ABSTRACT
Patients with Down syndrome (DS) are commonly affected by a pre-leukemic disorder known as transient abnormal myelopoiesis (TAM). This condition usually undergoes spontaneous remission within the first 2 months after birth; however, in children under 5, 20%-30% of cases evolve to myeloid leukemia of Down syndrome (ML-DS). TAM and ML-DS are caused by co-operation between trisomy 21 and acquired mutations in the GATA1 gene. Currently, only next-generation sequencing (NGS)-based methodologies are sufficiently sensitive for diagnosis in samples with small GATA1 mutant clones (≤10% blasts). Alternatively, this study presents research on a new, fast, sensitive, and inexpensive high-resolution melting (HRM)-based diagnostic approach that allows the detection of most cases of GATA1 mutations, including silent TAM. The algorithm first uses flow cytometry for blast count, followed by HRM and Sanger sequencing to search for mutations on exons 2 and 3 of GATA1. We analyzed 138 samples of DS patients: 110 of asymptomatic neonates, 10 suspected of having TAM, and 18 suspected of having ML-DS. Our algorithm enabled the identification of 33 mutant samples, among them five cases of silent TAM (5/110) and seven cases of ML-DS (7/18) with blast count ≤10%, in which GATA1 alterations were easily detected by HRM. Depending on the type of genetic variation and its location, our methodology reached sensitivity similar to that obtained by NGS (0.3%) at a considerably reduced time and cost, thus making it accessible worldwide.
Subject(s)
Down Syndrome , Leukemia, Myeloid , Leukemoid Reaction , Algorithms , Child , Down Syndrome/complications , Down Syndrome/diagnosis , Down Syndrome/genetics , GATA1 Transcription Factor/genetics , Humans , Infant, Newborn , Leukemia, Myeloid/genetics , Leukemoid Reaction/diagnosis , Leukemoid Reaction/genetics , MutationABSTRACT
A restrição de crescimento intra-uterino ocorre quando o feto não atingeo tamanho esperado ou determinado pelo seu potencial genético, sendoidentificada clinicamente quando o peso fetal está abaixo do percentil10 para a idade gestacional. Essa definição é a mais utilizada na literatura.A restrição de crescimento fetal é um problema clínico comum, associado ao aumento da morbidade e mortalidade perinatal sendo reconhecida em 7% a 15% das gestações. O objetivo dessa revisão foi relacionar os fatores envolvidos na etiologia da restrição de crescimento intra-uterino, por meio de revisão bibliográfica da literatura nas bases de dados medline, pubmed, scielo, além de livros, com ênfase nos últimos 10 anos. A análise da literatura permite concluir que, são múltiplosos fatores relacionados a essa intercorrência, abrangendo fatores maternos, placentários e fetais. Importante ressaltar que esses diferentes fatores podem atuar concomitantemente, alguns são preveníveis e muitos deles estão intimamente relacionados com o estado socioeconômico e cultural da população. Assim, as causas e incidência de RCIU são diferentes segundo a população estudada.
Intrauterine growth restriction (IUGR) happens when the fetus does notreach the expected size or determined by its genetic potential. It is clinicallyidentified when the fetal weight is below the 10th percentile for the gestational age. This definition is frequently used in the literature. Fetal growth restriction is a common clinical problem that is associated with the increase in perinatal morbidity and mortality, and is reported in 7 to 15% of pregnancies. The objective of this review is to describe the factors involved in the etiology of intrauterine growth restriction, by usingthe bibliographic review of the literature on the databases of Medline, Pubmed, Scielo, and also books, with emphasis on the past 10 years. The analysis of the consulted materials shows that there are many factors associated with this condition, including maternal, placental and fetal factors. It´s important to highlight that these different factors can act concomitantly, some of them are predictable, and many of them are intimately related with the socioeconomic and cultural status of the population. Thus, the causes and incidence of IUGR vary according to thestudy population.