{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T16:58:59Z","timestamp":1789664339740,"version":"4.0.1"},"reference-count":34,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2025,7,2]],"date-time":"2025-07-02T00:00:00Z","timestamp":1751414400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003196","name":"Italian Ministry of Health","doi-asserted-by":"publisher","award":["RCR-2022-23682289"],"award-info":[{"award-number":["RCR-2022-23682289"]}],"id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003196","name":"Italian Ministry of Health","doi-asserted-by":"publisher","award":["RF-2021-12374963"],"award-info":[{"award-number":["RF-2021-12374963"]}],"id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003196","name":"Italian Ministry of Health","doi-asserted-by":"publisher","award":["DN. 1553 11.10.2022"],"award-info":[{"award-number":["DN. 1553 11.10.2022"]}],"id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Ministry of University and Research (MUR)","award":["RCR-2022-23682289"],"award-info":[{"award-number":["RCR-2022-23682289"]}]},{"name":"Ministry of University and Research (MUR)","award":["RF-2021-12374963"],"award-info":[{"award-number":["RF-2021-12374963"]}]},{"name":"Ministry of University and Research (MUR)","award":["DN. 1553 11.10.2022"],"award-info":[{"award-number":["DN. 1553 11.10.2022"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background\/Objectives: Neurodevelopmental disorders (NDDs) represent a clinically diverse group of conditions that affect brain development, often leading to varying degrees of functional impairment. Many NDDs, particularly syndromic forms, are caused by genetic mutations affecting critical cellular pathways. Ribosomopathies, a subgroup of NDDs, are linked to defects in ribosomal function, including those involving the synthesis of diphthamide, a post-translational modification of translation elongation factor 2 (eEF2). Loss-of-function (LoF) mutations in genes involved in diphthamide biosynthesis, such as DPH1, DPH2, and DPH5, result in developmental delay (DD), intellectual disability (ID), and multisystemic abnormalities. DPH5-related diphthamide deficiency syndrome has recently been reported as an ultrarare disorder linked to LoF mutations in DPH5, encoding a methyltransferase required for diphthamide synthesis. Methods: Clinical, neurological, and dysmorphological evaluations were performed by a multidisciplinary team. Brain MRI was acquired on a 3T scanner. Craniofacial abnormalities were assessed using the GestaltMatcher phenotyping tool. Whole exome sequencing (WES) was conducted on leukocyte-derived DNA with a trio-based approach. Bioinformatic analyses included variant annotation, filtering, and pathogenicity prediction using established databases and tools. Results: The affected subject carried a previously reported missense change, p.His260Arg, suggesting the occurrence of genotype\u2013phenotype correlations and a hypomorphic behavior of the variant, likely explaining the overall milder phenotype compared to the previously reported patients with DPH5-related diphthamide deficiency syndrome. Conclusions: Overall, the co-occurrence of short stature, relative macrocephaly, congenital heart defects, variable DD\/ID, minor skeletal and ectodermal features, and consistent craniofacial features suggests a differential diagnosis with Noonan syndrome and related phenotypes.<\/jats:p>","DOI":"10.3390\/genes16070799","type":"journal-article","created":{"date-parts":[[2025,7,2]],"date-time":"2025-07-02T09:08:44Z","timestamp":1751447324000},"page":"799","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Expanding the Phenotypic Spectrum Associated with DPH5-Related Diphthamide Deficiency"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3795-1972","authenticated-orcid":false,"given":"Davide","family":"Politano","sequence":"first","affiliation":[{"name":"Department of Brain and Behavioural Sciences, University of Pavia, 27100 Pavia, Italy"},{"name":"Child Neurology and Psychiatry Unit, IRCCS Mondino Foundation, Via Mondino 2, 27100 Pavia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cecilia","family":"Mancini","sequence":"additional","affiliation":[{"name":"Molecular Genetics and Functional Genomics, Bambino Ges\u00f9 Children\u2019s Hospital, IRCCS, 00146 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-4408-8792","authenticated-orcid":false,"given":"Massimiliano","family":"Celario","sequence":"additional","affiliation":[{"name":"Department of Brain and Behavioural Sciences, University of Pavia, 27100 Pavia, Italy"},{"name":"Child Neurology and Psychiatry Unit, IRCCS Mondino Foundation, Via Mondino 2, 27100 