{"ddc":["570"],"keyword":["Genetics (clinical)","Genetics","Molecular Biology","Molecular Medicine"],"file_date_updated":"2023-12-04T08:15:43Z","year":"2023","volume":15,"intvolume":"        15","article_number":"102","_id":"14639","language":[{"iso":"eng"}],"article_type":"original","citation":{"ieee":"S.-J. Lin <i>et al.</i>, “Evaluating the association of biallelic OGDHL variants with significant phenotypic heterogeneity,” <i>Genome Medicine</i>, vol. 15. Springer Nature, 2023.","mla":"Lin, Sheng-Jia, et al. “Evaluating the Association of Biallelic OGDHL Variants with Significant Phenotypic Heterogeneity.” <i>Genome Medicine</i>, vol. 15, 102, Springer Nature, 2023, doi:<a href=\"https://doi.org/10.1186/s13073-023-01258-4\">10.1186/s13073-023-01258-4</a>.","short":"S.-J. Lin, B. Vona, T. Lau, K. Huang, M.S. Zaki, H.S. Aldeen, E.G. Karimiani, C. Rocca, M.M. Noureldeen, A.K. Saad, C. Petree, T. Bartolomaeus, R. Abou Jamra, G. Zifarelli, A. Gotkhindikar, I.M. Wentzensen, M. Liao, E.E. Cork, P. Varshney, N. Hashemi, M.H. Mohammadi, A. Rad, J. Neira, M.B. Toosi, C. Knopp, I. Kurth, T.D. Challman, R. Smith, A. Abdalla, T. Haaf, M. Suri, M. Joshi, W.K. Chung, A. Moreno-De-Luca, H. Houlden, R. Maroofian, G.K. Varshney, Genome Medicine 15 (2023).","apa":"Lin, S.-J., Vona, B., Lau, T., Huang, K., Zaki, M. S., Aldeen, H. S., … Varshney, G. K. (2023). Evaluating the association of biallelic OGDHL variants with significant phenotypic heterogeneity. <i>Genome Medicine</i>. Springer Nature. <a href=\"https://doi.org/10.1186/s13073-023-01258-4\">https://doi.org/10.1186/s13073-023-01258-4</a>","ista":"Lin S-J, Vona B, Lau T, Huang K, Zaki MS, Aldeen HS, Karimiani EG, Rocca C, Noureldeen MM, Saad AK, Petree C, Bartolomaeus T, Abou Jamra R, Zifarelli G, Gotkhindikar A, Wentzensen IM, Liao M, Cork EE, Varshney P, Hashemi N, Mohammadi MH, Rad A, Neira J, Toosi MB, Knopp C, Kurth I, Challman TD, Smith R, Abdalla A, Haaf T, Suri M, Joshi M, Chung WK, Moreno-De-Luca A, Houlden H, Maroofian R, Varshney GK. 2023. Evaluating the association of biallelic OGDHL variants with significant phenotypic heterogeneity. Genome Medicine. 15, 102.","chicago":"Lin, Sheng-Jia, Barbara Vona, Tracy Lau, Kevin Huang, Maha S. Zaki, Huda Shujaa Aldeen, Ehsan Ghayoor Karimiani, et al. “Evaluating the Association of Biallelic OGDHL Variants with Significant Phenotypic Heterogeneity.” <i>Genome Medicine</i>. Springer Nature, 2023. <a href=\"https://doi.org/10.1186/s13073-023-01258-4\">https://doi.org/10.1186/s13073-023-01258-4</a>.","ama":"Lin S-J, Vona B, Lau T, et al. Evaluating the association of biallelic OGDHL variants with significant phenotypic heterogeneity. <i>Genome Medicine</i>. 2023;15. doi:<a href=\"https://doi.org/10.1186/s13073-023-01258-4\">10.1186/s13073-023-01258-4</a>"},"publication_identifier":{"issn":["1756-994X"]},"has_accepted_license":"1","publication":"Genome Medicine","author":[{"first_name":"Sheng-Jia","last_name":"Lin","full_name":"Lin, Sheng-Jia"},{"first_name":"Barbara","last_name":"Vona","full_name":"Vona, Barbara"},{"first_name":"Tracy","last_name":"Lau","full_name":"Lau, Tracy"},{"last_name":"Huang","first_name":"Kevin","id":"3b3d2888-1ff6-11ee-9fa6-8f209ca91fe3","full_name":"Huang, Kevin","orcid":"0000-0002-2512-7812"},{"last_name":"Zaki","first_name":"Maha S.","full_name":"Zaki, Maha S."},{"last_name":"Aldeen","first_name":"Huda Shujaa","full_name":"Aldeen, Huda Shujaa"},{"last_name":"Karimiani","first_name":"Ehsan Ghayoor","full_name":"Karimiani, Ehsan Ghayoor"},{"full_name":"Rocca, Clarissa","first_name":"Clarissa","last_name":"Rocca"},{"full_name":"Noureldeen, Mahmoud M.","last_name":"Noureldeen","first_name":"Mahmoud M."},{"first_name":"Ahmed K.","last_name":"Saad","full_name":"Saad, Ahmed K."},{"full_name":"Petree, Cassidy","last_name":"Petree","first_name":"Cassidy"},{"full_name":"Bartolomaeus, Tobias","first_name":"Tobias","last_name":"Bartolomaeus"},{"full_name":"Abou Jamra, Rami","first_name":"Rami","last_name":"Abou Jamra"},{"first_name":"Giovanni","last_name":"Zifarelli","full_name":"Zifarelli, Giovanni"},{"full_name":"Gotkhindikar, Aditi","first_name":"Aditi","last_name":"Gotkhindikar"},{"last_name":"Wentzensen","first_name":"Ingrid M.","full_name":"Wentzensen, Ingrid M."},{"last_name":"Liao","first_name":"Mingjuan","full_name":"Liao, Mingjuan"},{"full_name":"Cork, Emalyn Elise","last_name":"Cork","first_name":"Emalyn Elise"},{"last_name":"Varshney","first_name":"Pratishtha","full_name":"Varshney, Pratishtha"},{"first_name":"Narges","last_name":"Hashemi","full_name":"Hashemi, Narges"},{"first_name":"Mohammad Hasan","last_name":"Mohammadi","full_name":"Mohammadi, Mohammad Hasan"},{"full_name":"Rad, Aboulfazl","last_name":"Rad","first_name":"Aboulfazl"},{"last_name":"Neira","first_name":"Juanita","full_name":"Neira, Juanita"},{"last_name":"Toosi","first_name":"Mehran Beiraghi","full_name":"Toosi, Mehran Beiraghi"},{"full_name":"Knopp, Cordula","last_name":"Knopp","first_name":"Cordula"},{"full_name":"Kurth, Ingo","last_name":"Kurth","first_name":"Ingo"},{"last_name":"Challman","first_name":"Thomas D.","full_name":"Challman, Thomas D."