Summary
Reactivation of fetal haemoglobin (HbF) expression is an effective way to treat β‐thalassaemia and sickle cell anaemia. In the present study, we identified a novel GATA zinc finger domain‐containing protein 2A (GATAD2A) mutation, which contributed to the elevation of HbF and ameliorated clinical severity in a patient with β‐thalassaemia, by targeted next‐generation sequencing. Knockout of GATAD2A led to a significant induction of HbF in both human umbilical cord blood‐derived erythroid progenitor‐2 (HUDEP‐2) and human cluster of differentiation (CD)34+ cells with a detectable impact on erythroid differentiation. Furthermore, heterozygous knockout of GATAD2A impaired recruitment of chromodomain helicase DNA‐binding protein 4 (CHD4) to the methyl‐binding domain protein 2 (MBD2)‐containing nucleosome remodelling and deacetylation (NuRD) complex. Our present data suggest that mutations causing the haploinsufficiency of GATAD2A might contribute to amelioration of clinical severity in patients with β‐thalassaemia.
Background
Aicardi–Goutières syndrome (AGS) is a rare, autosomal recessive, hereditary neurodegenerative disorder. It is characterized mainly by early onset progressive encephalopathy, concomitant with an increase in interferon-α levels in the cerebrospinal fluid. Preimplantation genetic testing (PGT) is a procedure that could be used to choose unaffected embryos for transfer after analysis of biopsied cells, which prevents at-risk couples from facing the risk of pregnancy termination.
Methods
Trio-based whole exome sequencing, karyotyping and chromosomal microarray analysis were used to determine the pathogenic mutations for the family. To block the inheritance of the disease, multiple annealing and looping-based amplification cycles was used for whole genome amplification of the biopsied trophectoderm cells. Sanger sequencing and next-generation sequencing (NGS)-based single nucleotide polymorphism (SNP) haplotyping were used to detect the state of the gene mutations. Copy number variation (CNV) analysis was also carried out to prevent embryonic chromosomal abnormalities. Prenatal diagnosis was preformed to verify the PGT outcomes.
Results
A novel compound heterozygous mutation in TREX1 gene was found in the proband causing AGS. A total of 3 blastocysts formed after intracytoplasmic sperm injection were biopsied. After genetic analyses, an embryo harbored a heterozygous mutation in TREX1 and without CNV was transferred. A healthy baby was born at 38th weeks and prenatal diagnosis results confirmed the accuracy of PGT.
Conclusions
In this study, we identified two novel pathogenic mutations in TREX1, which has not been previously reported. Our study extends the mutation spectrum of TREX1 gene and contributes to the molecular diagnosis as well as genetic counseling for AGS. Our results demonstrated that combining NGS-based SNP haplotyping for PGT-M with invasive prenatal diagnosis is an effective approach to block the transmission of AGS and could be applied to prevent other monogenic diseases.
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