Scott Barish, Mumine Senturk, Kelly Schoch, Amanda L Minogue, Diego Lopergolo, Chiara Fallerini, Jake Harland, Jacob H Seemann, Nicholas Stong, Peter G Kranz, Sujay Kansagra, Mohamad A Mikati, Joan Jasien, Mays El-Dairi, Paolo Galluzzi, Maria T Acosta, Margaret Adam, David R Adams, Pankaj B Agrawal, Mercedes E Alejandro, Justin Alvey, Laura Amendola, Ashley Andrews, Euan A Ashley, Mahshid S Azamian, Carlos A Bacino, Guney Bademci, Eva Baker, Ashok Balasubramanyam, Dustin Baldridge, Jim Bale, Michael Bamshad, Deborah Barbouth, Pinar Bayrak-Toydemir, Anita Beck, Alan H Beggs, Edward Behrens, Gill Bejerano, Jimmy Bennet, Beverly Berg-Rood, Jonathan A Bernstein, Gerard T Berry, Anna Bican, Stephanie Bivona, Elizabeth Blue, John Bohnsack, Carsten Bonnenmann, Devon Bonner, Lorenzo Botto, Brenna Boyd, Lauren C Briere, Elly Brokamp, Gabrielle Brown, Elizabeth A Burke, Lindsay C Burrage, Manish J Butte, Peter Byers, William E Byrd, John Carey, Olveen Carrasquillo, Ta Chen Peter Chang, Sirisak Chanprasert, Hsiao-Tuan Chao, Gary D Clark, Terra R Coakley, Laurel A Cobban, Joy D Cogan, Matthew Coggins, F Sessions Cole, Heather A Colley, Cynthia M Cooper, Heidi Cope, William J Craigen, Andrew B Crouse, Michael Cunningham, Precilla D'Souza, Hongzheng Dai, Surendra Dasari, Mariska Davids, Jyoti G Dayal, Matthew Deardorff, Esteban C Dell'Angelica, Shweta U Dhar, Katrina Dipple, Daniel Doherty, Naghmeh Dorrani, Emilie D Douine, David D Draper, Laura Duncan, Dawn Earl, David J Eckstein, Lisa T Emrick, Christine M Eng, Cecilia Esteves, Tyra Estwick, Marni Falk, Liliana Fernandez, Carlos Ferreira, Elizabeth L Fieg, Laurie C Findley, Paul G Fisher, Brent L Fogel, Irman Forghani, Laure Fresard, William A GahlIan-Glass, Rena A Godfrey, Katie Golden-Grant, Alica M Goldman, David B Goldstein, Alana Grajewski, Catherine A Groden, Andrea L Gropman, Irma Gutierrez, Sihoun Hahn, Rizwan Hamid, Neil A Hanchard, Kelly Hassey, Nichole Hayes, Frances High, Anne Hing, Fuki M Hisama, Ingrid A Holm, Jason Hom, Martha Horike-Pyne, Alden Huang, Yong Huang, Rosario Isasi, Fariha Jamal, Gail P Jarvik, Jeffrey Jarvik, Suman Jayadev, Jean M Johnston, Lefkothea Karaviti, Emily G Kelley, Jennifer Kennedy, Dana Kiley, Isaac S Kohane, Jennefer N Kohler, Deborah Krakow, Donna M Krasnewich, Elijah Kravets, Susan Korrick, Mary Koziura, Joel B Krier, Seema R Lalani, Byron Lam, Christina Lam, Brendan C Lanpher, Ian R Lanza, C Christopher Lau, Kimberly LeBlanc, Brendan H Lee, Hane Lee, Roy Levitt, Richard A Lewis, Sharyn A Lincoln, Pengfei Liu, Xue Zhong Liu, Nicola Longo, Sandra K Loo, Joseph Loscalzo, Richard L Maas, Ellen F Macnamara, Calum A MacRae, Valerie V Maduro, Marta M Majcherska, Bryan Mak, May Christine V Malicdan, Laura A Mamounas, Teri A Manolio, Rong Mao, Kenneth Maravilla, Thomas C Markello, Ronit Marom, Gabor Marth, Beth A Martin, Martin G Martin, Julian A Martínez-Agosto, Shruti Marwaha, Jacob McCauley, Allyn McConkie-Rosell, Colleen E McCormack, Alexa T McCray, Elisabeth McGee, Heather Mefford, J Lawrence Merritt, Matthew Might, Ghayda Mirzaa, Eva Morava, Paolo M Moretti, Marie Morimoto, John J Mulvihill, David R Murdock, Mariko Nakano-Okuno, Avi