Fuad Chowdhury1,2, Lei Wang3, Mohammed Al-Raqad4, David J Amor5, Alice Baxová6, Šárka Bendová7, Elisa Biamino8, Alfredo Brusco9, Oana Caluseriu10, Nancy J Cox11, Tawfiq Froukh12, Meral Gunay-Aygun13, Miroslava Hančárová7, Devon Haynes14, Solveig Heide15, George Hoganson16, Tadashi Kaname17, Boris Keren15, Kenjiro Kosaki18, Kazuo Kubota19, Jennifer M Lemons20, Maria A Magriña21, Paul R Mark22, Marie T McDonald23, Sarah Montgomery23, Gina M Morley16, Hidenori Ohnishi19, Nobuhiko Okamoto24, David Rodriguez-Buritica20, Patrick Rump25, Zdeněk Sedláček7, Krista Schatz13, Haley Streff26, Tomoko Uehara18, Jagdeep S Walia27, Patricia G Wheeler14, Antje Wiesener28, Christiane Zweier28, Koichi Kawakami29, Ingrid M Wentzensen30, Seema R Lalani26, Victoria M Siu1,2,31, Weimin Bi32,33, Tugce B Balci34,35,36. 1. Department of Paediatrics, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada. 2. Medical Genetics Program of Southwestern Ontario, London Health Sciences Centre, London, ON, Canada. 3. Baylor Genetics Laboratory, Houston, TX, USA. 4. Al-Balqa Applied University, Faculty of Medicine, Al-Salt, Jordan. 5. Murdoch Children's Research Institute and University of Melbourne Department of Paediatrics, Royal Children's Hospital, Parkville, Australia. 6. Department of Biology and Medical Genetics, 1st Faculty of Medicine and University Hospital, Charles University, Prague, Czech Republic. 7. Department of Biology and Medical Genetics, 2nd Faculty of Medicine and University Hospital Motol, Charles University, Prague, Czech Republic. 8. Department of Pediatrics, Regina Margherita Children Hospital, Turin, Italy. 9. Department of Medical Sciences, University of Torino, Torino, Italy. 10. Department of Medical Genetics, University of Alberta, Edmonton, AB, Canada. 11. Vanderbilt Genetics Institute, Vanderbilt University, Nashville, TN, USA. 12. Department of Biotechnology and Genetic Engineering, Philadelphia University, Amman, Jordan. 13. Department of Genetic Medicine, Johns Hopkins Hospital, Baltimore, MD, USA. 14. Division of Genetics, Arnold Palmer Hospital for Children-Orlando Health, Orlando, FL, USA. 15. Département de Génétique and CRMR « Déficience Intellectuelle », Hôpital de la Pitié Salpêtrière, APHP Sorbonne Université, Paris, France. 16. Department of Medical Genetics, Mercyhealth-Javon Bea Hospital, Rockford, IL, USA. 17. Department of Genome Medicine, National Center for Child Health and Development, Tokyo, Japan. 18. Center for Medical Genetics, Keio University School of Medicine, Tokyo, Japan. 19. Department of Pediatrics, Gifu University Graduate School of Medicine, Gifu, Japan. 20. Department of Pediatrics, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA. 21. Medical Specialties Unit from City Hall São Jose dos Campos, São Paulo, Brazil. 22. Division of Medical Genetics and Genomics, Spectrum Health, Grand Rapids, MI, USA. 23. Department of Pediatrics, Division of Medical Genetics, Duke University Medical Center, Durham, NC, USA. 24. Department of Medical Genetics, Osaka Women's and Children's Hospital, Osaka, Japan. 25. Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, Netherlands. 26. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA. 27. Department of Pediatrics, Division of Medical Genetics, Kingston General Hospital, Kingston, ON, Canada. 28. Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany. 29. Laboratory of Molecular and Developmental Biology, National Institute of Genetics, Mishima, Japan. 30. GeneDx, Gaithersburg, MD, USA. 31. Children's Health Research Institute, London, ON, Canada. 32. Baylor Genetics Laboratory, Houston, TX, USA. wbi@bcm.edu. 33. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA. wbi@bcm.edu. 34. Department of Paediatrics, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada. Tugce.Balci@lhsc.on.ca. 35. Medical Genetics Program of Southwestern Ontario, London Health Sciences Centre, London, ON, Canada. Tugce.Balci@lhsc.on.ca. 36. Children's Health Research Institute, London, ON, Canada. Tugce.Balci@lhsc.on.ca.
