Evaluating the association of biallelic OGDHL variants with significant phenotypic heterogeneity
Abstract 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...
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| Language: | English |
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BMC
2023-11-01
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| Series: | Genome Medicine |
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| Online Access: | https://doi.org/10.1186/s13073-023-01258-4 |
| _version_ | 1827603094146383872 |
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| author | Sheng-Jia Lin Barbara Vona Tracy Lau Kevin Huang Maha S. Zaki Huda Shujaa Aldeen Ehsan Ghayoor Karimiani Clarissa Rocca Mahmoud M. Noureldeen Ahmed K. Saad Cassidy Petree Tobias Bartolomaeus Rami Abou Jamra Giovanni Zifarelli Aditi Gotkhindikar Ingrid M. Wentzensen Mingjuan Liao Emalyn Elise Cork Pratishtha Varshney Narges Hashemi Mohammad Hasan Mohammadi Aboulfazl Rad Juanita Neira Mehran Beiraghi Toosi Cordula Knopp Ingo Kurth Thomas D. Challman Rebecca Smith Asmahan Abdalla Thomas Haaf Mohnish Suri Manali Joshi Wendy K. Chung Andres Moreno-De-Luca Henry Houlden Reza Maroofian Gaurav K. Varshney |
| author_facet | Sheng-Jia Lin Barbara Vona Tracy Lau Kevin Huang Maha S. Zaki Huda Shujaa Aldeen Ehsan Ghayoor Karimiani Clarissa Rocca Mahmoud M. Noureldeen Ahmed K. Saad Cassidy Petree Tobias Bartolomaeus Rami Abou Jamra Giovanni Zifarelli Aditi Gotkhindikar Ingrid M. Wentzensen Mingjuan Liao Emalyn Elise Cork Pratishtha Varshney Narges Hashemi Mohammad Hasan Mohammadi Aboulfazl Rad Juanita Neira Mehran Beiraghi Toosi Cordula Knopp Ingo Kurth Thomas D. Challman Rebecca Smith Asmahan Abdalla Thomas Haaf Mohnish Suri Manali Joshi Wendy K. Chung Andres Moreno-De-Luca Henry Houlden Reza Maroofian Gaurav K. Varshney |
| author_sort | Sheng-Jia Lin |
| collection | DOAJ |
| description | Abstract 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. Methods 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. Results 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. Conclusions 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”. |
| first_indexed | 2024-03-09T05:32:49Z |
| format | Article |
| id | doaj.art-f946c3f7f70a4b7caee99c8a98b2e0b2 |
| institution | Directory Open Access Journal |
| issn | 1756-994X |
| language | English |
| last_indexed | 2024-03-09T05:32:49Z |
| publishDate | 2023-11-01 |
| publisher | BMC |
| record_format | Article |
| series | Genome Medicine |
| spelling | doaj.art-f946c3f7f70a4b7caee99c8a98b2e0b22023-12-03T12:31:48ZengBMCGenome Medicine1756-994X2023-11-0115112410.1186/s13073-023-01258-4Evaluating the association of biallelic OGDHL variants with significant phenotypic heterogeneitySheng-Jia Lin0Barbara Vona1Tracy Lau2Kevin Huang3Maha S. Zaki4Huda Shujaa Aldeen5Ehsan Ghayoor Karimiani6Clarissa Rocca7Mahmoud M. Noureldeen8Ahmed K. Saad9Cassidy Petree10Tobias Bartolomaeus11Rami Abou Jamra12Giovanni Zifarelli13Aditi Gotkhindikar14Ingrid M. Wentzensen15Mingjuan Liao16Emalyn Elise Cork17Pratishtha Varshney18Narges Hashemi19Mohammad Hasan Mohammadi20Aboulfazl Rad21Juanita Neira22Mehran Beiraghi Toosi23Cordula Knopp24Ingo Kurth25Thomas D. Challman26Rebecca Smith27Asmahan Abdalla28Thomas Haaf29Mohnish Suri30Manali Joshi31Wendy K. Chung32Andres Moreno-De-Luca33Henry Houlden34Reza Maroofian35Gaurav K. Varshney36Genes & Human Disease Research Program, Oklahoma Medical Research FoundationInstitute of Human Genetics, Julius Maximilians University WürzburgDepartment of Neuromuscular Disorders, Queen Square Institute of Neurology, University College LondonGenes & Human Disease Research Program, Oklahoma Medical Research FoundationClinical Genetics Department, Human Genetics and Genome Research Institute, National Research CentreDepartment of Neuromuscular Disorders, Queen Square Institute of Neurology, University College LondonMolecular and Clinical Sciences Institute, St. George’s, University of London, Cranmer Terrace LondonDepartment of Neuromuscular Disorders, Queen Square Institute of Neurology, University