Contributions
Abstract: PB1473
Type: Publication Only
Session title: Bone marrow failure syndromes incl. PNH - Clinical
Background
Diamond-Blackfan anemia (DBA) is the second most common congenital bone marrow failure syndrome, after Fanconi anemia, characterized by erythroid aplasia. The estimated prevalence was 5~7 cases per 1000,000 live births in European population and 12 per 1000,000 live births in Japanese population in one year. It is typically occured during infancy and associated with physical abnormalities, such as short stature, craniofacial, upper limb, heart and genitourinary defects. DBA patients also have the tendency of tumor susceptibility, the incidence of which is lower than that in Fanconi anemia or dyskeratosis congenita patients. DBA is commonly diagnosed based on a positive family history, age of onset less than one year old and laboratory findings such as macrocytic anemia, reticulocytopenia, myeloproliferative activity with erythroid precursor cell reduction, elevated erythrocyte adenosine deaminase activity (eADA), and persistence of hemoglobin F (HbF), as well as associated congenital malformations. The phenotypic expression of DBA varies greatly, even in the same family.
Aims
We aimed to expand DBA-related gene mutations library and investigate the relationship between clinical phenotype and genotype in DBA.
Methods
Genomic DNA of 14 clinically suspected congenital DBA patients was selected to detect 71 known genes closely related to congenital bone marrow failure by next-generation sequencing (NGS). The relationship between clinical phenotype and genotype in DBA was analyzed.
Results
We have identified 13 pathogenic variants of 7 genes (RPL11, RPL5, RPS19, RPS26, RPL35A, RPS27, and TSR2) in 14 clinically suspected DBA patients. The ratio of male to female is 1:1. We have identified RPS19 mutations in six patients, and RPL11 and RPS26 mutations in two patients respectively. Among the mutations identified, five were previously reported, and eight variants were novel. Particularly, we have identified one stop-gain mutations, one splicing mutation, four frameshift variants, six missense variants, as well as one start-loss mutation. Except for two adult patients, the other patients were infants, and the median age of onset was one year old. There was no significant difference in gender and age. Among the cases, female patients are more prone to congenital dysplasia or tumor susceptibility. Compared with the European and American patients, the Asian patients with RPS19 and RPL5 gene mutations have a higher rate of congenital dysplasia.
Conclusion
Our study further fills genetic disease mutation database and enriches the corresponding clinical manifestations. Our results suggested that genetic diagnosis by NGS is a fast, economic and accurate way to detect and identify pathogenic alterations of inherited diseases like Diamond-Blackfan anemia.
Keyword(s): Diagnosis, Diamond-Blackfan anemia, Mutation analysis, Phenotype
Abstract: PB1473
Type: Publication Only
Session title: Bone marrow failure syndromes incl. PNH - Clinical
Background
Diamond-Blackfan anemia (DBA) is the second most common congenital bone marrow failure syndrome, after Fanconi anemia, characterized by erythroid aplasia. The estimated prevalence was 5~7 cases per 1000,000 live births in European population and 12 per 1000,000 live births in Japanese population in one year. It is typically occured during infancy and associated with physical abnormalities, such as short stature, craniofacial, upper limb, heart and genitourinary defects. DBA patients also have the tendency of tumor susceptibility, the incidence of which is lower than that in Fanconi anemia or dyskeratosis congenita patients. DBA is commonly diagnosed based on a positive family history, age of onset less than one year old and laboratory findings such as macrocytic anemia, reticulocytopenia, myeloproliferative activity with erythroid precursor cell reduction, elevated erythrocyte adenosine deaminase activity (eADA), and persistence of hemoglobin F (HbF), as well as associated congenital malformations. The phenotypic expression of DBA varies greatly, even in the same family.
Aims
We aimed to expand DBA-related gene mutations library and investigate the relationship between clinical phenotype and genotype in DBA.
Methods
Genomic DNA of 14 clinically suspected congenital DBA patients was selected to detect 71 known genes closely related to congenital bone marrow failure by next-generation sequencing (NGS). The relationship between clinical phenotype and genotype in DBA was analyzed.
Results
We have identified 13 pathogenic variants of 7 genes (RPL11, RPL5, RPS19, RPS26, RPL35A, RPS27, and TSR2) in 14 clinically suspected DBA patients. The ratio of male to female is 1:1. We have identified RPS19 mutations in six patients, and RPL11 and RPS26 mutations in two patients respectively. Among the mutations identified, five were previously reported, and eight variants were novel. Particularly, we have identified one stop-gain mutations, one splicing mutation, four frameshift variants, six missense variants, as well as one start-loss mutation. Except for two adult patients, the other patients were infants, and the median age of onset was one year old. There was no significant difference in gender and age. Among the cases, female patients are more prone to congenital dysplasia or tumor susceptibility. Compared with the European and American patients, the Asian patients with RPS19 and RPL5 gene mutations have a higher rate of congenital dysplasia.
Conclusion
Our study further fills genetic disease mutation database and enriches the corresponding clinical manifestations. Our results suggested that genetic diagnosis by NGS is a fast, economic and accurate way to detect and identify pathogenic alterations of inherited diseases like Diamond-Blackfan anemia.
Keyword(s): Diagnosis, Diamond-Blackfan anemia, Mutation analysis, Phenotype