Identification of a novel 91.5 kb-deletion (αα)^FJ in the α-globin gene cluster using single-molecule real-time (SMRT) sequencing

To present a novel 91.5-kb deletion of the α-globin gene cluster (αα)^FJ identified by genetic assay and prenatal diagnosis in a Chinese family. The proband was a 34-year-old G3P1 (Gravida 3, Para 1) female at the gestational age of 21⁺ weeks with a history of an edematous fetus. A routine genetic assay (reverse dot blot hybridization, RDB) was performed to detect common thalassemia mutations. Multiplex ligation-dependent probe amplification (MLPA) and single-molecule real-time technology (SMRT) were used to detect rare thalassemia mutations. The hematological phenotypes of the proband, her mother, elder sister, husband, daughter, and nephew were consistent with the phenotype of α-thalassemia trait. No mutations were found in these family members by RDB, except for the proband’s husband who carried an α-globin gene deletion --^SEA/αα. MLPA results showed that the proband and other α-thalassemia-suspected relatives had heterozygous deletions around the <i>POLR3K</i>-3-463nt, <i>HS40</i>-178nt, and <i>HBA-HS40</i>-382nt probes. The 5′-breakpoint was out of probe scope and could not be determined. SMRT was performed and a 91.5-kb deletion (NC_000016.10: g.39268_130758del) in the α-globin gene cluster (αα)^FJ was identified in the proband and other suspected relatives, which could explain their phenotypes. At the proband’s gestational age of 22⁺ weeks, an amniotic fluid sample was collected and analyzed. As only the 91.5-kb deletion (αα)^FJ was identified in the fetus with RDB, MLPA, and SMRT. The proband was suggested to continue the pregnancy. We first reported a 91.5-kb deletion (NC_000016.10: g.hg38-chr16:39268-_130758del) of the HS-40 region in the α-globin gene cluster (αα)^FJ identified in a Chinese family. Since the HS-40 loss of heterozygosity in combination with the heterozygous deletion --^SEA might result in Hb Bart’s hydrops fetalis, routine genetic assay, and SMRT were recommended to individuals at risk for prenatal diagnosis.