Complete blood count differences in a cohort of Down syndrome neonates with transient abnormal myelopoiesis screened for GATA1 pathogenic variants

Abstract

Transient abnormal myelopoiesis (TAM) raises the risk for acute myeloid leukemia of Down syndrome (DS) (ML‐DS), and both are related to GATA1 pathogenic variants. Here, we analyzed which findings on complete blood count (CBC) are associated with TAM in a cohort of neonates with DS screened for GATA1 pathogenic variants. The CBCs were compared among 70 newborns with DS, including 16 patients (22.9%) with TAM (cases), and 54 patients (77.1%) without TAM (controls). TAM was defined as peripheral circulating blasts (PCBs) ≥ 1%. PCR and direct sequencing were used to screen DNA samples from peripheral blood for GATA1 exon 2 mutations. Multivariate logistic regression analyses determined that the mean count of lymphocytes was significantly higher in DS infants with TAM (p = .035) and that lymphocytosis confers a risk for TAM (adjusted odds ratio = 7.23, 95% confidence intervals: 2.02–25.92). Pathogenic variants of GATA1 were identified in 2 of 70 analyzed DS neonates (2.9%), of which one had ML‐DS and another had an asymptomatic TAM. Among those DS infants with TAM, the GATA1 pathogenic variant detection was 12.5%. Our results indicated that lymphocytosis is associated with TAM in neonates with DS. However, since not all infants with an abnormal CBC had TAM, and not all infants with TAM had GATA1 pathogenic variants, we emphasize that only the search for GATA1 pathogenic variants allows the proper identification of the subgroup of DS infants with a real increasing in risk for ML‐DS.

Sensitive GATA1 mutation screening reliably identifies neonates with Down syndrome at risk for myeloid leukemia

“…As the WHO does not specify the percentage of blasts to define TAM, different groups use different blast percentages ranging from ≥1% to ≥10% to define TAM in neonates with DS [6][7][8][9]. Therefore, we defined TAM as either >5% blasts (as determined by immunophenotyping or morphology), and/or detection of a GATA1 mutation.…”

Myeloid Proliferations Associated with Down Syndrome: Clinicopathologic Characteristics of Forty Cases from Five Large Academic Institutions

“…Most notably, normal WBC count, hemoglobin, and MCV values decrease as neonates' age from infancy to 2 years old; therefore, the apparent macrocytosis and leukocytosis observed in TAM babies are likely due to physiologic CBC values rather than the myeloid pathology [10]. Prior studies have evaluated TAM CBC values compared to non-TAM patients with DS and showed no statistically significant difference with the exception of lymphocytosis identified in TAM [11]. Conversely, ML-DS was characterized by presentation at older age and with median hemoglobin and platelet values below what is considered normal for age, indicating that the anemia and thrombocytopenia seen in these patients was secondary to the underlying myeloid neoplasm.…”

Prenatal diagnosis of Down syndrome combined with transient abnormal myelopoiesis in foetuses with a GATA1 gene variant: Two case reports

“…Both of the variations c.220G > A and c.49dupC are absent in the general population according to public databases (gnomAD, 1000 Genomes Project, and Exome Aggregation Consortium). Mutation c.220G > A has been reported in several research as pathogenic according to the ACMG guideline [29][30][31] . At the same amino acid c.220G > C (p.Val74Leu) change has been previously reported as pathogenic in the ClinVar database.…”

“…At the same amino acid c.220G > C (p.Val74Leu) change has been previously reported as pathogenic in the ClinVar database. The consequence of the base c.220G > A substitution was a splice mutation that changed the amino acid sequence Val74Ile 29 .Also at the same amino acid c.49_50del (p.Gln17fs) and c.49C > T (p.Gln17Ter) already provide to be pathogenic in the ClinVar database. Cabelof, DC et al 32 and Kanezaki R et al 33 reported c.49 C > T in their case 10 and case 5, respectively.…”