Exome sequencing identifies a novel EP300 frame shift mutation in a patient with features that overlap Cornelia de Lange syndrome.

Rubinstein-Taybi syndrome (RTS) and Cornelia de Lange syndrome (CdLS) are genetically heterogeneous multiple anomalies syndromes, each having a distinctive facial gestalt. Two genes (CREBBP and EP300) are known to cause RTS, and five (NIPBL, SMC1A, SMC3, RAD21, and HDAC8) have been associated with CdLS. A diagnosis of RTS or CdLS is molecularly confirmed in only 65% of clinically identified cases, suggesting that additional causative genes exist for both conditions. In addition, although EP300 and CREBBP encode homologous proteins and perform similar functions, only eight EP300 positive RTS patients have been reported, suggesting that patients with EP300 mutations might be escaping clinical recognition. We report on a child with multiple congenital abnormalities and intellectual disability whose facial features and complex phenotype resemble CdLS. However, no mutations in CdLS-related genes were identified. Rather, a novel EP300 mutation was found on whole exome sequencing. Possible links between EP300 and genes causing CdLS are evident in the literature. Both EP300 and HDAC8 are involved in the regulation of TP53 transcriptional activity. In addition, p300 and other chromatin associated proteins, including NIPBL, SMCA1, and SMC3, have been found at enhancer regions in different cell types. It is therefore possible that EP300 and CdLS-related genes are involved in additional shared pathways, producing overlapping phenotypes. As whole exome sequencing becomes more widely utilized, the diverse phenotypes associated with EP300 mutations should be better understood. In the meantime, testing for EP300 mutations in those with features of CdLS may be warranted.

A spectrum of phenotypical expression OF Neu-Laxova syndrome: Three case reports and a review of the literature.

Neu-Laxova syndrome is a rare autosomal recessive disorder characterized by severe intra-uterine growth restriction, extreme microcephaly, marked edema with skin restriction, ichthyosis, craniofacial anomalies, limb deformities, and a spectrum of central nervous system malformations. Less than 70 cases have been described since the first report in 1971. To this day the etiology and genetic basis remains unknown. Consanguinity has been reported. Some authors have postulated the syndrome to be a form of neuro-ectodermal dysplasia, while others suggest that it is a malformation syndrome secondary to severe skin restriction. Although the outcome of this syndrome is lethal, a single case of longer survival (6 months) has been reported. The majority of cases are stillborn or die shortly after birth. Thus, it is clear that Neu-Laxova exhibits a spectrum of disease, with varying degrees of phenotypic expression. We are presenting three new cases of Neu-Laxova syndrome; two were stillbirths and one lived for eleven weeks. Our microscopic and post-mortem findings in these three cases display the vast spectrum of this rare syndrome.

The feasibility of using histologic placental sections to predict newborn nucleated red blood cell counts.

OBJECTIVE: To determine the feasibility of using calculated nucleated red blood cell (RBC) counts from histologic placental slides to predict newborn nucleated RBC counts. METHODS: This retrospective study compared absolute nucleated RBC counts from 24 newborns, diagnosed with fetal distress in labor, with counts calculated from their histologic placental slides. A simple linear regression model was tested with newborn nucleated RBC counts as the dependent variable and calculated placental nucleated RBC counts as the independent variable. RESULTS: The mean +/- standard deviation newborn nucleated RBC count was 4.81 x 10(9) +/- 5.46 x 10(9)/L compared with 1.37 x 10(9) +/- 1.78 x 10(9)/L calculated from placental sections. These data were normalized by logarithmic transformation. A significant linear regression was obtained, r(2) = 0.74, P <.001. The prediction equation obtained was natural logarithm (newborn nucleated RBC count) is equal to 1.002 x natural logarithm (placental nucleated RBC count) + 1.173. CONCLUSION: It is feasible to calculate nucleated RBC counts from histologic slides of the placenta that are predictive of newborn nucleated RBC counts. Further work on more homogeneous groups of subjects is necessary to increase the precision of the method. The placenta could serve as a surrogate source for newborn whole blood nucleated RBC counts around the time of birth.