Abstract
BackgroundCongenital 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.FindingsWe 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.ConclusionTo 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13045-015-0154-0) contains supplementary material, which is available to authorized users.
Highlights
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
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
Summary
The study protocol was approved by the Institutional Review Boards of the Hematology and Blood Diseases Hospital, CAMS/PUMC (Ethics No KT2013004-EC-1). Informed consent was obtained from the guardians of the patients following institutional guidelines. We designed a targeted capture sequencing assay to test a panel of 417 blood disease genes, including the seven known CSArelated genes. The targeted genes were enriched using a biotinylated capture probe (MyGenostics, Baltimore, MD, USA) as described previously [15]. Mitochondrial genome capture sequencing was performed using a mitochondria enrichment kit (MitoCapTM, MyGenostics, Beijing, China) as described previously [16]. The 417 genes in the panel that was used for targeted capture sequencing are listed in Additional file 1: Table S1. The primers used for Sanger sequencing are listed in Additional file 2: Table S2. Detailed experimental methods are described in Additional file 3: Figure S1
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