing in all family members revealed that all model 1 mutations were present in all individuals, while the model 2 mutation was present in all family members except the individual with unclear diagnosis. None of these variants were present in a second Portuguese PDB multiplex family. In conclusion, our findings support the notion that bioinformatics analyses of NGS data is a process requiring optimization. We found four novel variants which may cause PDB in this family with an autosomal dominant pattern of inheritance and incomplete penetrance. Further studies in other PDB families are warranted to determine the pathogenic potential of these genes/variants. |
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| Autores principais: | Santos, Patrícia Alexandra Silva, 1991- |
| Assunto: | Ossos Doença de Paget Variação genética Teses de mestrado - 2014 |
| Ano: | 2014 |
| País: | Portugal |
| Tipo de documento: | dissertação de mestrado |
| Tipo de acesso: | acesso aberto |
| Instituição associada: | Universidade de Lisboa |
| Idioma: | inglês |
| Origem: | Repositório da Universidade de Lisboa |
| Resumo: | Paget's disease of bone (PDB) is a systemic disease characterized by increased bone resorption and formation, causing gradual destruction of parts of the skeleton and subsequent reconstruction of a more fragile bone. PDB has an overall incidence of 2% in the population over 55 years. PDB is a complex disease with multiple genes implicated in its pathogenesis, but in its monogenic form, only one gene (SQSTM1) has been linked to PDB. To identify novel genes causing familial PDB, we performed whole exome sequencing (WES) in six individuals from a Portuguese multiplex family composed of five PDB cases, two unaffected individuals and one individual with unclear diagnosis. Given the uncertain diagnosis for one family member, we conducted two analyses: model 1, in which this individual is considered affected and model 2 where he is unaffected. DNA was captured using the SureSelect Target Enrichment System kit and sequenced using Hiseq2000 (Illumina’s Solexa). We identified three variants (c.C4786T (KIAA1875), c.C53T (NLRC3) and c.T566C (SRL)) in model 1 and one variant (c.G180A (SERINC2)) in model 2 that were present in all affected and absent from the unaffected in next-generation sequencing (NGS) data. Validation of these mutations by Sanger sequencing in all family members revealed that all model 1 mutations were present in all individuals, while the model 2 mutation was present in all family members except the individual with unclear diagnosis. None of these variants were present in a second Portuguese PDB multiplex family. In conclusion, our findings support the notion that bioinformatics analyses of NGS data is a process requiring optimization. We found four novel variants which may cause PDB in this family with an autosomal dominant pattern of inheritance and incomplete penetrance. Further studies in other PDB families are warranted to determine the pathogenic potential of these genes/variants. |
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