Abstract
PURPOSE: Proline Rich 12 (PRR12) is a gene of unknown function with suspected DNA-binding activity, expressed in developing mice and human brains. Predicted loss-of-function variants in this gene are extremely rare, indicating high intolerance of haploinsufficiency. METHODS: Three individuals with intellectual disability and iris anomalies and truncating de novo PRR12 variants were described previously. We add 21 individuals with similar PRR12 variants identified via matchmaking platforms, bringing the total number to 24. RESULTS: We observed 12 frameshift, 6 nonsense, 1 splice-site, and 2 missense variants and one patient with a gross deletion involving PRR12. Three individuals had additional genetic findings, possibly confounding the phenotype. All patients had developmental impairment. Variable structural eye defects were observed in 12/24 individuals (50%) including anophthalmia, microphthalmia, colobomas, optic nerve and iris abnormalities. Additional common features included hypotonia (61%), heart defects (52%), growth failure (54%), and kidney anomalies (35%). PrediXcan analysis showed that phecodes most strongly associated with reduced predicted PRR12 expression were enriched for eye- (7/30) and kidney- (4/30) phenotypes, such as wet macular degeneration and chronic kidney disease. CONCLUSION: These findings support PRR12 haploinsufficiency as a cause for a novel disorder with a wide clinical spectrum marked chiefly by neurodevelopmental and eye abnormalities.
PURPOSE: Proline Rich 12 (PRR12) is a gene of unknown function with suspected DNA-binding activity, expressed in developing mice and human brains. Predicted loss-of-function variants in this gene are extremely rare, indicating high intolerance of haploinsufficiency. METHODS: Three individuals with intellectual disability and iris anomalies and truncating de novo PRR12 variants were described previously. We add 21 individuals with similar PRR12 variants identified via matchmaking platforms, bringing the total number to 24. RESULTS: We observed 12 frameshift, 6 nonsense, 1 splice-site, and 2 missense variants and one patient with a gross deletion involving PRR12. Three individuals had additional genetic findings, possibly confounding the phenotype. All patients had developmental impairment. Variable structural eye defects were observed in 12/24 individuals (50%) including anophthalmia, microphthalmia, colobomas, optic nerve and iris abnormalities. Additional common features included hypotonia (61%), heart defects (52%), growth failure (54%), and kidney anomalies (35%). PrediXcan analysis showed that phecodes most strongly associated with reduced predicted PRR12 expression were enriched for eye- (7/30) and kidney- (4/30) phenotypes, such as wet macular degeneration and chronic kidney disease. CONCLUSION: These findings support PRR12 haploinsufficiency as a cause for a novel disorder with a wide clinical spectrum marked chiefly by neurodevelopmental and eye abnormalities.
Authors: P Y Billie Au; Jing You; A Micheil Innes; Antonie D Kline; Oana Caluseriu; Jeremy Schwartzentruber; Jacek Majewski; Francois P Bernier; Marcia Ferguson; David Valle; Jillian S Parboosingh; Nara Sobreira Journal: Hum Mutat Date: 2015-08-06 Impact factor: 4.878
Authors: Oliver James Dillon; Sebastian Lunke; Zornitza Stark; Alison Yeung; Natalie Thorne; Clara Gaff; Susan M White; Tiong Yang Tan Journal: Eur J Hum Genet Date: 2018-02-16 Impact factor: 4.246
