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Anales de Pediatria Feb 2024Hydrops fetalis (HF) is a rare condition with a high mortality. This study analysed the obstetric and perinatal outcomes of antenatally diagnosed HF according to its...
INTRODUCTION
Hydrops fetalis (HF) is a rare condition with a high mortality. This study analysed the obstetric and perinatal outcomes of antenatally diagnosed HF according to its aetiology and the possibility of intrauterine treatment (IUT).
PATIENTS AND METHODS
We carried out a retrospective review of the health records of 164 pregnant women with a prenatal diagnosis of HF in a tertiary care centre between 2011-2021. We analysed prenatal interventions, clinical findings, aetiologies and obstetric and live-born infant outcomes.
RESULTS
An invasive prenatal study had been performed in 79.3% cases. The most common aetiologies were genetic disorders (31%), TORCH and parvovirus B19 infections (9.7%) and structural heart diseases (9.1%). Intrauterine treatment was performed in 25.6%, and 74.4% of pregnancies were terminated. Pregnancies with a prenatal diagnosis of genetic or chromosomal disorders had higher rates of elective termination compared to other aetiologies (P < .01). Among all pregnancies, only 25.6% resulted in live births (LBs), most of them preterm. Perinatal and 1-year survival rates were higher in the group that received IUT (P < .001). Among the LBs, structural heart diseases had the worst survival rates, while the aetiology with the best outcomes was tachyarrhythmia. Survival at 1 year of life among those born alive was 70%, but 58.6% of these infants had significant morbidity at discharge.
CONCLUSIONS
Despite advances in the management of FH, the poor obstetric prognosis, perinatal mortality and morbidity of survivors is still significant. These data are important for the purpose of counselling families when HF is diagnosed antenatally.
Topics: Infant, Newborn; Humans; Pregnancy; Female; Hydrops Fetalis; Tertiary Care Centers; Prenatal Diagnosis; Retrospective Studies; Heart Diseases
PubMed: 38307752
DOI: 10.1016/j.anpede.2024.01.006 -
Pediatrics and Neonatology Mar 2024
Topics: Female; Humans; Hydrops Fetalis; Mucolipidoses
PubMed: 38296756
DOI: 10.1016/j.pedneo.2022.05.023 -
BioRxiv : the Preprint Server For... Jan 2024The transcription factor BCL11A is a critical regulator of the switch from fetal hemoglobin (HbF: α γ ) to adult hemoglobin (HbA: α β ) during development....
The transcription factor BCL11A is a critical regulator of the switch from fetal hemoglobin (HbF: α γ ) to adult hemoglobin (HbA: α β ) during development. BCL11A binds at a cognate recognition site (TGACCA) in the γ-globin gene promoter and represses its expression. DNA-binding is mediated by a triple zinc finger domain, designated ZnF456. Here, we report comprehensive investigation of ZnF456, leveraging X-ray crystallography and NMR to determine the structures in both the presence and absence of DNA. We delve into the dynamics and mode of interaction with DNA. Moreover, we discovered that the last zinc finger of BCL11A (ZnF6) plays a special role in DNA binding and γ-globin gene repression. Our findings help account for some rare γ-globin gene promoter mutations that perturb BCL11A binding and lead to increased HbF in adults (hereditary persistence of fetal hemoglobin). Comprehending the DNA binding mechanism of BCL11A opens avenues for the strategic, structure-based design of novel therapeutics targeting sickle cell disease and β-thalassemia.
PubMed: 38293057
DOI: 10.1101/2024.01.17.576058 -
Molecular Genetics & Genomic Medicine Jan 2024Rare and novel variants of HBA1/2 and HBB genes resulting in thalassemia and hemoglobin (Hb) variants have been increasingly identified. Our goal was to identify two...
BACKGROUND
Rare and novel variants of HBA1/2 and HBB genes resulting in thalassemia and hemoglobin (Hb) variants have been increasingly identified. Our goal was to identify two rare Hb variants in Chinese population using third-generation sequencing (TGS) technology.
METHODS
Enrolled in this study were two Chinese families from Fujian Province. Hematological screening was conducted using routine blood analysis and Hb capillary electrophoresis analysis. Routine thalassemia gene testing was carried out to detect the common mutations of α- and β-thalassemia in Chinese population. Rare or novel α- and β-globin gene variants were further investigated by TGS.
