Large-scale discovery of novel genetic causes of developmental disorders

Despite three decades of successful, predominantly phenotype-driven discovery of the genetic causes of monogenic disorders1, up to half of children with severe developmental disorders of probable genetic origin remain without a genetic diagnosis. Particularly challenging are those disorders rare enough to have eluded recognition as a discrete clinical entity, those with highly variable clinical manifestations, and those that are difficult to distinguish from other, very similar, disorders. Here we demonstrate the power of using an unbiased genotype-driven approach2 to identify subsets of patients with similar disorders. By studying 1,133 children with severe, undiagnosed developmental disorders, and their parents, using a combination of exome sequencing3,4,5,6,7,8,9,10,11 and array-based detection of chromosomal rearrangements, we discovered 12 novel genes associated with developmental disorders. These newly implicated genes increase by 10% (from 28% to 31%) the proportion of children that could be diagnosed. Clustering of missense mutations in six of these newly implicated genes suggests that normal development is being perturbed by an activating or dominant-negative mechanism. Our findings demonstrate the value of adopting a comprehensive strategy, both genome-wide and nationwide, to elucidate the underlying causes of rare genetic disorders

A nuclear orientation study of hyperfine interactions in terbium

Nous décrivons une méthode pour étudier l'interaction hyperfine et la distribution de l'aimantation locale dans les terres rares lourdes utilisant l'orientation nucléaire. Dans le cas du Mn-Tb dilué, le champ hyperfin sur le noyau de Mn est de 18,5 ± 1,5 T.It is shown that the hyperfine interactions of impurity nuclei and the magnetization distribution in magnetically hard rare earths may be studied by means of low temperature nuclear orientation. For dilute Mn-Tb the hyperfine field at the Mn nuclei is 18.5 ± 1.5 T

NMR DETECTED BY MÖSSBAUER-EFFECT APPLIED TO THE SYSTEM 57Co Fe

To appear in Z. Phy

X-RAY ABSORPTION ON URANIUM SYSTEMS AT VARIOUS THRESHOLDS

We have studied the near edge X-ray absorption fine structure of various metallic and non-metallic U compounds at the L3, M3, M4,5, N4,5, and O4,5 thresholds using transmission and total-electron-yield techniques. At the L3 thresholds, a chemical shift of ≈4 eV between trivalent and tetravalent U compounds is observed, which drops to ≈2eV between the latter and hexavalent U systems. This indicates extended 5f character and a 5f count close to two in the high oxidation states. The M4,5 thresholds are characterised by intense absorption peaks due to 3d-5f transitions which show no multiplet structure from 3d-5f exchange interaction. However, the linewidths of the M4,5 peaks decrease by ≈20% with increasing U-U distance in metallic systems, indicating a narrowing of the 5f band. The soft X-ray absorption spectra at the N4,5 thresholds behave very similarly to the M4,5 edges, except for a vanishing intensity of transitions into the continuum. Rich structures from 5d-5f exchange interaction are observed at the O4,5 edges of non-metallic U compounds, becoming broadened and partly vanishing in metallic systems, presumably due to the more itinerant nature of the 5f states