Nath, Stan F Nelson, John H Newman, Sarah K Nicholas, Deborah Nickerson, Shirley Nieves-Rodriguez, Donna Novacic, Devin Oglesbee, James P Orengo, Laura Pace, Stephen Pak, J Carl Pallais, Christina G S Palmer, Jeanette C Papp, Neil H Parker, John A Phillips III, Jennifer E Posey, Lorraine Potocki, Barbara N Pusey, Aaron Quinlan, Wendy Raskind, Archana N Raja, Deepak A Rao, Genecee Renteria, Chloe M Reuter, Lynette Rives, Amy K Robertson, Lance H Rodan, Jill A Rosenfeld, Natalie Rosenwasser, Maura Ruzhnikov, Ralph Sacco, Jacinda B Sampson, Susan L Samson, Mario Saporta, C Ron Scott, Judy Schaechter, Timothy Schedl, Kelly Schoch, Daryl A Scott, Prashant Sharma, Vandana Shashi, Jimann Shin, Rebecca Signer, Catherine H Sillari, Edwin K Silverman, Janet S Sinsheimer, Kathy Sisco, Edward C Smith, Kevin S Smith, Emily Solem, Lilianna Solnica-Krezel, Rebecca C Spillmann, Joan M Stoler, Nicholas StongJ, ennifer A Sullivan, Kathleen Sullivan, Angela Sun, Shirley Sutton, David A Sweetser, Virginia Sybert, Holly K Tabor, Cecelia P Tamburro, Queenie K-GTan, Mustafa Tekin, Fred Telischi, Willa Thorson, Cynthia J Tifft, Camilo Toro, Alyssa A Tran, Brianna M Tucker, Tiina K Urv, Adeline Vanderver, Matt Velinder, Dave Viskochil, Tiphanie P Vogel, Colleen E Wahl, Stephanie Wallace, Nicole M Walley, Chris A Walsh, Melissa Walker, Jennifer Wambach, Jijun Wan, Lee-kai Wang, Michael F Wangler, Patricia A Ward, Daniel Wegner, Mark Wener, Tara Wenger, Katherine Wesseling Perry, Monte Westerfield, Matthew T Wheeler, Jordan Whitlock, Lynne A Wolfe, Jeremy D Woods, Shinya Yamamoto, John Yang, Guoyun Yu, Diane B Zastrow, Chunli Zhao, Stephan Zuchner, Francesca Ariani, Alessandra Renieri, Francesca Mari, Michael F Wangler, Swathi Arur, Yong-Hui Jiang, Shinya Yamamoto, Vandana Shashi, Hugo J Bellen

DROSHA encodes a ribonuclease that is a subunit of the Microprocessor complex and is involved in the first step of microRNA (miRNA) biogenesis. To date, DROSHA has not yet been associated with a Mendelian disease. Here we describe two individuals with profound intellectual disability, epilepsy, white matter atrophy, microcephaly, and dysmorphic features, who carry damaging de novo heterozygous variants in DROSHA. DROSHA is constrained for missense variants and moderately intolerant to loss of function (o/e = 0.24). The loss of the fruit fly ortholog drosha causes developmental arrest and death in third instar larvae, a severe reduction in brain size, and loss of imaginal discs in the larva. Loss of drosha in eye clones causes small and rough eyes in adult flies. One of the identified DROSHA variants (p.Asp1219Gly) behaves as a strong loss-of-function allele in flies, while another variant (p.Arg1342Trp) is less damaging in our assays. In worms, a knock-in that mimics the p.Asp1219Gly variant at a worm equivalent residue causes loss of miRNA expression and heterochronicity, a phenotype characteristic of the loss of miRNA. Together, our data show that the DROSHA variants found in the individuals presented here are damaging based on functional studies in model organisms and likely underlie the severe phenotype involving the nervous system.