Search

Item does not contain fulltext, Cornelia de Lange syndrome (CdLS) is a multisystem genetic disorder with distinct facies, growth failure, intellectual disability, distal limb anomalies, gastrointestinal and neurological disease. Mutations in NIPBL, encoding a cohesin regulatory protein, account for >80% of cases with typical facies. Mutations in the core cohesin complex proteins, encoded by the SMC1A, SMC3 and RAD21 genes, together account for approximately 5% of subjects, often with atypical CdLS features. Recently, we identified mutations in the X-linked gene HDAC8 as the cause of a small number of CdLS cases. Here, we report a cohort of 38 individuals with an emerging spectrum of features caused by HDAC8 mutations. For several individuals, the diagnosis of CdLS was not considered prior to genomic testing. Most mutations identified are missense and de novo. Many cases are heterozygous females, each with marked skewing of X-inactivation in peripheral blood DNA. We also identified eight hemizygous males who are more severely affected. The craniofacial appearance caused by HDAC8 mutations overlaps that of typical CdLS but often displays delayed anterior fontanelle closure, ocular hypertelorism, hooding of the eyelids, a broader nose and dental anomalies, which may be useful discriminating features. HDAC8 encodes the lysine deacetylase for the cohesin subunit SMC3 and analysis of the functional consequences of the missense mutations indicates that all cause a loss of enzymatic function. These data demonstrate that loss-of-function mutations in HDAC8 cause a range of overlapping human developmental phenotypes, including a phenotypically distinct subgroup of CdLS.

In this part of the graduation report concerning the Jamuna Bridge Project in Bangla Desh, the main issues are the following : - An elaborate inventarisation of parameters and qualities of the Jamuna River system which are of consequence for the design concept of the river training works as weIl as the bridge itself. In this context special attention is given to the stability of the river in the past and the prediction of water- and bedlevels. - The development of a design philosophy and criterium for the lay-out of the bridge works. In this respect the length of the required training works versus the bridge length is of essential importance. - The determination of the principal design criteria for the structural design of the river training works. The aim of this part of the study is to arrive at a first configuration of the required training works. Due to the limited time span it was not possible to refine the configuration, i.e. a reconsideration of assumptions, starting points and design criteria as the scheme in appendix I suggests. In fact it is this scheme which has been run through one time. Also this report does not pretend to give a complete elaboration of all factors concerning the design of training works. It is therefore often only indicated that certain factors should be included in the design process possibly leading to another solution., Hydraulic Engineering, Civil Engineering and Geosciences