Pavia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1993-8018","authenticated-orcid":false,"given":"Francesca Clementina","family":"Radio","sequence":"additional","affiliation":[{"name":"Molecular Genetics and Functional Genomics, Bambino Ges\u00f9 Children\u2019s Hospital, IRCCS, 00146 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2470-665X","authenticated-orcid":false,"given":"Fulvio","family":"D'Abrusco","sequence":"additional","affiliation":[{"name":"Neurogenetics Research Center, IRCCS Mondino Foundation, 27100 Pavia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9885-1369","authenticated-orcid":false,"given":"Jessica","family":"Garau","sequence":"additional","affiliation":[{"name":"Neurogenetics Research Center, IRCCS Mondino Foundation, 27100 Pavia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9459-9741","authenticated-orcid":false,"given":"Silvia","family":"Kalantari","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine, University of Pavia, 27100 Pavia, Italy"},{"name":"Medical Genetics Unit, IRCCS San Matteo Foundation, 27100 Pavia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gaia","family":"Visani","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine, University of Pavia, 27100 Pavia, Italy"},{"name":"Medical Genetics Unit, IRCCS San Matteo Foundation, 27100 Pavia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simone","family":"Carbonera","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine, University of Pavia, 27100 Pavia, Italy"},{"name":"Medical Genetics Unit, IRCCS San Matteo Foundation, 27100 Pavia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simone","family":"Gana","sequence":"additional","affiliation":[{"name":"Neurogenetics Research Center, IRCCS Mondino Foundation, 27100 Pavia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Ferilli","sequence":"additional","affiliation":[{"name":"Molecular Genetics and Functional Genomics, Bambino Ges\u00f9 Children\u2019s Hospital, IRCCS, 00146 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luigi","family":"Chiriatti","sequence":"additional","affiliation":[{"name":"Molecular Genetics and Functional Genomics, Bambino Ges\u00f9 Children\u2019s Hospital, IRCCS, 00146 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Camilla","family":"Cappelletti","sequence":"additional","affiliation":[{"name":"Molecular Genetics and Functional Genomics, Bambino Ges\u00f9 Children\u2019s Hospital, IRCCS, 00146 Rome, Italy"},{"name":"Department of Biomedicine and Prevention, University \u201cTor Vergata\u201d, 00173 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katia","family":"Ellena","sequence":"additional","affiliation":[{"name":"Department of Clinical, Surgical, Diagnostic and Pediatric Sciences, University of Pavia, 27100 Pavia, Italy"},{"name":"Neuroradiology Department, IRCCS Mondino Foundation, 27100 Pavia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Prodi","sequence":"additional","affiliation":[{"name":"Neuroradiology Department, IRCCS Mondino Foundation, 27100 Pavia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renato","family":"Borgatti","sequence":"additional","affiliation":[{"name":"Department of Brain and Behavioural Sciences, University of Pavia, 27100 Pavia, Italy"},{"name":"Child Neurology and Psychiatry Unit, IRCCS Mondino Foundation, Via Mondino 2, 27100 Pavia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0600-6820","authenticated-orcid":false,"given":"Enza Maria","family":"Valente","sequence":"additional","affiliation":[{"name":"Neurogenetics Research Center, IRCCS Mondino Foundation, 27100 Pavia, Italy"},{"name":"Department of Molecular Medicine, University of Pavia, 27100 Pavia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8947-9342","authenticated-orcid":false,"given":"Simona","family":"Orcesi","sequence":"additional","affiliation":[{"name":"Department of Brain and Behavioural Sciences, University of Pavia, 27100 Pavia, Italy"},{"name":"Child Neurology and Psychiatry Unit, IRCCS Mondino Foundation, Via Mondino 2, 27100 Pavia, 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disorders\u2014The history and future of a diagnostic concept","volume":"22","author":"Crocq","year":"2020","journal-title":"Dialogues Clin. Neurosci."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"AlMutiri, R., Malta, M., Shevell, M.I., and Srour, M. (2023). Evaluation of Individuals with Non-Syndromic Global Developmental Delay and Intellectual Disability. Children, 10.","DOI":"10.3390\/children10030414"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"353","DOI":"10.31887\/DCNS.2017.19.4\/sscherer","article-title":"Syndromic autism spectrum disorders: Moving from a clinically defined to a molecularly defined approach","volume":"19","author":"Fernandez","year":"2017","journal-title":"Dialogues Clin. Neurosci."