--- _id: '14639' 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”." article_number: '102' article_processing_charge: Yes article_type: original author: - first_name: Sheng-Jia full_name: Lin, Sheng-Jia last_name: Lin - first_name: Barbara full_name: Vona, Barbara last_name: Vona - first_name: Tracy full_name: Lau, Tracy last_name: Lau - first_name: Kevin full_name: Huang, Kevin id: 3b3d2888-1ff6-11ee-9fa6-8f209ca91fe3 last_name: Huang orcid: 0000-0002-2512-7812 - first_name: Maha S. full_name: Zaki, Maha S. last_name: Zaki - first_name: Huda Shujaa full_name: Aldeen, Huda Shujaa last_name: Aldeen - first_name: Ehsan Ghayoor full_name: Karimiani, Ehsan Ghayoor last_name: Karimiani - first_name: Clarissa full_name: Rocca, Clarissa last_name: Rocca - first_name: Mahmoud M. full_name: Noureldeen, Mahmoud M. last_name: Noureldeen - first_name: Ahmed K. full_name: Saad, Ahmed K. last_name: Saad - first_name: Cassidy full_name: Petree, Cassidy last_name: Petree - first_name: Tobias full_name: Bartolomaeus, Tobias last_name: Bartolomaeus - first_name: Rami full_name: Abou Jamra, Rami last_name: Abou Jamra - first_name: Giovanni full_name: Zifarelli, Giovanni last_name: Zifarelli - first_name: Aditi full_name: Gotkhindikar, Aditi last_name: Gotkhindikar - first_name: Ingrid M. full_name: Wentzensen, Ingrid M. last_name: Wentzensen - first_name: Mingjuan full_name: Liao, Mingjuan last_name: Liao - first_name: Emalyn Elise full_name: Cork, Emalyn Elise last_name: Cork - first_name: Pratishtha full_name: Varshney, Pratishtha last_name: Varshney - first_name: Narges full_name: Hashemi, Narges last_name: Hashemi - first_name: Mohammad Hasan full_name: Mohammadi, Mohammad Hasan last_name: Mohammadi - first_name: Aboulfazl full_name: Rad, Aboulfazl last_name: Rad - first_name: Juanita full_name: Neira, Juanita last_name: Neira - first_name: Mehran Beiraghi full_name: Toosi, Mehran Beiraghi last_name: Toosi - first_name: Cordula full_name: Knopp, Cordula last_name: Knopp - first_name: Ingo full_name: Kurth, Ingo last_name: Kurth - first_name: Thomas D. full_name: Challman, Thomas D. last_name: Challman - first_name: Rebecca full_name: Smith, Rebecca last_name: Smith - first_name: Asmahan full_name: Abdalla, Asmahan last_name: Abdalla - first_name: Thomas full_name: Haaf, Thomas last_name: Haaf - first_name: Mohnish full_name: Suri, Mohnish last_name: Suri - first_name: Manali full_name: Joshi, Manali last_name: Joshi - first_name: Wendy K. full_name: Chung, Wendy K. last_name: Chung - first_name: Andres full_name: Moreno-De-Luca, Andres last_name: Moreno-De-Luca - first_name: Henry full_name: Houlden, Henry last_name: Houlden - first_name: Reza full_name: Maroofian, Reza last_name: Maroofian - first_name: Gaurav K. full_name: Varshney, Gaurav K. last_name: Varshney citation: ama: Lin S-J, Vona B, Lau T, et al. Evaluating the association of biallelic OGDHL variants with significant phenotypic heterogeneity. Genome Medicine. 2023;15. doi:10.1186/s13073-023-01258-4 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. Genome Medicine. Springer Nature. https://doi.org/10.1186/s13073-023-01258-4 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.” Genome Medicine. Springer Nature, 2023. https://doi.org/10.1186/s13073-023-01258-4. ieee: S.-J. Lin et al., “Evaluating the association of biallelic OGDHL variants with significant phenotypic heterogeneity,” Genome Medicine, vol. 15. Springer Nature, 2023. 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. mla: Lin, Sheng-Jia, et al. “Evaluating the Association of Biallelic OGDHL Variants with Significant Phenotypic Heterogeneity.” Genome Medicine, vol. 15, 102, Springer Nature, 2023, doi:10.1186/s13073-023-01258-4. 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). date_created: 2023-12-04T08:10:55Z date_published: 2023-11-23T00:00:00Z date_updated: 2023-12-04T08:17:22Z day: '23' ddc: - '570' doi: 10.1186/s13073-023-01258-4 extern: '1' file: - access_level: open_access checksum: 279efd212005549aba817a487d56d363 content_type: application/pdf creator: dernst date_created: 2023-12-04T08:15:43Z date_updated: 2023-12-04T08:15:43Z file_id: '14640' file_name: 2023_GenomeMed_Lin.pdf file_size: 14791081 relation: main_file success: 1 file_date_updated: 2023-12-04T08:15:43Z has_accepted_license: '1' intvolume: ' 15' keyword: - Genetics (clinical) - Genetics - Molecular Biology - Molecular Medicine language: - iso: eng license: https://creativecommons.org/licenses/by/4.0/ month: '11' oa: 1 oa_version: Published Version publication: Genome Medicine publication_identifier: issn: - 1756-994X publication_status: published publisher: Springer Nature quality_controlled: '1' status: public title: Evaluating the association of biallelic OGDHL variants with significant phenotypic heterogeneity tmp: image: /images/cc_by.png legal_code_url: https://creativecommons.org/licenses/by/4.0/legalcode name: Creative Commons Attribution 4.0 International Public License (CC-BY 4.0) short: CC BY (4.0) type: journal_article user_id: 2DF688A6-F248-11E8-B48F-1D18A9856A87 volume: 15 year: '2023' ... --- _id: '7717' abstract: - lang: eng text: "Background: DNA methylation levels change along with age, but few studies have examined the variation in the rate of such changes between individuals.