},{"full_name":"Smith, Rebecca","last_name":"Smith","first_name":"Rebecca"},{"last_name":"Abdalla","first_name":"Asmahan","full_name":"Abdalla, Asmahan"},{"full_name":"Haaf, Thomas","first_name":"Thomas","last_name":"Haaf"},{"full_name":"Suri, Mohnish","first_name":"Mohnish","last_name":"Suri"},{"full_name":"Joshi, Manali","first_name":"Manali","last_name":"Joshi"},{"full_name":"Chung, Wendy K.","first_name":"Wendy K.","last_name":"Chung"},{"last_name":"Moreno-De-Luca","first_name":"Andres","full_name":"Moreno-De-Luca, Andres"},{"first_name":"Henry","last_name":"Houlden","full_name":"Houlden, Henry"},{"first_name":"Reza","last_name":"Maroofian","full_name":"Maroofian, Reza"},{"last_name":"Varshney","first_name":"Gaurav K.","full_name":"Varshney, Gaurav K."}],"doi":"10.1186/s13073-023-01258-4","status":"public","quality_controlled":"1","title":"Evaluating the association of biallelic OGDHL variants with significant phenotypic heterogeneity","publisher":"Springer Nature","user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","date_created":"2023-12-04T08:10:55Z","oa_version":"Published Version","oa":1,"abstract":[{"lang":"eng","text":"Background: Biallelic variants in OGDHL, encoding part of the α-ketoglutarate dehydrogenase complex, have been associated with highly heterogeneous neurological and neurodevelopmental disorders. However, the validity of this association remains to be confirmed. A second OGDHL patient cohort was recruited to carefully assess the gene-disease relationship.\r\nMethods: Using an unbiased genotype-first approach, we screened large, multiethnic aggregated sequencing datasets worldwide for biallelic OGDHL variants. We used CRISPR/Cas9 to generate zebrafish knockouts of ogdhl, ogdh paralogs, and dhtkd1 to investigate functional relationships and impact during development. Functional complementation with patient variant transcripts was conducted to systematically assess protein functionality as a readout for pathogenicity.\r\nResults: A cohort of 14 individuals from 12 unrelated families exhibited highly variable clinical phenotypes, with the majority of them presenting at least one additional variant, potentially accounting for a blended phenotype and complicating phenotypic understanding. We also uncovered extreme clinical heterogeneity and high allele frequencies, occasionally incompatible with a fully penetrant recessive disorder. Human cDNA of previously described and new variants were tested in an ogdhl zebrafish knockout model, adding functional evidence for variant reclassification. We disclosed evidence of hypomorphic alleles as well as a loss-of-function variant without deleterious effects in zebrafish variant testing also showing discordant familial segregation, challenging the relationship of OGDHL as a conventional Mendelian gene. Going further, we uncovered evidence for a complex compensatory relationship among OGDH, OGDHL, and DHTKD1 isoenzymes that are associated with neurodevelopmental disorders and exhibit complex transcriptional compensation patterns with partial functional redundancy.\r\nConclusions: Based on the results of genetic, clinical, and functional studies, we formed three hypotheses in which to frame observations: biallelic OGDHL variants lead to a highly variable monogenic disorder, variants in OGDHL are following a complex pattern of inheritance, or they may not be causative at all. Our study further highlights the continuing challenges of assessing the validity of reported disease-gene associations and effects of variants identified in these genes. This is particularly more complicated in making genetic diagnoses based on identification of variants in genes presenting a highly heterogenous phenotype such as “OGDHL-related disorders”."}],"publication_status":"published","date_published":"2023-11-23T00:00:00Z","extern":"1","date_updated":"2023-12-04T08:17:22Z","tmp":{"image":"/images/cc_by.png","name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","short":"CC BY (4.0)","legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode"},"month":"11","article_processing_charge":"Yes","day":"23","type":"journal_article","file":[{"date_updated":"2023-12-04T08:15:43Z","file_id":"14640","success":1,"file_size":14791081,"date_created":"2023-12-04T08:15:43Z","relation":"main_file","checksum":"279efd212005549aba817a487d56d363","content_type":"application/pdf","file_name":"2023_GenomeMed_Lin.pdf","creator":"dernst","access_level":"open_access"}]}