Variants in PRKAR1B cause a neurodevelopmental disorder with autism spectrum disorder, apraxia, and insensitivity to pain
Felix Marbach(Heidelberg University), Georgi Stoyanov(University of Cologne), Florian Erger(University of Cologne), Constantine A. Stratakis(Eunice Kennedy Shriver National Institute of Child Health and Human Development), Nikolaos Settas(Eunice Kennedy Shriver National Institute of Child Health and Human Development), Edra London(Eunice Kennedy Shriver National Institute of Child Health and Human Development), Jill A. Rosenfeld(Baylor College of Medicine), Erin Torti, Chad Haldeman‐Englert, Evgenia Sklirou(University of Pittsburgh), E Kessler(University of Pittsburgh), Sophia Ceulemans(Rady Children's Hospital-San Diego), Stanley F. Nelson(University of California, Los Angeles), Julián A. Martínez-Agosto(University of California, Los Angeles), Christina G.S. Palmer(University of California, Los Angeles), Rebecca Signer(University of California, Los Angeles), Maria T. Acosta(National Institutes of Health), Margaret P Adam(Seattle Children's Hospital), David R. Adams(National Institutes of Health), Pankaj B. Agrawal(Brigham and Women's Hospital), Mercedes E. Alejandro(Baylor College of Medicine), Justin Alvey(University of Utah), Laura M. Amendola(Seattle Children's Hospital), Ashley Andrews(University of Utah), Euan A. Ashley(Stanford University), Mahshid S. Azamian(Baylor College of Medicine), Carlos A. Bacino(Baylor College of Medicine), Güney Bademci(University of Miami), Eva H. Baker(National Institutes of Health), Ashok Balasubramanyam(Baylor College of Medicine), Dustin Baldridge(Washington University in St. Louis), Jim Bale(University of Utah), Michael Bamshad(Seattle Children's Hospital), Deborah Barbouth(University of Miami), Pınar Bayrak‐Toydemir(University of Utah), Anita E. Beck(Seattle Children's Hospital), Alan H. Beggs(Brigham and Women's Hospital), Edward M. Behrens(Children's Hospital of Philadelphia), Gill Bejerano(Stanford University), Jimmy Bennett(Seattle Children's Hospital), Beverly Berg-Rood(Seattle Children's Hospital), Jonathan A. Bernstein(Stanford University), Gerard T. Berry(Brigham and Women's Hospital), Anna Bican(Vanderbilt University), Stephanie Bivona(University of Miami), Elizabeth Blue(Seattle Children's Hospital), John F. Bohnsack(University of Utah), Carsten Bonnenmann(National Institutes of Health), Devon Bonner(Stanford University), Lorenzo D. Botto(University of Utah), Brenna Boyd(Seattle Children's Hospital), Lauren C. Briere(Brigham and Women's Hospital), Elly Brokamp(Vanderbilt University), Gabrielle Brown(University of California, Los Angeles), Elizabeth A. Burke(National Institutes of Health), Lindsay C. Burrage(Baylor College of Medicine), Manish J. Butte(University of California, Los Angeles), Peter H. Byers(Seattle Children's Hospital), William E. Byrd(University of Alabama), John C. Carey(University of Utah), Olveen Carrasquillo(University of Miami), Ta Chen Chang(University of Miami), Sirisak Chanprasert(Seattle Children's Hospital), Hsiao‐Tuan Chao(Baylor College of Medicine), Gary Clark(Baylor College of Medicine), Terra R. Coakley(Stanford University), Laurel A. Cobban(Brigham and Women's Hospital), Joy D. Cogan(Vanderbilt University), Matthew Coggins(Brigham and Women's Hospital), F. Sessions Cole(Washington University in St. Louis), Heather A. Colley(National Institutes of Health), Cynthia M. Cooper(Brigham and Women's Hospital), Heidi Cope(Duke University), William J. Craigen(Baylor College of Medicine), Andrew B. Crouse(University of Alabama), Michael L. Cunningham(Seattle Children's Hospital), Precilla D’Souza(National Institutes of Health), Hongzheng Dai(Baylor College of Medicine), Surendra Dasari(Mayo Clinic in Florida), Joie Davis(National Institutes of Health), Jyoti G. Daya(National Institutes of Health), Matthew A. Deardorff(Children's Hospital of Philadelphia), Esteban C. Dell’Angelica(University