Rare deleterious mutations of HNRNP genes result in shared neurodevelopmental disorders
Authors: 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 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, 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, 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 Jensen, Alex E. Lash, Richard Marini, Vincent J. Myers, Eirene O’Connor, Chris Rigby, Beverly E. Robertson, Neelay Shah, Swapnil Shah, Emily Singer, Lee Anne G. Snyder, Alexandra N. Stephens, Jennifer Tjernagel, Brianna M. Vernoia, Natalia Volfovsky, Loran Casey White, Alexander Hsieh, Yufeng Shen, Xueya Zhou, Tychele N. Turner, Ethan Bahl, Taylor R. Thomas, Leo Brueggeman, Tanner Koomar, Jacob J. Michaelson, Brian J. O’Roak, Rebecca A. Barnard, Richard A. Gibbs, Donna Muzny, Aniko Sabo, Kelli L. Baalman Ahmed, Evan E. Eichler, Matthew Siegel, Leonard Abbeduto, David G. Amaral, Brittani A. Hilscher, Deana Li, Kaitlin Smith, Samantha Thompson, Charles Albright, Eric M. Butter, Sara Eldred, Nathan Hanna, Mark Jones, Daniel Lee Coury, Jessica Scherr, Taylor Pifher, Erin Roby, Brandy Dennis, Lorrin Higgins, Melissa 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 Shaffer, Carrie Thomas, Raphael A. Bernier, Emily A. Fox, Jennifer A. Gerdts, Micah Pepper, Theodore Ho, Daniel Cho, Joseph Piven, Holly Lechniak, Latha V. Soorya, Rachel Gordon, Allison Wainer, Lisa Yeh, Cesar Ochoa-Lubinoff, Nicole Russo, Elizabeth Berry-Kravis, Stephanie Booker, Craig A. Erickson, Lisa M. Prock, Katherine G. Pawlowski, Emily T. Matthews, Stephanie J. Brewster, Margaret A. Hojlo, Evi Abada, Elena Lamarche, Tianyun Wang, Shwetha C. Murali, William T. Harvey, Hannah E. Kaplan, Karen L. Pierce, Lindsey DeMarco, Susannah Horner, Juhi Pandey, Samantha Plate, Mustafa Sahin, Katherine D. Riley, Erin Carmody, Julia Constantini, Amy Esler, Ali Fatemi, Hanna Hutter, Rebecca J. Landa, Alexander P. McKenzie, Jason Neely, Vini Singh, Bonnie Van Metre, Ericka L. Wodka, Eric J. Fombonne, Lark Y. Huang-Storms, Lillian D. Pacheco, Sarah A. Mastel, Leigh A. Coppola, Sunday Francis, Andrea Jarrett, Suma Jacob, Natasha Lillie, Jaclyn Gunderson, Dalia Istephanous, Laura Simon, Ori Wasserberg, Angela L. Rachubinski, Cordelia R. 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 M. Taylor, Lauren K. Walsh, Katherine A. Dent, Andrew Mason, Anthony Sziklay, Christopher J. Smith, Rachel K. Earl, Tomasz Nowakowski, Raphael A. Bernier, Evan E. Eichler
Journal: Genome Medicine (2021)

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.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.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-disruptive single-nucleotide variants or indels and 15 cases with small copy number variants. Three hnRNP-encoding genes reach nominal or exome-wide significance for de novo variant enrichment, while nine are candidates for pathogenic mutations. Comparison of HNRNP gene expression shows a pattern consistent with a role in cerebral cortical development with enriched expression among radial glial progenitors. Clinical assessment of probands (n = 188-221) expands the phenotypes associated with HNRNP rare variants, and phenotypes associated with variation in the HNRNP genes distinguishes them as a subgroup of NDDs.Overall, our novel approach of exploiting gene families in NDDs identifies new HNRNP-related disorders, expands the phenotypes of known HNRNP-related disorders, strongly implicates disruption of the hnRNPs as a whole in NDDs, and supports that NDD subtypes likely have shared molecular pathogenesis. To date, this is the first study to identify novel genetic disorders based on the presence of disorders in related genes. We also perform the first phenotypic analyses focusing on related genes. Finally, we show that radial glial expression of these genes is likely critical during neurodevelopment. This is important for diagnostics, as well as developing strategies to best study these genes for the development of therapeutics.