{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T11:49:26Z","timestamp":1779104966719,"version":"3.51.4"},"reference-count":22,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2025,12,15]],"date-time":"2025-12-15T00:00:00Z","timestamp":1765756800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100008982","name":"Qatar National Research Fund","doi-asserted-by":"crossref","award":["NPRP 13S-0121-200129"],"award-info":[{"award-number":["NPRP 13S-0121-200129"]}],"id":[{"id":"10.13039\/100008982","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background and Clinical Significance: Methyltransferase-like protein 5 (METTL5) is a conserved RNA methyltransferase responsible for catalyzing the N6-methyladenosine (m6A) modification of 18S ribosomal RNA, a process critical for ribosome biogenesis and translational regulation. Biallelic variants in METTL5 have been linked to autosomal recessive intellectual developmental disorder-72 (MRT72), typically presenting with microcephaly, intellectual disability, and speech delay. However, the association between METTL5 and isolated attention-deficit\/hyperactivity disorder (ADHD) remains underexplored. Case Presentation: We report a 14-year-old Qatari female, born to consanguineous parents, who presented with microcephaly, speech delay, learning difficulties, and inattentive-type ADHD. Trio-based whole-genome sequencing identified a novel homozygous METTL5 variant (c.617G &gt; A; p. Arg206Gln), with both parent\u2019s heterozygous carriers. The variant is extremely rare (gnomAD MAF: 0.0000175) and predicted to be deleterious (CADD: 23.7; SIFT: damaging; PolyPhen-2: probably damaging). Structural modeling localized the change within the SAM-dependent catalytic domain, predicting protein destabilization (\u0394\u0394G = +1.8 kcal\/mol). The affected residue is highly conserved (ConSurf score: 8), and protein\u2013protein interaction analysis linked METTL5 with METTL14, METTL16, and ZCCHC4, key regulators of rRNA methylation. Conclusions: In silico evidence suggests that the p. Arg206Gln variant disrupts METTL5 function, likely contributing to the observed neurodevelopmental phenotype, including ADHD. This expands the clinical spectrum of METTL5-related disorders and supports its inclusion in neurodevelopmental gene panels.<\/jats:p>","DOI":"10.3390\/genes16121502","type":"journal-article","created":{"date-parts":[[2025,12,16]],"date-time":"2025-12-16T08:46:52Z","timestamp":1765874812000},"page":"1502","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Functional Interpretation of a Novel Homozygous METTL5 Variant Associated with ADHD and Neurodevelopmental Abnormalities: A Case Report and Literature Review"],"prefix":"10.3390","volume":"16","author":[{"given":"Sheema","family":"Hashem","sequence":"first","affiliation":[{"name":"College of Health and Life Sciences, Hamad Bin Khalifa University (HBKU), Doha P.O. Box 5825, Qatar"},{"name":"Department of Human Genetics, Sidra Medicine, Doha P.O. Box 26999, Qatar"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Saba F.","family":"Elhag","sequence":"additional","affiliation":[{"name":"College of Health and Life Sciences, Hamad Bin Khalifa University (HBKU), Doha P.O. Box 5825, Qatar"},{"name":"Metabolic and Mendelian Disorders Clinical Research Program, Precision OMICs Research & Translational Science, Sidra Medicine, Doha P.O. Box 26999, Qatar"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3640-6275","authenticated-orcid":false,"given":"Ajaz A.","family":"Bhat","sequence":"additional","affiliation":[{"name":"Metabolic and Mendelian Disorders Clinical Research Program, Precision OMICs Research & Translational Science, Sidra Medicine, Doha P.O. Box 26999, Qatar"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1324-3509","authenticated-orcid":false,"given":"Waleed","family":"Aamer","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Sidra Medicine, Doha P.O. Box 26999, Qatar"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aljazi","family":"Al-Maraghi","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Sidra Medicine, Doha P.O. Box 26999, Qatar"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-8595-8244","authenticated-orcid":false,"given":"Hala","family":"Alhaboub","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Sidra Medicine, Doha P.O. Box 26999, Qatar"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dalya","family":"Abuthaher","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Sidra Medicine, Doha P.O. Box 26999, Qatar"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ammira S. Al-Shabeeb","family":"Akil","sequence":"additional","affiliation":[{"name":"Metabolic and Mendelian Disorders Clinical Research Program, Precision OMICs Research & Translational Science, Sidra Medicine, Doha P.O. Box 26999, Qatar"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mohammad","family":"Haris","sequence":"additional","affiliation":[{"name":"Center for Advanced Metabolic Imaging in Precision Medicine, Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3150-1276","authenticated-orcid":false,"given":"Khalid","family":"Fakhro","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Sidra Medicine, Doha P.O. Box 26999, Qatar"},{"name":"Weill Cornell Medical College\u2013Qatar (WCM-Q), Cornell University, Doha P.O. Box 24144, Qatar"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2157-5279","authenticated-orcid":false,"given":"Georges","family":"Nemer","sequence":"additional","affiliation":[{"name":"College of Health and Life Sciences, Hamad Bin Khalifa University (HBKU), Doha P.O. Box 5825, Qatar"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Madeeha","family":"Kamal","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Sidra Medicine, Doha P.O. Box 26999, Qatar"},{"name":"Weill Cornell Medical College\u2013Qatar (WCM-Q), Cornell University, Doha P.O. Box 24144, Qatar"},{"name":"College of Medicine, QU Health, Qatar University, Doha P.O. Box 2713, Qatar"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"S23","DOI":"10.21037\/tp.2020.02.02","article-title":"A clinical primer on intellectual disability","volume":"9","author":"Patel","year":"2020","journal-title":"Transl. Pediatr."