of California, Los Angeles), Shweta U. Dhar(Baylor College of Medicine), Katrina M. Dipple(Seattle Children's Hospital), Daniel Doherty(Seattle Children's Hospital), Naghmeh Dorrani(University of California, Los Angeles), Argenia L. Doss(National Institutes of Health), Emilie D. Douine(University of California, Los Angeles), David D. Draper(National Institutes of Health), Laura Duncan(Vanderbilt University), Dawn Earl(Seattle Children's Hospital), David J. Eckstein(National Institutes of Health), Lisa Emrick(Baylor College of Medicine), Christine M. Eng(Baylor Genetics), Cecilia Esteves(Harvard University), Marni J. Falk(Children's Hospital of Philadelphia), Liliana Fernández(Stanford University), Carlos R. Ferreira(National Institutes of Health), Elizabeth L. Fieg(Brigham and Women's Hospital), Laurie C. Findley(National Institutes of Health), Paul G. Fisher(Stanford University), Brent L. Fogel(University of California, Los Angeles), Irman Forghani(University of Miami), Laure Frésard(Stanford University), William A. Gahl(National Institutes of Health), I. S. Glass(Seattle Children's Hospital), Bernadette R. Gochuico(National Institutes of Health), Rena A. Godfrey(National Institutes of Health), Katie Golden‐Grant(Seattle Children's Hospital), Alica M. Goldman(Baylor College of Medicine), Madison P. Goldrich(National Institutes of Health), David B. Goldstein(Columbia University), Alana Grajewski(University of Miami), Catherine Groden(National Institutes of Health), Irma Gutierrez(University of California, Los Angeles), Sihoun Hahn(Seattle Children's Hospital), Rizwan Hamid(Vanderbilt University), Neil A. Hanchard(Baylor College of Medicine), Kelly Hassey(Children's Hospital of Philadelphia), Nichole Hayes(Washington University in St. Louis), Frances A. High(Brigham and Women's Hospital), Anne Hing(Seattle Children's Hospital), Fuki M. Hisama(Seattle Children's Hospital), Ingrid A. Holm(Brigham and Women's Hospital), Jason Hom(Stanford University), Martha Horike‐Pyne(Seattle Children's Hospital), Alden Huang(University of California, Los Angeles), Yong Huang(Stanford University), Laryssa A. Huryn(National Institutes of Health), Rosario Isasi(University of Miami), Fariha Jamal(Baylor College of Medicine), Gail P. Jarvik(Seattle Children's Hospital), Jeffrey G. Jarvik(Seattle Children's Hospital), Suman Jayadev(Seattle Children's Hospital), Lefkothea Karaviti(Baylor College of Medicine), Jennifer A. Kennedy(Vanderbilt University), Dana Kiley(Washington University in St. Louis), Isaac S. Kohane(Harvard University), Jennefer N. Kohler(Stanford University), Susan Korrick(Brigham and Women's Hospital), Mary Kozuira(Vanderbilt University), Deborah Krakow(University of California, Los Angeles), Donna M. Krasnewich(National Institutes of Health), Elijah Kravets(Stanford University), Joel B. Krier(Brigham and Women's Hospital), Grace L. LaMoure(National Institutes of Health), Seema R. Lalani(Baylor College of Medicine), Byron Lam(University of Miami), Christina Lam(Seattle Children's Hospital), Brendan C. Lanpher(Mayo Clinic in Florida), Ian R. Lanza(Mayo Clinic in Florida), Lea Latham(National Institutes of Health), Kimberly LeBlanc(Harvard University), Brendan Lee(Baylor College of Medicine), Hane Lee(University of California, Los Angeles), Roy C. Levitt(University of Miami), Richard A. Lewis(Baylor College of Medicine), Sharyn A. Lincoln(Brigham and Women's Hospital), Pengfei Liu(Baylor Genetics), Xue Zhong Liu(University of Miami), Nicola Longo(University of Utah), Sandra K. Loo(University of California, Los Angeles), Joseph Loscalzo(Brigham and Women's Hospital), Richard L. Maas(Brigham and Women's Hospital), John MacDowall(National Institutes of Health), Calum A. MacRae(Brigham and Women's Hospital), Ellen F. Macnamara(National Institutes of Health), Valerie V. Maduro(National Institutes of Health), Marta M. Majcherska(Stanford University), Bryan C. Mak(University