A Novel Large Deletion Including the Major Regulatory Element Compounded with SEA Deletion Causing
Ping Liu1, Jieyu Wang2, Hongyu Luo1
1Prenatal Dagnosis Department Ganzhou Maternal and Child Health Hospital, Guangzhou, China.
Insights
A novel deletion in alpha-globin regulatory elements, combined with alpha-thalassemia, caused severe Hb Bart
Area of Science:
- Genetics
- Hematology
- Prenatal Diagnosis
Background:
- Alpha-globin regulatory elements (MCS-R) are crucial for alpha-globin synthesis.
- Deletions in these elements and alpha-globin genes can lead to Hb Bart's hydrops fetalis, a severe form of alpha-thalassemia.
Purpose of the Study:
- To investigate a case of suspected Hb Bart's hydrops fetalis.
- To identify the genetic cause of severe alpha-thalassemia in a fetus presenting with hydrops fetalis.
Main Methods:
- Fetal umbilical cord blood electrophoresis.
- Next-generation sequencing with targeted capture.
- Multiplex Ligation-dependent Probe Amplification (MLPA) with a self-designed probe.
Main Results:
- Electrophoresis confirmed 87.6% Hb Bart's, indicating Hb Bart's hydrops fetalis.
- Genetic analysis revealed -SEA deletion compounded with a novel large deletion of major alpha-globin regulatory elements (MCS-R2, R1, R3, R4).
- The novel deletion, spanning from the telomere with a breakpoint between 143702-144291 (GRch38/hg18), was also found in the mild anemia-affected father and grandfather.
Conclusions:
- This study identified a novel large deletion in MCS-R elements associated with alpha-thalassemia.
- The compound deletion resulted in the earliest presentation of fetal edema in reported cases of MCS deletion with alpha0-thalassemia.
- Findings provide crucial evidence for genetic counseling regarding MCS deletions.
Abstract:
MCS-R regulatory elements are very important for the synthesis of α-globin. Deletion of the major α-globin regulatory elements compounded with deletion of α-globin genes can cause Hb Bart's (c4) hydrops fetalis, which is the severe form of α-thalassemia. In this report, a 19-year-old female at the 16th week of gestation came to our center due to abnormal fetal cardiothoracic ratio and thickened placental depth. The electrophoresis result of fetal umbilical cord blood revealed the level of Hb Bart's band to be 87.6%, which suggested the fetus was Hb Bart's hydrops fetalis. Next generation sequencing screen using targeted capture was used to detect the genotype of the fetus to be -SEA deletion, βA/βA. Multiplex ligation-dependent probe amplification (MLPA) is very useful to detect copy number variation (deletions/duplications), the result of which suggested the existence of -SEA deletion compounded with the novel large deletion of the major α-globin regulatory element (MCS-R2, R1, R3 and R4). Using the self-designed MLPA probe, the deletion should extend from the telomere downstream and the downstream breakpoint was between 143702 and 144291(GRch38/hg18). The novel deletion was also observed in the fetus' father and grandfather who had mild anemia. Of cases with the MCS deletion compounded with α0-thalassemia, this was the earliest time when the fetus presented fetal edema. Our study gave more evidence for genetic counseling for MCS deletion.
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