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Mutation analysis of Chinese sporadic congenital sideroblastic anemia by targeted capture sequencing
Wenbin An1, Jingliao Zhang2, Lixian Chang3
1Division of Pediatric Blood Diseases Center, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, 288 Nanjing Road, Tianjin, 300020, People's Republic of China. annwenbin@163.com.
Insights
Genetic analysis of 10 Chinese patients with congenital sideroblastic anemias (CSAs) identified mutations in ALAS2 and SLC25A38, alongside mitochondrial DNA deletions. This study expands the known genetic causes of CSA and aids in diagnosis.
Area of Science:
- Genetics
- Hematology
- Molecular Biology
Background:
- Congenital sideroblastic anemias (CSAs) are rare genetic disorders affecting heme biosynthesis or iron metabolism.
- Approximately 40% of CSA cases lack identified pathogenic gene mutations, highlighting the need for further genetic investigation.
- This study focuses on sporadic CSA cases in a Chinese cohort.
Purpose of the Study:
- To systematically analyze the mutation profile in 10 Chinese patients with sporadic congenital sideroblastic anemia (CSA).
- To identify novel genetic mutations and expand the understanding of CSA pathogenesis.
- To evaluate the utility of targeted gene sequencing in diagnosing heterogeneous genetic CSAs.
Main Methods:
- Targeted deep sequencing of 417 known CSA-related genes.
- Mitochondrial genome analysis using next-generation sequencing.
- Confirmation of sequencing results via Sanger sequencing.
Main Results:
- Mutations in ALAS2 (one patient) and SLC25A38 (three patients, including three novel mutations) were identified.
- Mitochondrial DNA deletions were detected in two patients.
- No causative mutations were found in four patients, suggesting other genetic factors may be involved.
Conclusions:
- Novel mutations in ALAS2 (C471Y) and SLC25A38 (W87X, I143Pfs146X, R134C) were reported for the first time.
- These findings contribute to the CSA mutation database and expand the phenotypic spectrum of mitochondrial DNA deletion mutations.
- Targeted capture sequencing is effective for genetic screening and diagnosis of heterogeneous CSAs.
Background:
Congenital sideroblastic anemias (CSAs) comprise a group of heterogenous genetic diseases that are caused by the mutation of various genes involved in heme biosynthesis, iron-sulfur cluster biogenesis, or mitochondrial solute transport or metabolism. However, approximately 40% of patients with CSA have not been found to have pathogenic gene mutations. In this study, we systematically analyzed the mutation profile in 10 Chinese patients with sporadic CSA.
Findings:
We performed targeted deep sequencing analysis in ten patients with CSA using a panel of 417 genes that included known CSA-related genes. Mitochondrial genomes were analyzed using next-generation sequencing with a mitochondria enrichment kit and the HiSeq2000 sequencing platform. The results were confirmed by Sanger sequencing. The ALAS2 mutation was detected in one patient. SLC25A38 mutations were detected in three patients, including three novel mutations. Mitochondrial DNA deletions were detected in two patients. No disease-causing mutations were detected in four patients.
Conclusion:
To our knowledge, the pyridoxine-effective mutation C471Y of ALAS2, the compound heterozygous mutation W87X, I143Pfs146X, and the homozygous mutation R134C of SLC25A38 were found for the first time. Our findings add to the number of reported cases of this rare disease and to the CSA pathogenic mutation database. Our findings expand the phenotypic profile of mitochondrial DNA deletion mutations. This work also demonstrates the application of a congenital blood disease assay and targeted capture sequencing for the genetic screening analysis and diagnosis of heterogenous genetic CSA.