\r\nMethods: We performed a longitudinal analysis to quantify the variation in the rate of change of DNA methylation between individuals using whole blood DNA methylation array profiles collected at 2–4 time points (N = 2894) in 954 individuals (67–90 years).\r\nResults: After stringent quality control, we identified 1507 DNA methylation CpG sites (rsCpGs) with statistically significant variation in the rate of change (random slope) of DNA methylation among individuals in a mixed linear model analysis. Genes in the vicinity of these rsCpGs were found to be enriched in Homeobox transcription factors and the Wnt signalling pathway, both of which are related to ageing processes. Furthermore, we investigated the SNP effect on the random slope. We found that 4 out of 1507 rsCpGs had one significant (P < 5 × 10−8/1507) SNP effect and 343 rsCpGs had at least one SNP effect (436 SNP-probe pairs) reaching genome-wide significance (P < 5 × 10−8). Ninety-five percent of the significant (P < 5 × 10−8) SNPs are on different chromosomes from their corresponding probes.\r\nConclusions: We identified CpG sites that have variability in the rate of change of DNA methylation between individuals, and our results suggest a genetic basis of this variation. Genes around these CpG sites have been reported to be involved in the ageing process." article_number: '75' article_processing_charge: No article_type: original author: - first_name: Qian full_name: Zhang, Qian last_name: Zhang - first_name: Riccardo E full_name: Marioni, Riccardo E last_name: Marioni - first_name: Matthew Richard full_name: Robinson, Matthew Richard id: E5D42276-F5DA-11E9-8E24-6303E6697425 last_name: Robinson orcid: 0000-0001-8982-8813 - first_name: Jon full_name: Higham, Jon last_name: Higham - first_name: Duncan full_name: Sproul, Duncan last_name: Sproul - first_name: Naomi R full_name: Wray, Naomi R last_name: Wray - first_name: Ian J full_name: Deary, Ian J last_name: Deary - first_name: Allan F full_name: McRae, Allan F last_name: McRae - first_name: Peter M full_name: Visscher, Peter M last_name: Visscher citation: ama: Zhang Q, Marioni RE, Robinson MR, et al. Genotype effects contribute to variation in longitudinal methylome patterns in older people. Genome Medicine. 2018;10(1). doi:10.1186/s13073-018-0585-7 apa: Zhang, Q., Marioni, R. E., Robinson, M. R., Higham, J., Sproul, D., Wray, N. R., … Visscher, P. M. (2018). Genotype effects contribute to variation in longitudinal methylome patterns in older people. Genome Medicine. Springer Nature. https://doi.org/10.1186/s13073-018-0585-7 chicago: Zhang, Qian, Riccardo E Marioni, Matthew Richard Robinson, Jon Higham, Duncan Sproul, Naomi R Wray, Ian J Deary, Allan F McRae, and Peter M Visscher. “Genotype Effects Contribute to Variation in Longitudinal Methylome Patterns in Older People.” Genome Medicine. Springer Nature, 2018. https://doi.org/10.1186/s13073-018-0585-7. ieee: Q. Zhang et al., “Genotype effects contribute to variation in longitudinal methylome patterns in older people,” Genome Medicine, vol. 10, no. 1. Springer Nature, 2018. ista: Zhang Q, Marioni RE, Robinson MR, Higham J, Sproul D, Wray NR, Deary IJ, McRae AF, Visscher PM. 2018. Genotype effects contribute to variation in longitudinal methylome patterns in older people. Genome Medicine. 10(1), 75. mla: Zhang, Qian, et al. “Genotype Effects Contribute to Variation in Longitudinal Methylome Patterns in Older People.” Genome Medicine, vol. 10, no. 1, 75, Springer Nature, 2018, doi:10.1186/s13073-018-0585-7. short: Q. Zhang, R.E. Marioni, M.R. Robinson, J. Higham, D. Sproul, N.R. Wray, I.J. Deary, A.F. McRae, P.M. Visscher, Genome Medicine 10 (2018). date_created: 2020-04-30T10:42:50Z date_published: 2018-10-22T00:00:00Z date_updated: 2021-01-12T08:15:04Z day: '22' doi: 10.1186/s13073-018-0585-7 extern: '1' intvolume: ' 10' issue: '1' language: - iso: eng main_file_link: - open_access: '1' url: https://doi.org/10.1186/s13073-018-0585-7 month: '10' oa: 1 oa_version: Published Version publication: Genome Medicine publication_identifier: issn: - 1756-994X publication_status: published publisher: Springer Nature quality_controlled: '1' status: public title: Genotype effects contribute to variation in longitudinal methylome patterns in older people type: journal_article user_id: 2DF688A6-F248-11E8-B48F-1D18A9856A87 volume: 10 year: '2018' ...