RESUMEN
Embryonic development is dictated by tight regulation of DNA replication, cell division and differentiation. Mutations in DNA repair and replication genes disrupt this equilibrium, giving rise to neurodevelopmental disease characterized by microcephaly, short stature and chromosomal breakage. Here, we identify biallelic variants in two components of the RAD18-SLF1/2-SMC5/6 genome stability pathway, SLF2 and SMC5, in 11 patients with microcephaly, short stature, cardiac abnormalities and anemia. Patient-derived cells exhibit a unique chromosomal instability phenotype consisting of segmented and dicentric chromosomes with mosaic variegated hyperploidy. To signify the importance of these segmented chromosomes, we have named this disorder Atelís (meaning - incomplete) Syndrome. Analysis of Atelís Syndrome cells reveals elevated levels of replication stress, partly due to a reduced ability to replicate through G-quadruplex DNA structures, and also loss of sister chromatid cohesion. Together, these data strengthen the functional link between SLF2 and the SMC5/6 complex, highlighting a distinct role for this pathway in maintaining genome stability.
Asunto(s)
Proteínas de Ciclo Celular , Microcefalia , Humanos , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Microcefalia/genética , Reparación del ADN/genética , Cromosomas/metabolismo , Inestabilidad Genómica , Proteínas de Unión al ADN/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Proteínas Cromosómicas no Histona/metabolismoRESUMEN
PURPOSE: Data on early pulmonary arterial hypertension (PAH) in preterm infants is limited and outcomes are conflicting. Our objectives are to examine the risk factors and neonatal outcomes of early onset PAH (EOPAH) diagnosed in the first 2 weeks of age in preterm infants in a large perinatal center. METHODS: We performed a case-control study to assess the risk factors and clinical outcomes of preterm infants with EOPAH. Preterm infants (<34 weeks) admitted to NICU between 2009 and 2013 with a diagnosis of PAH in the first 2 weeks of age were matched to two consecutive controls for gestational age, birth weight, and year of birth. We performed univariate and multivariate analyses. RESULTS: Of 1798 eligible infants, 60 (3.3%) had EOPAH with 57/60 (95%) diagnosed in the first 7 d of age. Infants with early PAH had higher incidence of prolonged rupture of membrane (47% versus 29%), oligohydramnios (37% versus 16%) and received less antenatal steroids (78% versus 91%). Fifty-one infants received inhaled nitric oxide (iNO) and all responded well. The overall mortality rate was not significantly different between two groups (13.3% versus 8%). After adjusting for potential confounding variables, early PAH is associated with bronchopulmonary dysplasia (BPD) (aOR 3.06, 95% CI 1.43, 6.54) and BPD/death (aOR 2.65, 95% CI 1.25, 5.64) and severe intraventricular hemorrhage (aOR 3.08, 95% CI 1.28, 7.39). CONCLUSION: Early onset pulmonary arterial hypertension in preterm is not uncommon and is associated with bronchopulmonary dysplasia and severe intraventricular hemorrhage. Inhaled nitric oxide was used to treat in majority of cases with good response and survival is high.