Rare deleterious mutations of HNRNP genes result in shared neurodevelopmental disorders

作者：Madelyn A. Gillentine, Tianyun Wang, Kendra Hoekzema, Jill A. Rosenfeld, Pengfei Liu, Hui Guo, Chang N. Kim, Bert B. A. De Vries, Lisenka E.L.M. Vissers, Magnus Nordenskjöld, Malin Kvarnung, Anna Lindstrand, Ann Nordgren, Jozef Gécz, 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 S. Atwal, Carlos A. Bacino, Gifty Bhat, Katherine Cobian, Lynne M. Bird, Jennifer Friedman, Meredith S. Wright, Bert Callewaert, Florence Petit, Sophie Mathieu, Alexandra Afenjar, Celanie K. Christensen, Kerry White, Orly Elpeleg, Itai Berger, Edward J. Espineli, Christina Fagerberg, Charlotte Brasch‐Andersen, Lars Kjærsgaard Hansen, Timothy Feyma, Susan Hughes, Isabelle Thiffault, Bonnie Sullivan, Shuang Yan, Kory Keller, Boris Keren, Cyril Mignot, R. Frank Kooy, Marije Meuwissen, Alice Basinger, Mary K. Kukolich, Meredith Philips, Lucia Ortega, Margaret Drummond‐Borg, Mathilde Lauridsen, Kristina Sorensen, Anna Lehman, CAUSES Study, Elena Lopez‐Rangel, Paul A. Levy, Davor Lessel, Timothy Lotze, Suneeta Madan-Khetarpal, Jessica Sebastian, Jodie M. Vento, Divya Vats, L. Manace Benman, Shane McKee, Ghayda Mirzaa, Candace Muss, John Pappas, Hilde Peeters, Corrado Romano, Maurizio Elia, Ornella Galesi, Marleen Simon, Koen L.I. van Gassen, Kara Simpson, Robert F. Stratton, Shakir Syed, Julien Thévenon, Irene Valenzuela, Antonio Vitobello, Marie Bournez, Laurence Faivre, Kun Xia, John Acampado, Andrea J. Ace, Alpha Amatya, Irina Astrovskaya, Asif Bashar, Elizabeth Brooks, Martin E. Butler, Lindsey A. Cartner, Wubin Chin, Wendy K. Chung, Amy M. Daniels, Pamela Feliciano, Chris Fleisch, Swami Ganesan, William B. Jensen, Alex Lash, Richard P. Marini, Vincent J. Myers, Eirene O’Connor, Chris Rigby, B. E. Robertson, Neelay Shah, Swapnil Shah, Emily Singer, Lee Anne G. Snyder, Alexandra N. Stephens, Jennifer Tjernagel, Brianna M. Vernoia, Natalia Volfovsky, L. Casey White, Alexander Hsieh, Yufeng Shen, Xueya Zhou, Tychele N. Turner, Ethan Bahl, Taylor Thomas, Leo Brueggeman, Tanner Koomar, Jacob J. Michaelson, Brian J. O’Roak, Rebecca Barnard, Richard A. Gibbs, Donna M. Muzny, Aniko Sabo, Kelli L. Baalman Ahmed, Evan E. Eichler, Matthew Siegel, Leonard Abbeduto, David G. Amaral, Brittani A. Hilscher, Deana Li, Kaitlin N. Smith, Samantha Thompson, Charles F. Albright, Eric Butter, Sara Eldred, Nathan Hanna, Mark Jones, Daniel L. Coury, Jessica Scherr, Taylor Pifher, Erin Roby, Brandy Dennis, Lorrin Higgins, Melissa A. Brown, Michael Alessandri, Anibal Gutierrez, Melissa N. Hale, Lynette M. Herbert, Hoa Lam Schneider, Giancarla David, Robert D. Annett, Dustin E. Sarver, Ivette Arriaga, Alexies Camba, Amanda C. Gulsrud, Monica Haley, James T. McCracken, Sophia Sandhu, Maira Tafolla, Wha S. Yang, Laura A. Carpenter, Catherine C. Bradley, Frampton Gwynette, Patricia Manning, Rebecca C. Shaffer, Carrie Thomas, Raphael A. Bernier, Emily A. Fox, Jennifer A. Gerdts, Micah Pepper, Theodore Ho, Daniel Cho, Joseph Piven, Holly Lechniak, Latha Soorya, Rachel Gordon, Allison Wainer, Lisa C. Yeh, Cesar Ochoa-Lubinoff, Nicole M. Russo‐Ponsaran, Elizabeth Berry‐Kravis, Stephanie Booker, Craig A. Erickson, Lisa M. Prock, Katherine G. Pawlowski, Emily T. Matthews, Stephanie Brewster, Margaret A. Hojlo, Evi Abada, Elena Lamarche, Tianyun Wang, Shwetha C. Murali, William T. Harvey, Hannah E. Kaplan, Karen Pierce, Lindsey DeMarco, Susannah Horner, Juhi Pandey, Samantha Plate, Mustafa Şahin, Katherine D. Riley, Erin Carmody, Julia Constantini, Amy Esler, Ali Fatemi, Hanna Hutter, Rebecca Landa, Alexander P. McKenzie, Jason Neely, Vini Singh, Bonnie Van Metre, Ericka L. Wodka, Éric Fombonne, Lark Y. Huang-Storms, Lillian D. Pacheco, Sarah Mastel, Leigh A. Coppola, Sunday M. Francis, Andrea Jarrett, Suma Jacob, Natasha Lillie, Jaclyn Gunderson, Dalia Istephanous, Laura Simon, Ori Wasserberg, Angela L. Rachubinski, Cordelia Robinson Rosenberg, Stephen M. Kanne, Amanda D. Shocklee, Nicole Takahashi, Shelby L. Bridwell, Rebecca L. Klimczac, Melissa A. Mahurin, Hannah E. Cotrell, Cortaiga A. Grant, Samantha G. Hunter, Christa Lese Martin, Cora Taylor, Lauren K. Walsh, Katherine A. Dent, Andrew L. Mason, Anthony Sziklay, Christopher J. Smith, Rachel K. Earl, Tomasz J. Nowakowski, Raphael A. Bernier, Evan E. Eichler · 发表于：Genome Medicine · 年份：2021 · DOI：10.1186/s13073-021-00870-6 · 被引用次数：118 · 研究领域：Genomics and Rare Diseases、Genetic Neurodegenerative Diseases、Neurogenetic and Muscular Disorders Research

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 has 33 members, five of which have been recently identified as NDD genes (HNRNPK, HNRNPU, HNRNPH1, HNRNPH2, and HNRNPR) and two of which have significant enrichment in our previous meta-analysis of probands with NDDs (HNRNPU and SYNCRIP). Utilizing protein homology, mutation analyses, gene expression analyses, and phenotypic characterization, we provide evidence for variation in 12 HNRNP genes as candidates for NDDs. Seven are potentially novel while the remaining genes in the family likely do not significantly contribute to NDD risk. RESULTS: We report 119 new NDD cases (64 de novo variants) through sequencing and international collaborations and combined with published clinical case reports. We consider 235 cases with gene-disruptiv...