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1111\/cge.13946","article-title":"De novo variants in neurodevelopmental disorders-experiences from a tertiary care center","volume":"100","author":"Brunet","year":"2021","journal-title":"Clin. Genet."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"608","DOI":"10.1016\/j.tins.2020.05.004","article-title":"Neurodevelopmental Disorders: From Genetics to Functional Pathways","volume":"43","author":"Parenti","year":"2020","journal-title":"Trends Neurosci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1013","DOI":"10.1093\/nar\/gkz637","article-title":"Hallmarks of ribosomopathies","volume":"48","author":"Kampen","year":"2020","journal-title":"Nucleic Acids Res."},{"key":"ref_7","first-page":"7","article-title":"Ribosomopathies: Mechanisms of Disease","volume":"7","author":"Nakhoul","year":"2014","journal-title":"Clin. Med. Insights Blood Disord."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"dmm050207","DOI":"10.1242\/dmm.050207","article-title":"DPH1 and DPH2 variants that confer susceptibility to diphthamide deficiency syndrome in human cells and yeast models","volume":"16","author":"Mayer","year":"2023","journal-title":"Dis. Model. Mech."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"515","DOI":"10.3109\/10409238.2013.831023","article-title":"The biosynthesis and biological function of diphthamide","volume":"48","author":"Su","year":"2013","journal-title":"Crit. Rev. Biochem. Mol. Biol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1406","DOI":"10.1021\/acs.jcim.8b00217","article-title":"QM\/MM Studies of Dph5\u2014A Promiscuous Methyltransferase in the Eukaryotic Biosynthetic Pathway of Diphthamide","volume":"58","author":"Eriksson","year":"2018","journal-title":"J. Chem. Inf. Model."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1213","DOI":"10.1111\/mmi.12845","article-title":"The diphthamide modification pathway from Saccharomyces cerevisiae\u2014revisited","volume":"94","author":"Schaffrath","year":"2014","journal-title":"Mol. Microbiol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1015","DOI":"10.1002\/humu.22843","article-title":"Matching Two Independent Cohorts Validates DPH1 as a Gene Responsible for Autosomal Recessive Intellectual Disability with Short Stature, Craniofacial, and Ectodermal Anomalies","volume":"36","author":"Loucks","year":"2015","journal-title":"Hum. Mutat."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1186\/s40246-016-0082-2","article-title":"Exome sequencing discloses KALRN homozygous variant as likely cause of intellectual disability and short stature in a consanguineous pedigree","volume":"10","author":"Makrythanasis","year":"2016","journal-title":"Hum. Genom."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1497","DOI":"10.1038\/s41431-020-0668-y","article-title":"Diphthamide-deficiency syndrome: A novel human developmental disorder and ribosomopathy","volume":"28","author":"Hawer","year":"2020","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1567","DOI":"10.1016\/j.gim.2022.03.014","article-title":"A novel DPH5-related diphthamide-deficiency syndrome causing embryonic lethality or profound neurodevelopmental disorder","volume":"24","author":"Shankar","year":"2022","journal-title":"Genet. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1016\/j.redox.2018.09.015","article-title":"Diphthamide affects selenoprotein expression: Diphthamide deficiency reduces selenocysteine incorporation, decreases selenite sensitivity and pre-disposes to oxidative stress","volume":"20","author":"Mayer","year":"2019","journal-title":"Redox Biol."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Kaltschmidt, C., Greiner, J.F.W., and Kaltschmidt, B. (2021). The Transcription Factor NF-\u03baB in Stem Cells and Development. Cells, 10.","DOI":"10.3390\/cells10082042"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1038\/s41588-021-01010-x","article-title":"GestaltMatcher facilitates rare disease matching using facial phenotype descriptors","volume":"54","author":"Hsieh","year":"2022","journal-title":"Nat. Genet."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1016\/j.ajhg.2020.06.018","article-title":"Enhanced MAPK1 Function Causes a Neurodevelopmental Disorder within the RASopathy Clinical Spectrum","volume":"107","author":"Motta","year":"2020","journal-title":"Am. J. Hum. Genet."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"502","DOI":"10.1016\/j.ajhg.2021.01.015","article-title":"SPEN haploinsufficiency causes a neurodevelopmental disorder overlapping proximal 1p36 deletion syndrome with an episignature of X chromosomes in females","volume":"108","author":"Radio","year":"2021","journal-title":"Am. J. Hum. Genet."