The OSR1 rs12329305 Polymorphism Contributes to the Development of Congenital Malformations in Cases of Stillborn/Neonatal Death

Abstract

BackgroundInvolvement of development-related gene polymorphisms in multifactorial/polygenic etiology of stillborn/neonatal deaths due to malformations has been insufficiently tested. Since these genes showed evolutional stability and their mutations are very rare, we can assume that their polymorphic variants may be a risk factor associated with the occurrence of developmental disorders of unknown etiology or can enhance the phenotypic variability of known genetic disorders.Material/MethodsTo determine the association of 3 polymorphisms involved in the regulation of the early embryonic development of different organs, we conducted an association study of their relation to the particular malformation. We selected 140 samples of archived paraffin tissue samples from deceased patients in which fetal/neonatal autopsy examination had shown congenital abnormalities as the most likely cause of death. The polymorphisms of OSR1 rs12329305, rs9936833 near FOXF1, and HOXA1 rs10951154 were genotyped using the TaqMan allelic discrimination assay.ResultsAfter Bonferroni correction for multiple testing, significant allelic association with stillborn/neonatal deaths was observed for rs12329305 (p=7×10−4). In addition, association analysis for the same polymorphism was shown in the subgroup with isolated anomalies (1.25×10−5), particularly in the subgroup of cases with kidney and heart anomalies (p=4.18×10−5, p=5.12×10−8, respectively).ConclusionsThe findings of the present study showed, for the first time, the role of the OSR1 rs12329305 polymorphism in the development of congenital malformations in cases of stillborn/neonatal death, particularly in those with congenital kidney and heart developmental defects.

High Maternal Body Mass Index in Early Pregnancy and Risks of Stillbirth and Infant Mortality—A Population-Based Sibling Study in Sweden

“…Quantitative genetic analyses show that maternal genetic factors are of importance for preterm birth ( 21 ). Congenital anomalies are commonly seen in both stillbirths and infant mortality ( 22 , 23 ) and may be caused by genetic factors ( 24 ).…”

Evid�ncias cient�ficas dos fatores de risco para anomalias cong�nitas: revis�o integrativa

“…To estimate sex ratios in specific major CA diagnoses using a large source of routine healthcare data representative of the United Kingdom (U.K.) population and to examine the effects of sociodemographic and maternal factors on these ratios. Q (30) The OSR1 rs12329305 Polymorphism Contributes to the Development of Congenital Malformations in Cases of Stillborn/Neonatal Death.…”

“…Destaca-se ainda que os fatores maternos e sociodemográficos não influenciaram na relação entre AC e sexo (29) . Estudo norte-americano identificou 61% das AC ocorreram no sexo masculino (30) , e apontou fatores de regulação na morfogenética e diferenciação celular no desenvolvimento de AC em natimortos e em crianças com óbitos neonatais (30) . Dentre os tipos de AC mais identificadas nos artigos revistos destacam-se as do Sistema Cardiovascular, Musculoesquelético, Osteomuscular (20) e Urogenital (15) , e as mais detectadas por exame de imagem pré-natal foram às do Sistema Nervoso Central, as Cardíacas (23) e Osteomusculares (20) .…”

“…Outro estudo, em Cali, apesar da obrigatoriedade da ultrassonografia, uma a cada quatro mães de recém-nascidos com AC (17) . E ainda, uma pesquisa pioneira nos EUA, com amostras de fetos mortos mantidas com parafina durante 12 anos, concluiu pela importância das autópsias para a investigação das malformações raras (30) .…”

Osr1 Interacts Synergistically with Wt1 to Regulate Kidney Organogenesis

“…Recently, a single nucleotide variant in an exonic splice enhancer in the OSR1 gene was associated with reduction in newborn kidney size and function in humans [ 31 ]. In addition, homozygosity of the same variant OSR1 allele was associated with neonatal lethality with congenital kidney defects [ 32 ]. In this report, we demonstrate that Osr1 interacts synergistically with another important kidney developmental regulator Wt1 [ 33 ] to control nephron endowment through regulation of MM specification.…”