Authors: Anne H O'Donnell-Luria; Lynn S Pais; Víctor Faundes; Jordan C Wood; Abigail Sveden; Victor Luria; Rami Abou Jamra; Andrea Accogli; Kimberly Amburgey; Britt Marie Anderlid; Silvia Azzarello-Burri; Alice A Basinger; Claudia Bianchini; Lynne M Bird; Rebecca Buchert; Wilfrid Carre; Sophia Ceulemans; Perrine Charles; Helen Cox; Lisa Culliton; Aurora Currò; Florence Demurger; James J Dowling; Benedicte Duban-Bedu; Christèle Dubourg; Saga Elise Eiset; Luis F Escobar; Alessandra Ferrarini; Tobias B Haack; Mona Hashim; Solveig Heide; Katherine L Helbig; Ingo Helbig; Raul Heredia; Delphine Héron; Bertrand Isidor; Amy R Jonasson; Pascal Joset; Boris Keren; Fernando Kok; Hester Y Kroes; Alinoë Lavillaureix; Xin Lu; Saskia M Maas; Gustavo H B Maegawa; Carlo L M Marcelis; Paul R Mark; Marcelo R Masruha; Heather M McLaughlin; Kirsty McWalter; Esther U Melchinger; Saadet Mercimek-Andrews; Caroline Nava; Manuela Pendziwiat; Richard Person; Gian Paolo Ramelli; Luiza L P Ramos; Anita Rauch; Caitlin Reavey; Alessandra Renieri; Angelika Rieß; Amarilis Sanchez-Valle; Shifteh Sattar; Carol Saunders; Niklas Schwarz; Thomas Smol; Myriam Srour; Katharina Steindl; Steffen Syrbe; Jenny C Taylor; Aida Telegrafi; Isabelle Thiffault; Doris A Trauner; Helio van der Linden; Silvana van Koningsbruggen; Laurent Villard; Ida Vogel; Julie Vogt; Yvonne G Weber; Ingrid M Wentzensen; Elysa Widjaja; Jaroslav Zak; Samantha Baxter; Siddharth Banka; Lance H Rodan Journal: Am J Hum Genet Date: 2019-05-09 Impact factor: 11.043
Authors: Daniel Trujillano; Aida M Bertoli-Avella; Krishna Kumar Kandaswamy; Maximilian Er Weiss; Julia Köster; Anett Marais; Omid Paknia; Rolf Schröder; Jose Maria Garcia-Aznar; Martin Werber; Oliver Brandau; Maria Calvo Del Castillo; Caterina Baldi; Karen Wessel; Shivendra Kishore; Nahid Nahavandi; Wafaa Eyaid; Muhammad Talal Al Rifai; Ahmed Al-Rumayyan; Waleed Al-Twaijri; Ali Alothaim; Amal Alhashem; Nouriya Al-Sannaa; Mohammed Al-Balwi; Majid Alfadhel; Arndt Rolfs; Rami Abou Jamra Journal: Eur J Hum Genet Date: 2016-11-16 Impact factor: 4.246
Authors: Kym M Boycott; Ana Rath; Jessica X Chong; Taila Hartley; Fowzan S Alkuraya; Gareth Baynam; Anthony J Brookes; Michael Brudno; Angel Carracedo; Johan T den Dunnen; Stephanie O M Dyke; Xavier Estivill; Jack Goldblatt; Catherine Gonthier; Stephen C Groft; Ivo Gut; Ada Hamosh; Philip Hieter; Sophie Höhn; Matthew E Hurles; Petra Kaufmann; Bartha M Knoppers; Jeffrey P Krischer; Milan Macek; Gert Matthijs; Annie Olry; Samantha Parker; Justin Paschall; Anthony A Philippakis; Heidi L Rehm; Peter N Robinson; Pak-Chung Sham; Rumen Stefanov; Domenica Taruscio; Divya Unni; Megan R Vanstone; Feng Zhang; Han Brunner; Michael J Bamshad; Hanns Lochmüller Journal: Am J Hum Genet Date: 2017-05-04 Impact factor: 11.025
Authors: Jeremy A Miller; Song-Lin Ding; Susan M Sunkin; Kimberly A Smith; Lydia Ng; Aaron Szafer; Amanda Ebbert; Zackery L Riley; Joshua J Royall; Kaylynn Aiona; James M Arnold; Crissa Bennet; Darren Bertagnolli; Krissy Brouner; Stephanie Butler; Shiella Caldejon; Anita Carey; Christine Cuhaciyan; Rachel A Dalley; Nick Dee; Tim A Dolbeare; Benjamin A C Facer; David Feng; Tim P Fliss; Garrett Gee; Jeff Goldy; Lindsey Gourley; Benjamin W Gregor; Guangyu Gu; Robert E Howard; Jayson M Jochim; Chihchau L Kuan; Christopher Lau; Chang-Kyu Lee; Felix Lee; Tracy A Lemon; Phil Lesnar; Bergen McMurray; Naveed Mastan; Nerick Mosqueda; Theresa Naluai-Cecchini; Nhan-Kiet Ngo; Julie Nyhus; Aaron Oldre; Eric Olson; Jody Parente; Patrick D Parker; Sheana E Parry; Allison Stevens; Mihovil Pletikos; Melissa Reding; Kate Roll; David Sandman; Melaine Sarreal; Sheila Shapouri; Nadiya V Shapovalova; Elaine H Shen; Nathan Sjoquist; Clifford R Slaughterbeck; Michael Smith; Andy J Sodt; Derric Williams; Lilla Zöllei; Bruce Fischl; Mark B Gerstein; Daniel H Geschwind; Ian A Glass; Michael J Hawrylycz; Robert F Hevner; Hao Huang; Allan R Jones; James A Knowles; Pat Levitt; John W Phillips; Nenad Sestan; Paul Wohnoutka; Chinh Dang; Amy Bernard; John G Hohmann; Ed S Lein Journal: Nature Date: 2014-04-02 Impact factor: 49.962