@article {566, title = {ROBO4 variants predispose individuals to bicuspid aortic valve and thoracic aortic aneurysm.}, journal = {Nat Genet}, volume = {51}, year = {2019}, month = {2019 01}, pages = {42-50}, abstract = {

Bicuspid aortic valve (BAV) is a common congenital heart defect (population incidence, 1-2\%) that frequently presents with ascending aortic aneurysm (AscAA). BAV/AscAA shows autosomal dominant inheritance with incomplete penetrance and male predominance. Causative gene mutations (for example, NOTCH1, SMAD6) are known for <=1\% of nonsyndromic BAV cases with and without AscAA, impeding mechanistic insight and development of therapeutic strategies. Here, we report the identification of variants in ROBO4 (which encodes a factor known to contribute to endothelial performance) that segregate with disease in two families. Targeted sequencing of ROBO4 showed enrichment for rare variants in BAV/AscAA probands compared with controls. Targeted silencing of ROBO4 or mutant ROBO4 expression in endothelial cell lines results in impaired barrier function and a synthetic repertoire suggestive of endothelial-to-mesenchymal transition. This is consistent with BAV/AscAA-associated findings in patients and in animal models deficient for ROBO4. These data identify a novel endothelial etiology for this common human disease phenotype.

}, keywords = {Animals, Aortic Aneurysm, Thoracic, Aortic Valve, Cells, Cultured, Disease Models, Animal, Endothelial Cells, Female, Heart Valve Diseases, Humans, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Mutation, Phenotype, Receptors, Cell Surface, Zebrafish}, issn = {1546-1718}, doi = {10.1038/s41588-018-0265-y}, author = {Gould, Russell A and Aziz, Hamza and Woods, Courtney E and Seman-Senderos, Manuel Alejandro and Sparks, Elizabeth and Preuss, Christoph and W{\"u}nnemann, Florian and Bedja, Djahida and Moats, Cassandra R and McClymont, Sarah A and Rose, Rebecca and Sobreira, Nara and Ling, Hua and MacCarrick, Gretchen and Kumar, Ajay Anand and Luyckx, Ilse and Cannaerts, Elyssa and Verstraeten, Aline and Bj{\"o}rk, Hanna M and Lehsau, Ann-Cathrin and Jaskula-Ranga, Vinod and Lauridsen, Henrik and Shah, Asad A and Bennett, Christopher L and Ellinor, Patrick T and Lin, Honghuang and Isselbacher, Eric M and Lino Cardenas, Christian Lacks and Butcher, Jonathan T and Hughes, G Chad and Lindsay, Mark E and Mertens, Luc and Franco-Cereceda, Anders and Verhagen, Judith M A and Wessels, Marja and Mohamed, Salah A and Eriksson, Per and Mital, Seema and Van Laer, Lut and Loeys, Bart L and Andelfinger, Gregor and McCallion, Andrew S and Dietz, Harry C} } @article {533, title = {Family Based Whole Exome Sequencing Reveals the Multifaceted Role of Notch Signaling in Congenital Heart Disease.}, journal = {PLoS Genet}, volume = {12}, year = {2016}, month = {2016 Oct}, pages = {e1006335}, abstract = {

Left-ventricular outflow tract obstructions (LVOTO) encompass a wide spectrum of phenotypically heterogeneous heart malformations which frequently cluster in families. We performed family based whole-exome and targeted re-sequencing on 182 individuals from 51 families with multiple affected members. Central to our approach is the family unit which serves as a reference to identify causal genotype-phenotype correlations. Screening a multitude of 10 overlapping phenotypes revealed disease associated and co-segregating variants in 12 families. These rare or novel protein altering mutations cluster predominantly in genes (NOTCH1, ARHGAP31, MAML1, SMARCA4, JARID2, JAG1) along the Notch signaling cascade. This is in line with a significant enrichment (Wilcoxon, p< 0.05) of variants with a higher pathogenicity in the Notch signaling pathway in patients compared to controls. The significant enrichment of novel protein truncating and missense mutations in NOTCH1 highlights the allelic and phenotypic heterogeneity in our pediatric cohort. We identified novel co-segregating pathogenic mutations in NOTCH1 associated with left and right-sided cardiac malformations in three independent families with a total of 15 affected individuals. In summary, our results suggest that a small but highly pathogenic fraction of family specific mutations along the Notch cascade are a common cause of LVOTO.

}, keywords = {Aortic Valve, Codon, Nonsense, Constriction, Pathologic, Exome, Female, Genetic Association Studies, Genetic Linkage, Genome, Human, Heart Defects, Congenital, Humans, Male, Pedigree, Receptor, Notch1, Receptors, Notch, Sequence Deletion, Signal Transduction, Ventricular Outflow Obstruction}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1006335}, author = {Preuss, Christoph and Capredon, Melanie and W{\"u}nnemann, Florian and Chetaille, Philippe and Prince, Andrea and Godard, Beatrice and Leclerc, Severine and Sobreira, Nara and Ling, Hua and Awadalla, Philip and Thibeault, Maryse and Khairy, Paul and Samuels, Mark E and Andelfinger, Gregor} } @article {327, title = {Haploinsufficiency of SF3B4, a component of the pre-mRNA spliceosomal complex, causes Nager syndrome.}, journal = {Am J Hum Genet}, volume = {90}, year = {2012}, month = {2012 May 04}, pages = {925-33}, abstract = {

Nager syndrome, first described more than 60 years ago, is the archetype of a class of disorders called the acrofacial dysostoses, which are characterized by craniofacial and limb malformations. Despite intensive efforts, no gene for Nager syndrome has yet been identified. In an international collaboration, FORGE Canada and the National Institutes of Health Centers for Mendelian Genomics used exome sequencing as a discovery tool and found that mutations in SF3B4, a component of the U2 pre-mRNA spliceosomal complex, cause Nager syndrome. After Sanger sequencing of SF3B4 in a validation cohort, 20 of 35 (57\%) families affected by Nager syndrome had 1 of 18 different mutations, nearly all of which were frameshifts. These results suggest that most cases of Nager syndrome are caused by haploinsufficiency of SF3B4. Our findings add Nager syndrome to a growing list of disorders caused by mutations in genes that encode major components of the spliceosome and also highlight the synergistic potential of international collaboration when exome sequencing is applied in the search for genes responsible for rare Mendelian phenotypes.

}, keywords = {Adult, Child, Child, Preschool, Cohort Studies, Exome, Female, Haploinsufficiency, Humans, Limb Deformities, Congenital, Male, Mandibulofacial Dysostosis, Mutation, Reproducibility of Results, RNA Precursors, RNA Splicing Factors, RNA-Binding Proteins, Spliceosomes, Young Adult}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2012.04.004}, author = {Bernier, Francois P and Caluseriu, Oana and Ng, Sarah and Schwartzentruber, Jeremy and Buckingham, Kati J and Innes, A Micheil and Jabs, Ethylin Wang and Innis, Jeffrey W and Schuette, Jane L and Gorski, Jerome L and Byers, Peter H and Andelfinger, Gregor and Siu, Victoria and Lauzon, Julie and Fernandez, Bridget A and McMillin, Margaret and Scott, Richard H and Racher, Hilary and Majewski, Jacek and Nickerson, Deborah A and Shendure, Jay and Bamshad, Michael J and Parboosingh, Jillian S} }