The First Compound Heterozygosity for Two Different α-Thalassemia Determinants Causes Hb Bart's Hydrops Fetalis in a Chinese Family.

In southern China, α-thalassemia is the most prevalent hereditary monogenic disorder, and deletion variants are the predominant form. Conventional thalassemia diagnosis techniques are numerous, however they are all limited in their ability to detect rare deletions. Here, we discuss a family who sought genetic counseling during their fourth pregnancy after experiencing Hb Bart's hydrops fetalis in two of their previous pregnancies. To ascertain the thalassemia genotype, the family members underwent hematological testing, routine genetic analysis and multiplex ligation-dependent probe amplification (MLPA). The precise deletion locations could not be identified, while MLPA detected an unknown copy number variant. Lastly, a rare 11.1 kb deletion located in the gene (Chr16: 170,832-182,004, GRch38/hg38) was directly identified by single-molecule real-time technology (SMRT) sequencing. Furthermore, we confirmed the compound heterozygosity of -- allele and -- allele, which contributed to the explanation of the Hb Bart's hydrops fetalis syndrome in the fetuses from the second and third pregnancies. We have first verified a compound heterozygosity for -- allele and -- allele. This study may provide a reference strategy for the discovery of rare and potentially novel thalassemia variants using a comprehensive method combining SMRT sequencing and conventional diagnostic technology, improving the accuracy and efficacy of thalassemia diagnosis.