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Sickle cell disease (SCD) is a group of related yet genetically complex hemoglobinopathies. Universal newborn screening (NBS) for SCD is performed in the United States and many other nations. Classical, protein-based laboratory methods are often adequate for the diagnosis of SCD but have specific limitations in the context of NBS. A particular challenge is the differentiation of sickle cell anemia (SCA) from the benign condition, compound heterozygosity for HbS and gene-deletion hereditary persistence of fetal hemoglobin (HbS/HPFH). We describe a sequential cohort of 44 newborns identified over 4.5 years who had molecular genetic testing incorporated into NBS for presumed SCA (an “FS” pattern). The final diagnosis was something other than SCA in six newborns (12%). Three (7%) had HbS/HPFH. All had a final, correct diagnosis at the time of their first scheduled clinic visit in our center (median 8 weeks of age). None received initial counseling for an incorrect diagnosis. In summary, genetic testing as a component of NBS for SCD is necessary to provide correct genetic counseling and education for all newborns' families at their first visit to a sickle cell center. Genetic testing also permits the use of early, pre-symptomatic hydroxyurea therapy by preventing infants with HbS/HPFH from receiving unnecessary therapy. We argue that genetic testing should be incorporated into contemporary NBS for SCD.

Supplemental Digital Content is available in the text., We identified a child with KLF1-E325K congenital dyserythropoietic anemia type IV who experienced a severe clinical course, fetal anemia, hydrops fetalis, and postnatal transfusion dependence only partially responsive to splenectomy. The child also had complete sex reversal, the cause which remains undetermined. To gain insights into our patient’s severe hematologic phenotype, detailed analyses were performed. Erythrocytes from the patient and parents demonstrated functional abnormalities of the erythrocyte membrane, attributed to variants in the α-spectrin gene. Hypomorphic alleles in SEC23B and YARS2 were also identified. We hypothesize that coinheritance of variants in relevant erythrocyte genes contribute to the clinical course in our patient and other E325K-linked congenital dyserythropoietic anemia IV patients with severe clinical phenotypes.

FHb and alpha-thal are two genetic factors that modulate the clinical expression of sickle cell disease. Objective: to determine the beneficial role of FHb and alpha-thal on fetal and maternal morbidity during pregnancy in sickle cell patients. This is a documentary and analytical study that included 960 deliveries of homozygous sickle cell patients. The deliveries were divided into three genotype subgroups: Hb-SS / alpha-thal, HbSS / HPFH and HbSS. The diagnosis of SCD and the quantification of FHb were performed by the capillary electrophoresis technique. The diagnosis of SCD has been confirmed by the molecular test. The diagnosis of alpha-thal was made by the multiplex ligation dependent probe amplification (MLPA) technique. Sickle cell pregnancies were followed according to the protocol of care in force in our service. The variables of interest were: hematological variables, sickle cell crises during pregnancy, maternal and fetal complications. Statistical analyzes were performed with SPSS 20.0 software. Means and standard deviations were compared with the Student's t and Annova tests. The value of p

Impaired switching from fetal haemoglobin (HbF) to adult globin gene expression leads to hereditary persistence of fetal haemoglobin (HPFH) in adult life. This is of prime interest because elevated HbF levels ameliorate beta-thalassaemia and sickle cell anaemia. Fetal haemoglobin levels are regulated by complex mechanisms involving factors linked or not to the beta-globin gene (HBB) locus. To search for factors putatively involved in gamma-globin gene expression, we examined the reticulocyte transcriptome of three siblings who had different HbF levels and different degrees of beta-thalassaemia severity although they had the same beta- and alpha-cluster genotypes. By mRNA differential display we isolated the cDNA coding for the cold shock domain protein A (CSDA), also known as dbpA, previously reported to interact in vitro with the gamma-globin gene promoter. Expression studies performed in K562 and in primary erythroid cells showed an inverse relationship between gamma-globin and CSDA expression levels. Functional studies performed by Chromatin Immunoprecipitation and reporter gene assays in K562 cells demonstrated that CSDA is able to bind the promoter of the gamma-globin gene and to suppress its expression. Therefore, our study demonstrates that CSDA is a trans-acting repressor factor of gamma-globin gene expression and contributes to modulate the HPFH phenotype.