@article{3ab39edbbd8948aebf5bdfb6672d326d,
title = "HNRNPC haploinsufficiency affects alternative splicing of intellectual disability-associated genes and causes a neurodevelopmental disorder",
abstract = "Heterogeneous nuclear ribonucleoprotein C (HNRNPC) is an essential, ubiquitously abundant protein involved in mRNA processing. Genetic variants in other members of the HNRNP family have been associated with neurodevelopmental disorders. Here, we describe 13 individuals with global developmental delay, intellectual disability, behavioral abnormalities, and subtle facial dysmorphology with heterozygous HNRNPC germline variants. Five of them bear an identical in-frame deletion of nine amino acids in the extreme C terminus. To study the effect of this recurrent variant as well as HNRNPC haploinsufficiency, we used induced pluripotent stem cells (iPSCs) and fibroblasts obtained from affected individuals. While protein localization and oligomerization were unaffected by the recurrent C-terminal deletion variant, total HNRNPC levels were decreased. Previously, reduced HNRNPC levels have been associated with changes in alternative splicing. Therefore, we performed a meta-analysis on published RNA-seq datasets of three different cell lines to identify a ubiquitous HNRNPC-dependent signature of alternative spliced exons. The identified signature was not only confirmed in fibroblasts obtained from an affected individual but also showed a significant enrichment for genes associated with intellectual disability. Hence, we assessed the effect of decreased and increased levels of HNRNPC on neuronal arborization and neuronal migration and found that either condition affects neuronal function. Taken together, our data indicate that HNRNPC haploinsufficiency affects alternative splicing of multiple intellectual disability-associated genes and that the developing brain is sensitive to aberrant levels of HNRNPC. Hence, our data strongly support the inclusion of HNRNPC to the family of HNRNP-related neurodevelopmental disorders.",
keywords = "HNRNP, HNRNPC, NDD, RNA processing, alternative splicing, heterogeneous ribonucleoprotein C, iPSCs, induced pluripotent stem cells, intellectual disability, neurodevelopmental disorder",
author = "{Genomics England Research Consortium} and {Undiagnosed Diseases Network} and Eva Niggl and Arjan Bouman and Briere, {Lauren C.} and Hoogenboezem, {Remco M.} and Ilse Wallaard and Joohyun Park and Jakob Admard and Martina Wilke and Harris-Mostert, {Emilio D.R.O.} and Minetta Elgersma and Jennifer Bain and Meena Balasubramanian and Siddharth Banka and Benke, {Paul J.} and Miriam Bertrand and Blesson, {Alyssa E.} and Jill Clayton-Smith and Ellingford, {Jamie M.} and Gillentine, {Madelyn A.} and Goodloe, {Dana H.} and Haack, {Tobias B.} and Mahim Jain and Ian Krantz and Luu, {Sharon M.} and Molly McPheron and Muss, {Candace L.} and Raible, {Sarah E.} and Robin, {Nathaniel H.} and Michael Spiller and Susan Starling and Sweetser, {David A.} and Isabelle Thiffault and Francesco Vetrini and Dennis Witt and Emily Woods and Dihong Zhou and Ambrose, {J. C.} and P. Arumugam and R. Bevers and M. Bleda and F. Boardman-Pretty and Boustred, {C. R.} and H. Brittain and Brown, {M. A.} and Caulfield, {M. J.} and Chan, {G. C.} and A. Giess and Griffin, {J. N.} and A. Hamblin and S. Henderson and Hubbard, {T. J.P.} and R. Jackson and Jones, {L. J.} and D. Kasperaviciute and M. Kayikci and A. Kousathanas and L. Lahnstein and A. Lakey and Leigh, {S. E.A.} and Leong, {I. U.S.} and Lopez, {F. J.} and F. Maleady-Crowe and M. McEntagart and F. Minneci and J. Mitchell and L. Moutsianas and M. Mueller and N. Murugaesu and Need, {A. C.} and P. O{\textquoteleft}Donovan and Odhams, {C. A.} and C. Patch and D. Perez-Gil and Pereira, {M. B.} and J. Pullinger and T. Rahim and A. Rendon and T. Rogers and K. Savage and K. Sawant and Scott, {R. H.} and A. Siddiq and A. Sieghart and Smith, {S. C.} and A. Sosinsky and A. Stuckey and M. Tanguy and {Taylor Tavares}, {A. L.} and Thomas, {E. R.A.} and Thompson, {S. R.} and A. Tucci and Welland, {M. J.} and E. Williams and K. Witkowska and Wood, {S. M.} and M. Zarowiecki and Acosta, {Maria T.} and Adams, {David R.} and Alvarez, {Raquel L.} and Justin Alvey and Aimee Allworth and Ashley Andrews and Ashley, {Euan A.} and Ben Afzali and Bacino, {Carlos A.} and Guney Bademci and Ashok Balasubramanyam and Dustin Baldridge and Jim Bale and Michael Bamshad and Deborah Barbouth and Pinar Bayrak-Toydemir and Anita Beck and Beggs, {Alan H.} and Edward Behrens and Gill Bejerano and Bellen, {Hugo J.} and Jimmy Bennet and Bernstein, {Jonathan A.} and Berry, {Gerard T.} and Anna Bican and Stephanie Bivona and Elizabeth Blue and John Bohnsack and Devon Bonner and Lorenzo Botto and Gabrielle Brown and Burke, {Elizabeth A.} and Burrage, {Lindsay C.} and Butte, {Manish J.} and Peter Byers and Byrd, {William E.} and John Carey and Olveen Carrasquillo and Thomas Cassini and Chang, {Ta Chen} and Sirisak Chanprasert and Chao, {Hsiao Tuan} and Ivan Chinn and Clark, {Gary D.} and Coakley, {Terra R.} and Cobban, {Laurel A.} and Cogan, {Joy D.} and Matthew Coggins and Cole, {F. Sessions} and Colley, {Heather A.} and Heidi Cope and Rosario Corona and Craigen, {William J.} and Crouse, {Andrew B.} and Michael Cunningham and Precilla D'Souza and Hongzheng Dai and Surendra Dasari and Joie Davis and Dayal, {Jyoti G.} and Margaret Delgado and Dell'Angelica, {Esteban C.} and Katrina Dipple and Daniel Doherty and Naghmeh Dorrani and Doss, {Argenia L.} and Douine, {Emilie D.} and Dawn Earl and Eckstein, {David J.} and Emrick, {Lisa T.} and Eng, {Christine M.} and Marni Falk and Fieg, {Elizabeth L.} and Fisher, {Paul G.} and Fogel, {Brent L.} and Irman Forghani and Jiayu Fu and Gahl, {William A.} and Ian Glass and Goddard, {Page C.} and Godfrey, {Rena A.} and Alana Grajewski and Halley, {Meghan C.} and Rizwan Hamid and Neal Hanchard and Kelly Hassey and Nichole Hayes and Frances High and Anne Hing and Hisama, {Fuki M.} and Holm, {Ingrid A.} and Jason Hom and Martha Horike-Pyne and Alden Huang and Yan Huang and Sarah Hutchison and Wendy Introne and Rosario Isasi and Kosuke Izumi and Stephen Pak and Timothy Schedl and Jimann Shin and Lilianna Solnica-Krezel and Jennifer Wambach",
note = "Publisher Copyright: {\textcopyright} 2023 American Society of Human Genetics",
year = "2023",
month = aug,
day = "3",
doi = "10.1016/j.ajhg.2023.07.005",
language = "English",
volume = "110",
pages = "1414--1435",
journal = "American journal of human genetics",
issn = "0002-9297",
number = "8",
}