Dataset Information

Detection of maternal carriers of common α-thalassemia deletions from cell-free DNA.

ABSTRACT: α-Thalassemia is a common inherited blood disorder manifested mainly by the deletions of α-globin genes. In geographical areas with high carrier frequencies, screening of α-thalassemia carrier state is therefore of vital importance. This study presents a novel method for identifying female carriers of common α-thalassemia deletions using samples routinely taken for non-invasive prenatal tests for screening of fetal chromosomal aneuploidies. A total of 68,885 Vietnamese pregnant women were recruited and α-thalassemia statuses were determined by gap-PCR, revealing 5344 women (7.76%) carried deletions including αα/--^SEA (4.066%), αα/-α^3.7 (2.934%), αα/-α^4.2 (0.656%), and rare genotypes (0.102%). A two-stage model was built to predict these α-thalassemia deletions from targeted sequencing of the HBA gene cluster on maternal cfDNA. Our method achieved F1-scores of 97.14-99.55% for detecting the three common genotypes and 94.74% for detecting rare genotypes (-α^3.7/-α^4.2, αα/--^THAI, -α^3.7/--^SEA, -α^4.2/--^SEA). Additionally, the positive predictive values were 100.00% for αα/αα, 99.29% for αα/--^SEA, 94.87% for αα/-α^3.7, and 96.51% for αα/-α^4.2; and the negative predictive values were 97.63%, 99.99%, 99.99%, and 100.00%, respectively. As NIPT is increasingly adopted for pregnant women, utilizing cfDNA from NIPT to detect maternal carriers of common α-thalassemia deletions will be cost-effective and expand the benefits of NIPT.

SUBMITTER: Doan PL

PROVIDER: S-EPMC9363435 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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Publications

Detection of maternal carriers of common α-thalassemia deletions from cell-free DNA.

Doan Phuoc-Loc PL Nguyen Duy-Anh DA Le Quang Thanh QT Hoang Diem-Tuyet Thi DT Nguyen Huu Du HD Nguyen Canh Chuong CC Doan Kim Phuong Thi KPT Tran Nhat Thang NT Ha Thi Minh Thi TMT Trinh Thu Huong Nhat THN Nguyen Van Thong VT Bui Chi Thuong CT Lai Ngoc-Diep Thi NT Duong Thanh Hien TH Mai Hai-Ly HL Huynh Pham-Uyen Vinh PV Huynh Thu Thanh Thi TTT Le Quang Vinh QV Vo Thanh Binh TB Dao Thi Hong-Thuy TH Vo Phuong Anh PA Le Duy-Khang Nguyen DN Tran Ngoc Nhu Thi NNT Tran Quynh Nhu Thi QNT Van Yen-Linh Thi YT Tran Huyen-Trang Thi HT Nguyen Hoai Thi HT Nguyen Phuong-Uyen PU Do Thanh-Thuy Thi TT Truong Dinh-Kiet DK Tang Hung Sang HS Cao Ngoc-Phuong Thi NT Lam Tuan-Thanh TT Tran Le Son LS Nguyen Hoai-Nghia HN Giang Hoa H Phan Minh-Duy MD

Scientific reports 20220809 1

α-Thalassemia is a common inherited blood disorder manifested mainly by the deletions of α-globin genes. In geographical areas with high carrier frequencies, screening of α-thalassemia carrier state is therefore of vital importance. This study presents a novel method for identifying female carriers of common α-thalassemia deletions using samples routinely taken for non-invasive prenatal tests for screening of fetal chromosomal aneuploidies. A total of 68,885 Vietnamese pregnant women were recrui ...[more]

PMID: 35945425

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Project description:α-thalassemia is characterized in about 80% of cases by deletions generated by the presence of duplications and interspersed repeated sequences in the α-globin gene cluster. In a project on the molecular basis of α-thalassemia in Southern Italy, we identified six families, showing an absence of the most common deletions, and normal α-globin gene sequences. Multiplex Ligation-dependent Probe Amplification (MLPA), qRT-PCR, and the sequencing of long-range PCR amplicon have been used for the identification and characterization of new deletions. MLPA analysis for the identification of α- and β-globin rearrangement revealed the presence of five new α-thalassemia deletions. The set-up of qRT-PCR allowed us to delimit the extent of the deletions ranging from about 10 kb to more than 250 kb, two of them being of the telomeric type. The long-range PCR generated a specific anomalous fragment in three deletions, and only several unspecific bands in the other two deletions. The sequencing of the anomalous amplicons revealed the breakpoints of two deletions: the --PA, 34 kb long, identified in two families, and the telomeric --AG, 274 kb long. The anomalous fragment containing the breakpoint of the deletion --FG was partially sequenced, and it was not possible to identify the breakpoints due to the presence of several repetitive Alu sequences. The analysis of the breakpoint regions of the --Sciacca and --Puglia, respectively, are about 10 and 165 kb long, and revealed the presence of repeats that most likely impaired the amplification of a specific fragment for the identification of the breakpoint. MLPA, in association with qRT-PCR and long-range PCR, is a good approach for the identification and molecular characterization of rare or new deletions. Breakpoint analysis confirms that Alu sequences play an important role in favoring unequal crossing-over. Southern Italy shows considerable genetic heterogeneity, as expected with its central position in the Mediterranean basin, favoring migratory flows.

Dataset Information

Detection of maternal carriers of common α-thalassemia deletions from cell-free DNA.

Publications

Detection of maternal carriers of common α-thalassemia deletions from cell-free DNA.

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