RESULTS
The proband of family 1 was a female aged 32, with decreased levels of mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), Hb A2, and abnormal Hb bands in zone 5 and zone 12. No common thalassemia mutations were detected by routine thalassemia analysis, while a rare α-globin gene variant Hb Jilin [α139(HC1)Lys>Gln (AAA>CAA); HBA2:c.418A>C] was identified by TGS. Subsequent pedigree analysis showed that the proband's son also harbored the Hb Jilin variant with slightly low levels of MCH, Hb A2, and abnormal Hb bands. The proband of family 2 was a male at 41 years of age, exhibiting normal MCV and MCH, but a low level of Hb A2 and an abnormal Hb band in zone 12 without any common α- and β-thalassemia mutations. The subsequent TGS detection demonstrated a rare Hb Beijing [α16(A14)Lys>Asn (AAG>AAT); HBA2:c.51G>T] variant in HBA2 gene.
CONCLUSION
In this study, for the first time, we present two rare Hb variants of Hb Jilin and Hb Beijing in Fujian Province, Southeast China, using TGS technology.
Topics: Humans; Male; Female; beta-Thalassemia; Thalassemia; Mutation; Erythrocyte Indices; China
PubMed: 38284449
DOI: 10.1002/mgg3.2365 -
Hematology, Transfusion and Cell Therapy Jan 2024
PubMed: 38272736
DOI: 10.1016/j.htct.2023.11.010 -
Blood Jan 2024
Keith J, Christakopoulos GE, Fernandez AG, et al. Loss of miR-144/451 alleviates β-thalassemia by stimulating ULK1-mediated autophagy of free α-globin. Blood. 2023;142(10):918-932.
PubMed: 38270940
DOI: 10.1182/blood.2023023251 -
Brazilian Journal of Medical and... 2024Variations in lipid profile have been observed in sickle cell disease (SCD) and understanding their relationship with disease severity is crucial. This study aimed to...
Variations in lipid profile have been observed in sickle cell disease (SCD) and understanding their relationship with disease severity is crucial. This study aimed to investigate the association of polymorphisms of the CETP gene and laboratory markers of disease severity with lipid profile in a pediatric population with SCD. Biochemical and anthropometric analyses and CETP and alpha-thalassemia genotyping were performed. The study included 133 children and adolescents with sickle cell anemia (SCA) or hemoglobin SC disease (SCC), in steady-state. The SCA and no hydroxyurea (no HU) groups had higher values of ApoB, total cholesterol, low-density lipoprotein cholesterol (LDL-C), and non-high-density lipoprotein cholesterol (non-HDL-C) compared to the SCC and HU groups. However, there were no significant differences in ApoA1 and HDL-C levels between the groups based on genotype. Furthermore, the groups with altered levels of ApoA1, HDL-C, and the triglyceride/HDL ratio exhibited lower hemoglobin (Hb) levels and higher white blood cell counts. Hb level was associated to HDL-C levels. Analysis of CETP gene variants showed that the minor alleles of rs3764261 (C>A), rs247616 (C>T), and rs183130 (C>T), as well as the TTA haplotype, are explanatory variables for HDL-C levels. These findings suggested that dyslipidemia in SCD, specifically related to HDL-C levels, may be influenced by individual genetic background. Additionally, further investigation is needed to determine if clinical manifestations are impacted by CETP gene variants.
Topics: Child; Adolescent; Humans; Haplotypes; Cholesterol, HDL; Anemia, Sickle Cell; Genotype; Alleles; Cholesterol Ester Transfer Proteins
PubMed: 38265339
DOI: 10.1590/1414-431X2023e12879 -
BMC Medical Genomics Jan 2024Preimplantation genetic testing for monogenic disorders (PGT-M) has been used for over 20 years to detect many serious genetic conditions. However, there is still a lack...
OBJECTIVE
Preimplantation genetic testing for monogenic disorders (PGT-M) has been used for over 20 years to detect many serious genetic conditions. However, there is still a lack of reference materials (RMs) to validate the test performance during the development and quality control of PGT-M.
METHOD
Sixteen thalassemia cell lines from four thalassemia families were selected to establish the RMs. Each family consisted of parents with heterozygous mutations for α- and/or β-thalassemia and two children, at least one of whom carried a homozygous thalassemia mutation (proband). The RM panel consisted of 12 DNA samples (parents and probands in 4 families) and 4 simulated embryos (cell lines constructed from blood samples from the four nonproband children). Four accredited genetics laboratories that offer verification of thalassemia samples were invited to evaluate the performance of the RM panel. Furthermore, the stability of the RMs was determined by testing after freeze‒thaw cycles and long-term storage.
