Medicine and Health Sciences Commons^™

Rare Variants In Kdr, Encoding Vegf Receptor 2, Are Associated With Tetralogy Of Fallot., Doris Škorić-Milosavljević, Najim Lahrouchi, Fernanda M. Bosada, Gregor Dombrowsky, Simon G. Williams, Robert Lesurf, Fleur V Y Tjong, Roddy Walsh, Ihssane El Bouchikhi, Jeroen Breckpot, Enrique Audain, Aho Ilgun, Leander Beekman, Ilham Ratbi, Alanna Strong, Maximilian Muenke, Solveig Heide, Alison M. Muir, Mariam Hababa, Laura A. Cross, Dihong Zhou, T Pastinen, German Competence Network For Congenital Heart Defects, Elaine Zackai, Samir Atmani, Karim Ouldim, Najlae Adadi, Katharina Steindl, Anita Rauch, David Brook, Anna Wilsdon, Irene Kuipers, Nico A. Blom, Barbara J. Mulder, Heather C. Mefford, Boris Keren, Pascal Joset, Paul Kruszka, Isabelle Thiffault, Sarah E. Sheppard, Amy Roberts, Elisabeth M. Lodder, Bernard D. Keavney, Sally-Ann B. Clur, Seema Mital, Marc-Philip Hitz, Vincent M. Christoffels, Alex V. Postma, Connie R. Bezzina

Manuscripts, Articles, Book Chapters and Other Papers

Purpose: Rare genetic variants in KDR, encoding the vascular endothelial growth factor receptor 2 (VEGFR2), have been reported in patients with tetralogy of Fallot (TOF). However, their role in disease causality and pathogenesis remains unclear.

Methods: We conducted exome sequencing in a familial case of TOF and large-scale genetic studies, including burden testing, in >1,500 patients with TOF. We studied gene-targeted mice and conducted cell-based assays to explore the role of KDR genetic variation in the etiology of TOF.

Results: Exome sequencing in a family with two siblings affected by TOF revealed biallelic missense variants in KDR. Studies in knock-in …

Investigation Of Alpl Variant States And Clinical Outcomes: An Analysis Of Adults And Adolescents With Hypophosphatasia Treated With Asfotase Alfa., Priya S. Kishnani, Guillermo Del Angel, Shanggen Zhou, Eric T. Rush

Manuscripts, Articles, Book Chapters and Other Papers

Background: Hypophosphatasia (HPP), a rare metabolic disease, can be inherited in an autosomal recessive (biallelic) or an autosomal dominant (monoallelic) manner. Most of the severe, early-onset, frequently lethal HPP in infants is acquired through recessive inheritance; less severe, later-onset, typically nonlethal HPP phenotypes are acquired through either dominant or recessive inheritance. HPP's variable clinical presentation arises from >400 identified ALPL pathogenic variants with likely variable penetrance, especially with autosomal dominant inheritance. This post hoc analysis investigated the relationship between ALPL variant state (biallelic and monoallelic) and clinical outcomes with asfotase alfa in HPP.

Methods: Data were pooled from two phase …

Rare Deleterious Mutations Of Hnrnp Genes Result In Shared Neurodevelopmental Disorders., Madelyn A. Gillentine, Tianyun Wang, Kendra Hoekzema, Jill Rosenfeld, Pengfei Liu, Hui Guo, Chang N. Kim, Bert B A De Vries, Lisenka E L M Vissers, Magnus Nordenskjold, Malin Kvarnung, Anna Lindstrand, Ann Nordgren, Jozef Gecz, Maria Iascone, Anna Cereda, Agnese Scatigno, Silvia Maitz, Ginevra Zanni, Enrico Bertini, Christiane Zweier, Sarah Schuhmann, Antje Wiesener, Micah Pepper, Heena Panjwani, Erin Torti, Farida Abid, Irina Anselm, Siddharth Srivastava, Paldeep Atwal, Carlos A. Bacino, Gifty Bhat, Katherine Cobian, Lynne M. Bird, Jennifer Friedman, Meredith S. Wright, Bert Callewaert, Florence Petit, Sophie Mathieu, Alexandra Afenjar, Celenie K. Christensen, Kerry M. White, Orly Elpeleg, Itai Berger, Edward J. Espineli, Christina Fagerberg, Charlotte Brasch-Andersen, Lars Kjærsgaard Hansen, Timothy Feyma, Susan Starling Hughes, Isabelle Thiffault, Bonnie Sullivan, Shuang Yan, Kory Keller, Boris Keren, Cyril Mignot, Frank Kooy, Marije Meuwissen, Alice Basinger, Mary Kukolich, Meredith Philips, Lucia Ortega, Margaret Drummond-Borg, Mathilde Lauridsen, Kristina Sorensen, Anna Lehman, Causes Study, Elena Lopez-Rangel, Paul Levy, Davor Lessel, Timothy Lotze, Suneeta Madan-Khetarpal, Jessica Sebastian, Jodie Vento, Divya Vats, L Manace Benman, Shane Mckee, Ghayda M. Mirzaa, Candace Muss, John Pappas, Hilde Peeters, Corrado Romano, Maurizio Elia, Ornella Galesi, Marleen E H Simon, Koen L I Van Gassen, Kara Simpson, Robert Stratton, Sabeen Syed, Julien Thevenon, Irene Valenzuela Palafoll, Antonio Vitobello, Marie Bournez, Laurence Faivre, Kun Xia, Spark Consortium, Rachel K. Earl, Tomasz Nowakowski, Raphael A. Bernier, Evan E. Eichler

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND: With the increasing number of genomic sequencing studies, hundreds of genes have been implicated in neurodevelopmental disorders (NDDs). The rate of gene discovery far outpaces our understanding of genotype-phenotype correlations, with clinical characterization remaining a bottleneck for understanding NDDs. Most disease-associated Mendelian genes are members of gene families, and we hypothesize that those with related molecular function share clinical presentations.