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"101590","DOI":"10.1016\/j.jbc.2022.101590","article-title":"The METTL5-TRMT112 N6-methyladenosine methyltransferase complex regulates mRNA translation via 18S rRNA methylation","volume":"298","author":"Zheng","year":"2022","journal-title":"J. Biol. Chem."},{"key":"ref_3","unstructured":"(OMIM) OMIiM (2024, May 16). OMIM Entry #618665\u2014Intellectual Developmental Disorder, Autosomal Recessive 72; MRT722025-05-13. Available online: https:\/\/www.omim.org\/entry\/618665."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"869","DOI":"10.1016\/j.ajhg.2019.09.007","article-title":"Bi-allelic Variants in METTL5 Cause Autosomal-Recessive Intellectual Disability and Microcephaly","volume":"105","author":"Richard","year":"2019","journal-title":"Am. J. Hum. Genet."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1038\/s10038-025-01354-w","article-title":"Microcephaly-related global developmental delay caused by a pathogenic METTL5 splicing mutation in a Chinese family","volume":"70","author":"Zhou","year":"2025","journal-title":"J. Hum. Genet."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"956","DOI":"10.24953\/turkjped.2020.3992","article-title":"Three Afghani siblings with a novel homozygous variant and further delineation of the clinical features of METTL5 related intellectual disability syndrome","volume":"64","author":"Torun","year":"2022","journal-title":"Turk. J. Pediatr."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1007\/s12041-023-01441-x","article-title":"A novel METTL5 variant disrupting a donor splice site leads to primary microcephaly-related intellectual disability in an Iranian family: Clinical features and literature review","volume":"102","author":"Shakarami","year":"2023","journal-title":"J. Genet."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1617","DOI":"10.1038\/s12276-022-00869-y","article-title":"The emerging importance of METTL5-mediated ribosomal RNA methylation","volume":"54","author":"Turkalj","year":"2022","journal-title":"Exp. Mol. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1016\/j.gendis.2020.07.004","article-title":"Mettl5 mediated 18S rRNA N6-methyladenosine (m6A) modification controls stem cell fate determination and neural function","volume":"9","author":"Wang","year":"2022","journal-title":"Genes Dis."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"7719","DOI":"10.1093\/nar\/gkz619","article-title":"The human 18S rRNA m6A methyltransferase METTL5 is stabilized by TRMT112","volume":"47","author":"Ernst","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Fernandez-Castillo, N., Cabana-Dominguez, J., Kappel, D.B., Torrico, B., Weber, H., Lesch, K.P., Lao, O., Reif, A., and Cormand, B. (2021). Exploring the Contribution to ADHD of Genes Involved in Mendelian Disorders Presenting with Hyperactivity and\/or Inattention. Genes, 13.","DOI":"10.3390\/genes13010093"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"e12444","DOI":"10.1111\/gbb.12444","article-title":"Role of RNA modifications in brain and behavior","volume":"17","author":"Jung","year":"2018","journal-title":"Genes Brain Behav."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Kuehner, J.N., Bruggeman, E.C., Wen, Z., and Yao, B. (2019). Epigenetic Regulations in Neuropsychiatric Disorders. Front. Genet., 10.","DOI":"10.3389\/fgene.2019.00268"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1038\/s41586-021-03819-2","article-title":"Highly accurate protein structure prediction with AlphaFold","volume":"596","author":"Jumper","year":"2021","journal-title":"Nature"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"W350","DOI":"10.1093\/nar\/gky300","article-title":"DynaMut: Predicting the impact of mutations on protein conformation, flexibility and stability","volume":"46","author":"Rodrigues","year":"2018","journal-title":"Nucleic Acids Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"W344","DOI":"10.1093\/nar\/gkw408","article-title":"ConSurf 2016: An improved methodology to estimate and visualize evolutionary conservation in macromolecules","volume":"44","author":"Ashkenazy","year":"2016","journal-title":"Nucleic Acids Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"D607","DOI":"10.1093\/nar\/gky1131","article-title":"STRING v11: Protein\u2013protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets","volume":"47","author":"Szklarczyk","year":"2018","journal-title":"Nucleic Acids Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology","volume":"17","author":"Richards","year":"2015","journal-title":"Genet. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1017\/S0021932004007060","article-title":"Consanguineous marriage in a newly developed country: The Qatari population","volume":"38","author":"Bener","year":"2006","journal-title":"J. Biosoc. Sci."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Abdu, Y., Ahmed, K., Ibrahim, M.I.M., Abdou, M., Ali, A., Alsiddig, H., Selim, N.A., and Yassin, M.A. (2023). Perception of consanguineous marriage among the qatari population. Front. Public Health, 11.","DOI":"10.3389\/fpubh.2023.1228010"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1779","DOI":"10.1073\/pnas.0906079106","article-title":"Evolution in health and medicine Sackler colloquium: Consanguinity, human evolution, and complex diseases","volume":"107","author":"Bittles","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1186\/1742-4755-6-17","article-title":"Consanguinity and reproductive health among Arabs","volume":"6","author":"Tadmouri","year":"2009","journal-title":"Reprod. Health"}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/16\/12\/1502\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,17]],"date-time":"2025-12-17T05:14:32Z","timestamp":1765948472000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/16\/12\/1502"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,15]]},"references-count":22,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["genes16121502"],"URL":"https:\/\/doi.org\/10.3390\/genes16121502","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,15]]}}}