%0 Journal Article %J NPJ Genom Med %D 2022 %T Whole genome sequencing delineates regulatory, copy number, and cryptic splice variants in early onset cardiomyopathy. %A Lesurf, Robert %A Said, Abdelrahman %A Akinrinade, Oyediran %A Breckpot, Jeroen %A Delfosse, Kathleen %A Liu, Ting %A Yao, Roderick %A Persad, Gabrielle %A McKenna, Fintan %A Noche, Ramil R %A Oliveros, Winona %A Mattioli, Kaia %A Shah, Shreya %A Miron, Anastasia %A Yang, Qian %A Meng, Guoliang %A Yue, Michelle Chan Seng %A Sung, Wilson W L %A Thiruvahindrapuram, Bhooma %A Lougheed, Jane %A Oechslin, Erwin %A Mondal, Tapas %A Bergin, Lynn %A Smythe, John %A Jayappa, Shashank %A Rao, Vinay J %A Shenthar, Jayaprakash %A Dhandapany, Perundurai S %A Semsarian, Christopher %A Weintraub, Robert G %A Bagnall, Richard D %A Ingles, Jodie %A Melé, Marta %A Maass, Philipp G %A Ellis, James %A Scherer, Stephen W %A Mital, Seema %X

Cardiomyopathy (CMP) is a heritable disorder. Over 50% of cases are gene-elusive on clinical gene panel testing. The contribution of variants in non-coding DNA elements that result in cryptic splicing and regulate gene expression has not been explored. We analyzed whole-genome sequencing (WGS) data in a discovery cohort of 209 pediatric CMP patients and 1953 independent replication genomes and exomes. We searched for protein-coding variants, and non-coding variants predicted to affect the function or expression of genes. Thirty-nine percent of cases harbored pathogenic coding variants in known CMP genes, and 5% harbored high-risk loss-of-function (LoF) variants in additional candidate CMP genes. Fifteen percent harbored high-risk regulatory variants in promoters and enhancers of CMP genes (odds ratio 2.25, p = 6.70 × 10 versus controls). Genes involved in α-dystroglycan glycosylation (FKTN, DTNA) and desmosomal signaling (DSC2, DSG2) were most highly enriched for regulatory variants (odds ratio 6.7-58.1). Functional effects were confirmed in patient myocardium and reporter assays in human cardiomyocytes, and in zebrafish CRISPR knockouts. We provide strong evidence for the genomic contribution of functionally active variants in new genes and in regulatory elements of known CMP genes to early onset CMP.

%B NPJ Genom Med %V 7 %P 18 %8 2022 Mar 14 %G eng %N 1 %R 10.1038/s41525-022-00288-y %0 Journal Article %J Acta Crystallogr C Struct Chem %D 2017 %T Water-mediated intermolecular interactions in 1,2-O-cyclohexylidene-myo-inositol: a quantitative analysis. %A Purushothaman, Gayathri %A Juvale, Kapil %A Kirubakaran, Sivapriya %A Vemula, Praveen Kumar %A Thiruvenkatam, Vijay %X

The syntheses of new myo-inositol derivatives have received much attention due to their important biological activities. 1,2-O-Cyclohexylidene-myo-inositol is an important intermediate formed during the syntheses of certain myo-inositol derivatives. We report herein the crystal structure of 1,2-O-cyclohexylidene-myo-inositol dihydrate, CHO·2HO, which is an intermediate formed during the syntheses of myo-inositol phosphate derivatives, to demonstrate the participation of water molecules and hydroxy groups in the formation of several intermolecular O-H...O interactions, and to determine a low-energy conformation. The title myo-inositol derivative crystallizes with two water molecules in the asymmetric unit in the space group C2/c, with Z = 8. The water molecules facilitate the formation of an extensive O-H...O hydrogen-bonding network that assists in the formation of a dense crystal packing. Furthermore, geometrical optimization and frequency analysis was carried out using density functional theory (DFT) calculations with B3LYP hybrid functionals and 6-31G(d), 6-31G(d,p) and 6-311G(d,p) basis sets. The theoretical and experimental structures were found to be very similar, with only slight deviations. The intermolecular interactions were quantitatively analysed using Hirshfeld surface analysis and 2D (two-dimensional) fingerplot plots, and the total lattice energy was calculated.

%B Acta Crystallogr C Struct Chem %V 73 %P 20-27 %8 2017 Jan 01 %G eng %N Pt 1 %R 10.1107/S2053229616018581