@article{2436ff210cb847f0b3ef9aadeee9163a,
title = "A novel DPH5-related diphthamide-deficiency syndrome causing embryonic lethality or profound neurodevelopmental disorder",
abstract = "Purpose: Diphthamide is a post-translationally modified histidine essential for messenger RNA translation and ribosomal protein synthesis. We present evidence for DPH5 as a novel cause of embryonic lethality and profound neurodevelopmental delays (NDDs). Methods: Molecular testing was performed using exome or genome sequencing. A targeted Dph5 knockin mouse (C57BL/6Ncrl-Dph5em1Mbp/Mmucd) was created for a DPH5 p.His260Arg homozygous variant identified in 1 family. Adenosine diphosphate–ribosylation assays in DPH5-knockout human and yeast cells and in silico modeling were performed for the identified DPH5 potential pathogenic variants. Results: DPH5 variants p.His260Arg (homozygous), p.Asn110Ser and p.Arg207Ter (heterozygous), and p.Asn174LysfsTer10 (homozygous) were identified in 3 unrelated families with distinct overlapping craniofacial features, profound NDDs, multisystem abnormalities, and miscarriages. Dph5 p.His260Arg homozygous knockin was embryonically lethal with only 1 subviable mouse exhibiting impaired growth, craniofacial dysmorphology, and multisystem dysfunction recapitulating the human phenotype. Adenosine diphosphate–ribosylation assays showed absent to decreased function in DPH5-knockout human and yeast cells. In silico modeling of the variants showed altered DPH5 structure and disruption of its interaction with eEF2. Conclusion: We provide strong clinical, biochemical, and functional evidence for DPH5 as a novel cause of embryonic lethality or profound NDDs with multisystem involvement and expand diphthamide-deficiency syndromes and ribosomopathies.",
keywords = "Nonverbal neurodevelopment delays, Novel gene discovery, Precision animal modeling, Precision genomics, Translational genetics",
author = "{Undiagnosed Diseases Network} and Shankar, {Suma P.} and Kristin Grimsrud and Louise Lanoue and Alena Egense and Brandon Willis and Johanna H{\"o}rberg and Lama AlAbdi and Klaus Mayer and Koray {\"U}tk{\"u}r and Monaghan, {Kristin G.} and Joel Krier and Joan Stoler and Maha Alnemer and Shankar, {Prabhu R.} and Raffael Schaffrath and Alkuraya, {Fowzan S.} and Ulrich Brinkmann and Eriksson, {Leif A.} and Kent Lloyd and Rauen, {Katherine A.} and Acosta, {Maria T.} and Margaret Adam and Adams, {David R.} and Justin Alvey and Laura Amendola and Ashley Andrews and Ashley, {Euan A.} and Azamian, {Mahshid S.} 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 Jimmy Bennet and Beverly Berg-Rood 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 Brenna Boyd and Briere, {Lauren C.} and Elly Brokamp 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 {Peter Chang}, {Ta Chen} and Sirisak Chanprasert and Chao, {Hsiao Tuan} 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 Cooper, {Cynthia M.} and Heidi Cope 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 Matthew Deardorff and Dell'Angelica, {Esteban C.} and Katrina Dipple and Daniel Doherty and Naghmeh Dorrani and Doss, {Argenia L.} and Douine, {Emilie D.} and Laura Duncan and Dawn Earl and Eckstein, {David J.} and Emrick, {Lisa T.} and Eng, {Christine M.} and Cecilia Esteves and Marni Falk and Liliana Fernandez and Fieg, {Elizabeth L.} and Fisher, {Paul G.} and Fogel, {Brent L.} and Irman Forghani and Gahl, {William A.} and Ian Glass and Bernadette Gochuico and Godfrey, {Rena A.} and Katie Golden-Grant and Goldrich, {Madison P.} and Alana Grajewski and Irma Gutierrez and Don Hadley and Sihoun Hahn and Rizwan Hamid 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 Yong Huang and Wendy Introne and Rosario Isasi and Kosuke Izumi and Fariha Jamal and Jarvik, {Gail P.} and Jeffrey Jarvik and Suman Jayadev and Orpa Jean-Marie and Vaidehi Jobanputra and Lefkothea Karaviti and Jennifer Kennedy and Shamika Ketkar and Dana Kiley and Gonench Kilich and Kobren, {Shilpa N.} and Kohane, {Isaac S.} and Kohler, {Jennefer N.} and Deborah Krakow and Krasnewich, {Donna M.} and Elijah Kravets and Susan Korrick and Mary Koziura and Lalani, {Seema R.} and Byron Lam and Christina Lam and LaMoure, {Grace L.} and Lanpher, {Brendan C.} and Lanza, {Ian R.} and Kimberly LeBlanc and Lee, {Brendan H.} and Roy Levitt and Lewis, {Richard A.} and Pengfei Liu and Liu, {Xue Zhong} and Nicola Longo and Loo, {Sandra K.} and Joseph Loscalzo and Maas, {Richard L.} and Macnamara, {Ellen F.} and MacRae, {Calum A.} and Maduro, {Valerie V.} and Mak, {Bryan C.} and Malicdan, {May Christine V.} and Mamounas, {Laura A.} and Manolio, {Teri A.} and Rong Mao and Kenneth Maravilla and Ronit Marom and Gabor Marth and Martin, {Beth A.} and Martin, {Martin G.} and Mart{\'i}nez-Agosto, {Julian A.} and Shruti Marwaha and Jacob McCauley and Allyn McConkie-Rosell and McCray, {Alexa T.} and Elisabeth McGee and Heather Mefford and Merritt, {J. Lawrence} and Matthew Might and Ghayda Mirzaa and Eva Morava and Moretti, {Paolo M.} and Mariko Nakano-Okuno and Nelson, {Stan F.} and Newman, {John H.} and Nicholas, {Sarah K.} and Deborah Nickerson and Shirley Nieves-Rodriguez and Donna Novacic and Devin Oglesbee and Orengo, {James P.} and Laura Pace and Stephen Pak and Timothy Schedl and Jimann Shin and Lilianna Solnica-Krezel and Jennifer Wambach",
note = "Publisher Copyright: {\textcopyright} 2022",
year = "2022",
month = jul,
doi = "10.1016/j.gim.2022.03.014",
language = "English",
volume = "24",
pages = "1567--1582",
journal = "Genetics in Medicine",
issn = "1098-3600",
number = "7",
}