The microRNA processorDROSHAis a candidate gene for a severe progressive neurological disorder
Authors: Barish Scott , Senturk Mumine , Schoch Kelly , Minogue Amanda L , Lopergolo Diego , Fallerini Chiara , Harland Jake , Seemann Jacob H , Stong Nicholas , Kranz Peter G , Kansagra Sujay , Mikati Mohamad A , Jasien Joan , El-Dairi Mays , Galluzzi Paolo ,   Undiagnosed Diseases Network, Acosta Maria T , Adam Margaret , Adams David R , Agrawal Pankaj B , Alejandro Mercedes E , Alvey Justin , Amendola Laura , Andrews Ashley , Ashley Euan A , Azamian Mahshid S , Bacino Carlos A , Bademci Guney , Baker Eva , Balasubramanyam Ashok , Baldridge Dustin , Bale Jim , Bamshad Michael , Barbouth Deborah , Bayrak-Toydemir Pinar , Beck Anita , Beggs Alan H , Behrens Edward , Bejerano Gill , Bennet Jimmy , Berg-Rood Beverly , Bernstein Jonathan A , Berry Gerard T , Bican Anna , Bivona Stephanie , Blue Elizabeth , Bohnsack John , Bonnenmann Carsten , Bonner Devon , Botto Lorenzo , Boyd Brenna , Briere Lauren C , Brokamp Elly , Brown Gabrielle , Burke Elizabeth A , Burrage Lindsay C , Butte Manish J , Byers Peter , Byrd William E , Carey John , Carrasquillo Olveen , Chang Ta Chen Peter , Chanprasert Sirisak , Chao Hsiao-Tuan , Clark Gary D , Coakley Terra R , Cobban Laurel A , Cogan Joy D , Coggins Matthew , Cole F Sessions , Colley Heather A , Cooper Cynthia M , Cope Heidi , Craigen William J , Crouse Andrew B , Cunningham Michael , D'Souza Precilla , Dai Hongzheng , Dasari Surendra , Davids Mariska , Dayal Jyoti G , Deardorff Matthew , Dell'Angelica Esteban C , Dhar Shweta U , Dipple Katrina , Doherty Daniel , Dorrani Naghmeh , Douine Emilie D , Draper David D , Duncan Laura , Earl Dawn , Eckstein David J , Emrick Lisa T , Eng Christine M , Esteves Cecilia , Estwick Tyra , Falk Marni , Fernandez Liliana , Ferreira Carlos , Fieg Elizabeth L , Findley Laurie C , Fisher Paul G , Fogel Brent L , Forghani Irman , Fresard Laure , GahlIan-Glass William A , Godfrey Rena A , Golden-Grant Katie , Goldman Alica M , Goldstein David B , Grajewski Alana , Groden Catherine A , Gropman Andrea L , Gutierrez Irma , Hahn Sihoun , Hamid Rizwan , Hanchard Neil A , Hassey Kelly , Hayes Nichole , High Frances , Hing Anne , Hisama Fuki M , Holm Ingrid A , Hom Jason , Horike-Pyne Martha , Huang Alden , Huang Yong , Isasi Rosario , Jamal Fariha , Jarvik Gail P , Jarvik Jeffrey , Jayadev Suman , Johnston Jean M , Karaviti Lefkothea , Kelley Emily G , Kennedy Jennifer , Kiley Dana , Kohane Isaac S , Kohler Jennefer N , Krakow Deborah , Krasnewich Donna M , Kravets Elijah , Korrick Susan , Koziura Mary , Krier Joel B , Lalani Seema R , Lam Byron , Lam Christina , Lanpher Brendan C , Lanza Ian R , Lau C Christopher , LeBlanc Kimberly , Lee Brendan H , Lee Hane , Levitt Roy , Lewis Richard A , Lincoln Sharyn A , Liu Pengfei , Liu Xue Zhong , Longo Nicola , Loo Sandra K , Loscalzo Joseph , Maas Richard L , Macnamara Ellen F , MacRae Calum A , Maduro Valerie V , Majcherska Marta M , Mak Bryan , Malicdan May Christine V , Mamounas Laura A , Manolio Teri A , Mao Rong , Maravilla Kenneth , Markello Thomas C , Marom Ronit , Marth Gabor , Martin Beth A , Martin Martin G , Martínez-Agosto Julian A , Marwaha Shruti , McCauley Jacob , McConkie-Rosell Allyn , McCormack Colleen E , McCray Alexa T , McGee Elisabeth , Mefford Heather , Merritt J Lawrence , Might Matthew , Mirzaa Ghayda , Morava Eva , Moretti Paolo M , Morimoto Marie , Mulvihill John J , Murdock David R , Nakano-Okuno Mariko , Nath Avi , Nelson Stan F , Newman John H , Nicholas Sarah K , Nickerson Deborah , Nieves-Rodriguez Shirley , Novacic Donna , Oglesbee Devin , Orengo James P , Pace Laura , Pak Stephen , Pallais J Carl , Palmer Christina G S , Papp Jeanette C , Parker Neil H , Phillips III John A , Posey Jennifer E , Potocki Lorraine , Pusey Barbara N , Quinlan Aaron , Raskind Wendy , Raja Archana N , Rao Deepak A , Renteria Genecee , Reuter Chloe M , Rives Lynette , Robertson Amy K , Rodan Lance H , Rosenfeld Jill A , Rosenwasser Natalie , Ruzhnikov Maura , Sacco Ralph , Sampson Jacinda B , Samson Susan L , Saporta Mario , Scott C Ron , Schaechter Judy , Schedl Timothy , Schoch Kelly , Scott Daryl A , Sharma Prashant , Shashi Vandana , Shin Jimann , Signer Rebecca , Sillari Catherine H , Silverman Edwin K , Sinsheimer Janet S , Sisco Kathy , Smith Edward C , Smith Kevin S , Solem Emily , Solnica-Krezel Lilianna , Spillmann Rebecca C , Stoler Joan M , StongJ Nicholas , Sullivan ennifer A , Sullivan Kathleen , Sun Angela , Sutton Shirley , Sweetser David A , Sybert Virginia , Tabor Holly K , Tamburro Cecelia P , K-GTan Queenie , Tekin Mustafa , Telischi Fred , Thorson Willa , Tifft Cynthia J , Toro Camilo , Tran Alyssa A , Tucker Brianna M , Urv Tiina K , Vanderver Adeline , Velinder Matt , Viskochil Dave , Vogel Tiphanie P , Wahl Colleen E , Wallace Stephanie , Walley Nicole M , Walsh Chris A , Walker Melissa , Wambach Jennifer , Wan Jijun , Wang Lee-kai , Wangler Michael F , Ward Patricia A , Wegner Daniel , Wener Mark , Wenger Tara , Perry Katherine Wesseling , Westerfield Monte , Wheeler Matthew T , Whitlock Jordan , Wolfe Lynne A , Woods Jeremy D , Yamamoto Shinya , Yang John , Yu Guoyun , Zastrow Diane B , Zhao Chunli , Zuchner Stephan , Ariani Francesca , Renieri Alessandra , Mari Francesca , Wangler Michael F , Arur Swathi , Jiang Yong-Hui , Yamamoto Shinya , Shashi Vandana , Bellen Hugo J 
Published: April 2022

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.