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Van der Auwera, G.A., Carneiro, M.O., Hartl, C., Poplin, R., Del Angel, G., Levy-Moonshine, A., Jordan, T., Shakir, K., Roazen, D., and Thibault, J. (2013). From FastQ Data to High-Confidence Variant Calls: The Genome Analysis Toolkit Best Practices Pipeline. Curr. Protoc. Bioinform., 43.","DOI":"10.1002\/0471250953.bi1110s43"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1754","DOI":"10.1093\/bioinformatics\/btp324","article-title":"Fast and accurate short read alignment with Burrows\u2013Wheeler transform","volume":"25","author":"Li","year":"2009","journal-title":"Bioinformatics"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"80","DOI":"10.4161\/fly.19695","article-title":"A program for annotating and predicting the effects of single nucleotide polymorphisms, SnpEff","volume":"6","author":"Cingolani","year":"2012","journal-title":"Fly"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1038\/ng.2892","article-title":"A general framework for estimating the relative pathogenicity of human genetic variants","volume":"46","author":"Kircher","year":"2014","journal-title":"Nat. Genet."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1581","DOI":"10.1038\/ng.3703","article-title":"M-CAP eliminates a majority of variants of uncertain significance in clinical exomes at high sensitivity","volume":"48","author":"Jagadeesh","year":"2016","journal-title":"Nat. Genet."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1016\/j.ajhg.2017.01.004","article-title":"InterVar: Clinical Interpretation of Genetic Variants by the 2015 ACMG-AMP Guidelines","volume":"100","author":"Li","year":"2017","journal-title":"Am. J. Hum. Genet."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Popov, I.K., Hiatt, S.M., Whalen, S., Keren, B., Ruivenkamp, C., van Haeringen, A., Chen, M.J., Cooper, G.M., Korf, B.R., and Chang, C. (2019). A YWHAZ Variant Associated with Cardiofaciocutaneous Syndrome Activates the RAF-ERK Pathway. Front. Physiol., 10.","DOI":"10.3389\/fphys.2019.00388"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1038\/s41392-021-00728-8","article-title":"Ribosomal proteins and human diseases: Molecular mechanisms and targeted therapy","volume":"6","author":"Kang","year":"2021","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1016\/j.gde.2009.04.001","article-title":"The RASopathies: Developmental syndromes of Ras\/MAPK pathway dysregulation","volume":"19","author":"Tidyman","year":"2009","journal-title":"Curr. Opin. Genet. Dev."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1111\/j.1749-6632.2010.05790.x","article-title":"Disorders of dysregulated signal traffic through the RAS-MAPK pathway: Phenotypic spectrum and molecular mechanisms","volume":"1214","author":"Tartaglia","year":"2010","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1002\/ajmg.c.32012","article-title":"The molecular genetics of RASopathies: An update on novel disease genes and new disorders","volume":"190","author":"Tartaglia","year":"2022","journal-title":"Am. J. Med. Genet. C Semin. Med. Genet."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1111\/gtc.12742","article-title":"Diphthamide modification of eEF2 is required for gut tumor-like hyperplasia induced by oncogenic Ras","volume":"25","author":"Kimura","year":"2020","journal-title":"Genes. Cells"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Al Hmada, Y., Brodell, R.T., Kharouf, N., Flanagan, T.W., Alamodi, A.A., Hassan, S.Y., Shalaby, H., Hassan, S.L., Haikel, Y., and Megahed, M. (2024). Mechanisms of Melanoma Progression and Treatment Resistance: Role of Cancer Stem-like Cells. Cancers, 16.","DOI":"10.3390\/cancers16020470"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2351","DOI":"10.1158\/1535-7163.MCT-17-0456","article-title":"Targeting the MAPK Signaling Pathway in Cancer: Promising Preclinical Activity with the Novel Selective ERK1\/2 Inhibitor BVD-523 (Ulixertinib)","volume":"16","author":"Germann","year":"2017","journal-title":"Mol. Cancer Ther."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/16\/7\/799\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:03:12Z","timestamp":1760032992000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/16\/7\/799"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,2]]},"references-count":34,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2025,7]]}},"alternative-id":["genes16070799"],"URL":"https:\/\/doi.org\/10.3390\/genes16070799","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,7,2]]}}}