of California, Los Angeles), May Christine V. Malicdan(National Institutes of Health), Laura A. Mamounas(National Institutes of Health), Teri A. Manolio(National Institutes of Health), Rong Mao(University of Utah), Kenneth R. Maravilla(Seattle Children's Hospital), Thomas C. Markello(National Institutes of Health), Ronit Marom(Baylor College of Medicine), Gábor Marth(University of Utah), Beth A. Martin(Stanford University), Martín G. Martín(University of California, Los Angeles), Julián A. Martínez-Agosto(University of California, Los Angeles), Shruti Marwaha(Stanford University), Jacob L. McCauley(University of Miami), Allyn McConkie‐Rosell(Duke University), Colleen E. McCormack(Stanford University), Alexa T. McCray(Harvard University), Elisabeth McGee(University of California, Los Angeles), Heather Mefford(Seattle Children's Hospital), J. Lawrence Merritt(Seattle Children's Hospital), Matthew Might(University of Alabama), Ghayda Mirzaa(Seattle Children's Hospital), Éva Morava(Mayo Clinic in Florida), Paolo Moretti(Baylor College of Medicine), Paolo Moretti(University of Utah), Deborah Mosbrook-Davis(National Institutes of Health), John J. Mulvihill(National Institutes of Health), David R. Murdock(Baylor College of Medicine), Anna Nagy(Harvard University), Mariko Nakano‐Okuno(University of Alabama), Avi Nath(National Institutes of Health), Stanley F. Nelson(University of California, Los Angeles), John H. Newman(Vanderbilt University), Sarah K. Nicholas(Baylor College of Medicine), Deborah A. Nickerson(Seattle Children's Hospital), Shirley Nieves‐Rodriguez(University of California, Los Angeles), Donna Novacic(National Institutes of Health), Devin Oglesbee(Mayo Clinic in Florida), James P. Orengo(Baylor College of Medicine), Laura Pace(University of Utah), Stephen Pak, J. Carl Pallais(Brigham and Women's Hospital), Christina G.S. Palmer(University of California, Los Angeles), Jeanette C. Papp(University of California, Los Angeles), Neil H. Parker(University of California, Los Angeles), John A. Phillips(Vanderbilt University), Jennifer E. Posey(Baylor College of Medicine), Lorraine Potocki(Baylor College of Medicine), Bradley Power(National Institutes of Health), Barbara N. Pusey(National Institutes of Health), Aaron R. Quinlan(University of Utah), Archana N. Raja(Stanford University), Deepak A. Rao(Brigham and Women's Hospital), Wendy H. Raskind(Seattle Children's Hospital), Genecee Renteria(University of California, Los Angeles), Chloe M. Reuter(Stanford University), Lynette Rives(Vanderbilt University), Amy K. Robertson(Vanderbilt University), Lance H. Rodan(Brigham and Women's Hospital), Jill A. Rosenfeld(Baylor College of Medicine), Natalie Rosenwasser(Seattle Children's Hospital), Francis Rossignol(National Institutes of Health), Maura Ruzhnikov(Stanford University), Ralph L. Sacco(University of Miami), Jacinda B. Sampson(Stanford University), Susan L. Samson(Baylor College of Medicine), Mario Saporta(University of Miami), Judy Schaechter(University of Miami), Timothy Schedl, Kelly Schoch(Duke University), C. Ron Scott(National Institutes of Health), Daryl A. Scott(Baylor College of Medicine), Vandana Shashi(Duke University), Jimann Shin, Rebecca Signer(University of California, Los Angeles), Edwin K. Silverman(Brigham and Women's Hospital), Janet S. Sinsheimer(University of California, Los Angeles), Kathy Sisco(Washington University in St. Louis), Edward C. Smith(Duke University), Kevin S. Smith(Stanford University), Emily Solem(Vanderbilt University), Lilianna Solnica‐Krezel, Ben Solomon(National Institutes of Health), Rebecca C. Spillmann(Duke University), Joan M. Stoler(Brigham and Women's Hospital), Jennifer A. Sullivan(Duke University), Kathleen E. Sullivan(Children's Hospital of Philadelphia), Angela Sun(Seattle Children's Hospital), Shirley Sutton(Stanford University), David A. Sweetser(Brigham and Women's Hospital), Virginia P. Sybert(Seattle Children's Hospital), Holly K. Tabor(Stanford University), Amelia L.M. Tan(Harvard University), Queenie K.