METHODS: We tested our hypothesis by considering gene families that have multiple members with an enrichment of de novo variants among NDDs, as determined by previous meta-analyses. One of these gene families is the heterogeneous nuclear ribonucleoproteins (hnRNPs), which …

Genetic Perturbation Of Pu.1 Binding And Chromatin Looping At Neutrophil Enhancers Associates With Autoimmune Disease., Stephen Watt, Louella Vasquez, Klaudia Walter, Alice L. Mann, Kousik Kundu, Lu Chen, Ying Sims, Simone Ecker, Frances Burden, Samantha Farrow, Ben Farr, Valentina Iotchkova, Heather Elding, Daniel Mead, Manuel Tardaguila, Hannes Ponstingl, David Richardson, Avik Datta, Paul Flicek, Laura Clarke, Kate Downes, T Pastinen, Peter Fraser, Mattia Frontini, Biola-Maria Javierre, Mikhail Spivakov, Nicole Soranzo

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Neutrophils play fundamental roles in innate immune response, shape adaptive immunity, and are a potentially causal cell type underpinning genetic associations with immune system traits and diseases. Here, we profile the binding of myeloid master regulator PU.1 in primary neutrophils across nearly a hundred volunteers. We show that variants associated with differential PU.1 binding underlie genetically-driven differences in cell count and susceptibility to autoimmune and inflammatory diseases. We integrate these results with other multi-individual genomic readouts, revealing coordinated effects of PU.1 binding variants on the local chromatin state, enhancer-promoter contacts and downstream gene expression, and providing a functional interpretation for …

Delta-Like 4 Is Required For Pulmonary Vascular Arborization And Alveolarization In The Developing Lung., Sheng Xia, Heather Menden, Nick Townley, Sherry M. Mabry, Jeffrey J. Johnston, Michael F. Nyp, Daniel P. Heruth, Thomas Korfhagen, Venkatesh Sampath

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The molecular mechanisms by which endothelial cells (ECs) regulate pulmonary vascularization and contribute to alveolar epithelial cell development during lung morphogenesis remain unknown. We tested the hypothesis that delta-like 4 (DLL4), an EC Notch ligand, is critical for alveolarization by combining lung mapping and functional studies in human tissue and DLL4-haploinsufficient mice (Dll4+/lacz). DLL4 expressed in a PECAM-restricted manner in capillaries, arteries, and the alveolar septum from the canalicular to alveolar stage in mice and humans. Dll4 haploinsufficiency resulted in exuberant, nondirectional vascular patterning at E17.5 and P6, followed by smaller capillaries and fewer intermediate blood vessels at P14. Vascular …

Racial Disparities In Necrotizing Enterocolitis., Alain Cuna, Venkatesh Sampath, Minesh Khashu

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Necrotizing enterocolitis (NEC) is a serious disease of the intestinal tract affecting 5-10% of pre-term infants with up to 50% mortality in those that require surgery. There is wide variation in the rates and outcomes of NEC by race and ethnicity, and the reasons for this disparity are poorly understood. In this article, we review the epidemiology and discuss possible explanations for racial and ethnic differences in NEC. Most of the current evidence investigating the role of race in NEC comes from North America and suggests that Hispanic ethnicity and non-Hispanic Black race are associated with higher risk of NEC …

Impaired Eif5a Function Causes A Mendelian Disorder That Is Partially Rescued In Model Systems By Spermidine., Víctor Faundes, Martin D. Jennings, Siobhan Crilly, Sarah Legraie, Sarah E. Withers, Sara Cuvertino, Sally J. Davies, Andrew G L Douglas, Andrew E. Fry, Victoria Harrison, Jeanne Amiel, Daphné Lehalle, William G. Newman, Patricia Newkirk, Judith Ranells, Miranda Splitt, Laura A. Cross, Carol J. Saunders, Bonnie Sullivan, Jorge L. Granadillo, Christopher T. Gordon, Paul R. Kasher, Graham D. Pavitt, Siddharth Banka

Manuscripts, Articles, Book Chapters and Other Papers

The structure of proline prevents it from adopting an optimal position for rapid protein synthesis. Poly-proline-tract (PPT) associated ribosomal stalling is resolved by highly conserved eIF5A, the only protein to contain the amino acid hypusine. We show that de novo heterozygous EIF5A variants cause a disorder characterized by variable combinations of developmental delay, microcephaly, micrognathia and dysmorphism. Yeast growth assays, polysome profiling, total/hypusinated eIF5A levels and PPT-reporters studies reveal that the variants impair eIF5A function, reduce eIF5A-ribosome interactions and impair the synthesis of PPT-containing proteins. Supplementation with 1 mM spermidine partially corrects the yeast growth defects, improves the polysome profiles …