College LondonDepartment of Pediatrics, Faculty of Medicine, Beni-Suef UniversityMedical Molecular Genetics Department, Human Genetics and Genome Research Institute, National Research CentreGenes & Human Disease Research Program, Oklahoma Medical Research FoundationInstitute of Human Genetics, University of Leipzig Medical CenterInstitute of Human Genetics, University of Leipzig Medical CenterCentogene GmbHBioinformatics Centre, S. P. Pune UniversityGeneDxGeneDxDepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount SinaiGenes & Human Disease Research Program, Oklahoma Medical Research FoundationDepartment of Pediatrics, School of Medicine, Mashhad University of Medical SciencesDepartment of Pediatrics, Zabol University of Medical SciencesDepartment of Otolaryngology-Head and Neck Surgery, Tübingen Hearing Research Center, Eberhard Karls UniversityDepartment of Human Genetics, Emory UniversityDepartment of Pediatrics, School of Medicine, Mashhad University of Medical SciencesInstitute for Human Genetics and Genomic Medicine, RWTH Aachen UniversityInstitute for Human Genetics and Genomic Medicine, RWTH Aachen UniversityAutism & Developmental Medicine InstituteAutism & Developmental Medicine InstituteDepartment of Pediatric Endocrinology, Gaafar Ibn Auf Children’s Tertiary HospitalInstitute of Human Genetics, Julius Maximilians University WürzburgNottingham Clinical Genetics Service, Nottingham University Hospitals NHS TrustBioinformatics Centre, S. P. Pune UniversityDepartment of Pediatrics, Boston Children’s Hospitaland, Harvard Medical School Department of Diagnostic Radiology, Kingston Health Sciences Centre, Queen’s UniversityDepartment of Neuromuscular Disorders, Queen Square Institute of Neurology, University College LondonDepartment of Neuromuscular Disorders, Queen Square Institute of Neurology, University College LondonGenes & Human Disease Research Program, Oklahoma Medical Research FoundationAbstract 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. Methods 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. Results 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. Conclusions 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”.https://doi.org/10.1186/s13073-023-01258-42-oxo acid dehydrogenaseOGDHLGenetic compensationDisease modelZebrafishNeurodevelopmental disorders |
| spellingShingle | Sheng-Jia Lin Barbara Vona Tracy Lau Kevin Huang Maha S. Zaki Huda Shujaa Aldeen Ehsan Ghayoor Karimiani Clarissa Rocca Mahmoud M. Noureldeen Ahmed K. Saad Cassidy Petree Tobias Bartolomaeus Rami Abou Jamra Giovanni Zifarelli Aditi Gotkhindikar Ingrid M. Wentzensen Mingjuan Liao Emalyn Elise Cork Pratishtha Varshney Narges Hashemi Mohammad Hasan Mohammadi Aboulfazl Rad Juanita Neira Mehran Beiraghi Toosi Cordula Knopp Ingo Kurth Thomas D. Challman Rebecca Smith Asmahan Abdalla Thomas Haaf Mohnish Suri Manali Joshi Wendy K. Chung Andres Moreno-De-Luca Henry Houlden Reza Maroofian Gaurav K. Varshney Evaluating the association of biallelic OGDHL variants with significant phenotypic heterogeneity Genome Medicine 2-oxo acid dehydrogenase OGDHL Genetic compensation Disease model Zebrafish Neurodevelopmental disorders |
| title | Evaluating the association of biallelic OGDHL variants with significant phenotypic heterogeneity |
| title_full | Evaluating the association of biallelic OGDHL variants with significant phenotypic heterogeneity |
| title_fullStr | Evaluating the association of biallelic OGDHL variants with significant phenotypic heterogeneity |
| title_full_unstemmed | Evaluating the association of biallelic OGDHL variants with significant phenotypic heterogeneity |
| title_short | Evaluating the association of biallelic OGDHL variants with significant phenotypic heterogeneity |
| title_sort | evaluating the association of biallelic ogdhl variants with significant phenotypic heterogeneity |
| topic | 2-oxo acid dehydrogenase OGDHL Genetic compensation Disease model Zebrafish Neurodevelopmental disorders |
| url | https://doi.org/10.1186/s13073-023-01258-4 |
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