‐G. Tan(Duke University), Mustafa Tekin(University of Miami), Fred F. Telischi(University of Miami), Willa Thorson(University of Miami), Audrey Thurm(National Institutes of Health), Cynthia J. Tifft(National Institutes of Health), Camilo Toro(National Institutes of Health), Alyssa A. Tran(Baylor College of Medicine), Brianna M. Tucker(Stanford University), Tiina K. Urv(National Institutes of Health), Adeline Vanderver(Children's Hospital of Philadelphia), Matt Velinder(University of Utah), Dave Viskochil(University of Utah), Tiphanie P. Vogel(Baylor College of Medicine), Colleen E. Wahl(National Institutes of Health), Melissa Walker(Brigham and Women's Hospital), Stephanie E Wallace(Seattle Children's Hospital), Nicole M. Walley(Duke University), Chris A. Walsh(Brigham and Women's Hospital), Jennifer Wambach(Washington University in St. Louis), Jijun Wan(University of California, Los Angeles), Lee-kai Wang(University of California, Los Angeles), Michael F. Wangler(Baylor College of Medicine), Patricia A. Ward(Baylor Genetics), Daniel Wegner(Washington University in St. Louis), Mark H. Wener(Seattle Children's Hospital), Tara Wenger(Seattle Children's Hospital), Katherine Wesseling Perry(University of California, Los Angeles), Monte Westerfield(University of Oregon), Matthew T. Wheeler(Stanford University), Jordan Whitlock(University of Alabama), Lynne A. Wolfe(National Institutes of Health), Jeremy D. Woods(University of California, Los Angeles), Shinya Yamamoto(Baylor College of Medicine), John Yang(National Institutes of Health), Muhammad Yousef(National Institutes of Health), Diane B. Zastrow(Stanford University), Wadih M. Zein(National Institutes of Health), Chunli Zhao(Stanford University), Stephan Züchner(University of Miami), Marisa V. Andrews(Washington University in St. Louis), Dorothy K. Grange(Washington University in St. Louis), Rebecca Willaert(Baylor Genetics), Richard Person, Aida Telegrafi, Aaron Sievers(Heidelberg University), Magdalena Laugsch(Heidelberg University), Susanne Theiß(Heidelberg University), Yuzhu Cheng(Centre for Life), Olivier Lichtarge(Baylor College of Medicine), Panagiotis Katsonis(Baylor College of Medicine), Amber Stocco(Integris Health), Christian P. Schaaf(Baylor College of Medicine)
Cited by 27Open Access
Abstract
PURPOSE: We characterize the clinical and molecular phenotypes of six unrelated individuals with intellectual disability and autism spectrum disorder who carry heterozygous missense variants of the PRKAR1B gene, which encodes the R1β subunit of the cyclic AMP-dependent protein kinase A (PKA). METHODS: Variants of PRKAR1B were identified by single- or trio-exome analysis. We contacted the families and physicians of the six individuals to collect phenotypic information, performed in vitro analyses of the identified PRKAR1B-variants, and investigated PRKAR1B expression during embryonic development. RESULTS: Recent studies of large patient cohorts with neurodevelopmental disorders found significant enrichment of de novo missense variants in PRKAR1B. In our cohort, de novo origin of the PRKAR1B variants could be confirmed in five of six individuals, and four carried the same heterozygous de novo variant c.1003C>T (p.Arg335Trp; NM_001164760). Global developmental delay, autism spectrum disorder, and apraxia/dyspraxia have been reported in all six, and reduced pain sensitivity was found in three individuals carrying the c.1003C>T variant. PRKAR1B expression in the brain was demonstrated during human embryonal development. Additionally, in vitro analyses revealed altered basal PKA activity in cells transfected with variant-harboring PRKAR1B expression constructs. CONCLUSION: Our study provides strong evidence for a PRKAR1B-related neurodevelopmental disorder.
Related Papers
No related papers found
Powered by citation graph analysis