RESULTS
PGT-M reference materials containing 12 genome DNA (gDNA) reference materials and 4 simulated embryo reference materials for thalassemia testing were successfully established. Next-generation sequencing was performed on the samples. The genotypes and haplotypes of all 16 PGT-M reference materials were concordant across the four labs, which used various testing workflows. These well-characterized PGT-M reference materials retained their stability even after 3 years of storage.
CONCLUSION
The establishment of PGT-M reference materials for thalassemia will help with the standardization and accuracy of PGT-M in clinical use.
Topics: Child; Humans; Genetic Testing; High-Throughput Nucleotide Sequencing; Mutation; beta-Thalassemia; DNA
PubMed: 38262988
DOI: 10.1186/s12920-024-01803-z -
Cells Jan 2024Besides visceral heterotaxia, null mouse embryos exhibit general edema and perinatal lethality. In humans, congenital chylothorax (CCT) is a frequent cause of fetal...
Besides visceral heterotaxia, null mouse embryos exhibit general edema and perinatal lethality. In humans, congenital chylothorax (CCT) is a frequent cause of fetal hydrops. In 2021, Correa and colleagues reported ultrarare compound heterozygous variants in exhibiting in two consecutive fetuses with severe hydrops, implicating a direct role of in fetal hydrops formation. Here, we performed an exome survey and identified ultrarare compound heterozygous variants in in two of the five case-parent trios with CCT. In one family, the affected carried the ultrarare missense variants c.1543G>A(p.Gly515Arg) and c.3845T>A(p.Val1282Glu). In the other family, the affected carried the ultrarare loss-of-function variant (LoF) c.863delA(p.Asn288Thrfs*3) and the ultrarare missense variant c.6549G>T(p.Gln2183His). Investigation of the variants' impact on PKD1L1 protein localization suggests the missense variants cause protein dysfunction and the LoF variant causes protein mislocalization. Further analysis of mutant mouse embryos revealed about 20% of embryos display general edema and pleural effusion at 14.5 dpc. Immunofluorescence staining at 14.5 dpc in embryos displayed both normal and massively altered lymphatic vessel morphologies. Together, our studies suggest the implication of in congenital lymphatic anomalies, including CCTs.
Topics: Animals; Female; Humans; Mice; Pregnancy; Chylothorax; Fetus; Genetic Diseases, X-Linked; Hydrops Fetalis; Membrane Proteins; Mice, Knockout
PubMed: 38247840
DOI: 10.3390/cells13020149 -
Blood Advances Apr 2024Iron plays a major role in the deterioration of β-thalassemia. Indeed, the high levels of transferrin saturation and iron delivered to erythroid progenitors are...
Iron plays a major role in the deterioration of β-thalassemia. Indeed, the high levels of transferrin saturation and iron delivered to erythroid progenitors are associated with production of α-globin precipitates that negatively affect erythropoiesis. Matriptase-2/TMPRSS6, a membrane-bound serine protease expressed in hepatocytes, negatively modulates hepcidin production and thus is a key target to prevent iron overload in β-thalassemia. To address safety concerns raised by the suppression of Tmprss6 by antisense oligonucleotides or small interfering RNA, we tested a fully human anti-matriptase-2 antibody, RLYB331, which blocks the protease activity of matriptase-2. When administered weekly to Hbbth3/+ mice, RLYB331 induced hepcidin expression, reduced iron loading, prevented the formation of toxic α-chain/heme aggregates, reduced ros oxygen species formation, and improved reticulocytosis and splenomegaly. To increase the effectiveness of RLYB331 in β-thalassemia treatment even further, we administered RLYB331 in combination with RAP-536L, a ligand-trapping protein that contains the extracellular domain of activin receptor type IIB and alleviates anemia by promoting differentiation of late-stage erythroid precursors. RAP-536L alone did not prevent iron overload but significantly reduced apoptosis in the erythroid populations of the bone marrow, normalized red blood cell counts, and improved hemoglobin and hematocrit levels. Interestingly, the association of RLYB331 with RAP-536L entirely reversed the β-thalassemia phenotype in Hbbth3/+ mice and simultaneously corrected iron overload, ineffective erythropoiesis, splenomegaly, and hematological parameters, suggesting that a multifunctional molecule consisting of the fusion of RLYB331 with luspatercept (human version of RAP-536L) would allow administration of a single medication addressing simultaneously the different pathophysiological aspects of β-thalassemia.
Topics: Mice; Humans; Animals; Hepcidins; beta-Thalassemia; Splenomegaly; Iron Overload; Iron; Membrane Proteins; Serine Endopeptidases
PubMed: 38241484
DOI: 10.1182/bloodadvances.2023012010