@article{14639,
  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”.},
  author       = {Lin, Sheng-Jia and Vona, Barbara and Lau, Tracy and Huang, Kevin and Zaki, Maha S. and Aldeen, Huda Shujaa and Karimiani, Ehsan Ghayoor and Rocca, Clarissa and Noureldeen, Mahmoud M. and Saad, Ahmed K. and Petree, Cassidy and Bartolomaeus, Tobias and Abou Jamra, Rami and Zifarelli, Giovanni and Gotkhindikar, Aditi and Wentzensen, Ingrid M. and Liao, Mingjuan and Cork, Emalyn Elise and Varshney, Pratishtha and Hashemi, Narges and Mohammadi, Mohammad Hasan and Rad, Aboulfazl and Neira, Juanita and Toosi, Mehran Beiraghi and Knopp, Cordula and Kurth, Ingo and Challman, Thomas D. and Smith, Rebecca and Abdalla, Asmahan and Haaf, Thomas and Suri, Mohnish and Joshi, Manali and Chung, Wendy K. and Moreno-De-Luca, Andres and Houlden, Henry and Maroofian, Reza and Varshney, Gaurav K.},
  issn         = {1756-994X},
  journal      = {Genome Medicine},
  keywords     = {Genetics (clinical), Genetics, Molecular Biology, Molecular Medicine},
  publisher    = {Springer Nature},
  title        = {{Evaluating the association of biallelic OGDHL variants with significant phenotypic heterogeneity}},
  doi          = {10.1186/s13073-023-01258-4},
  volume       = {15},
  year         = {2023},
}

@article{7717,
  abstract     = {Background: DNA methylation levels change along with age, but few studies have examined the variation in the rate of such changes between individuals.
Methods: 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).
Results: 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.
Conclusions: 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.},
  author       = {Zhang, Qian and Marioni, Riccardo E and Robinson, Matthew Richard and Higham, Jon and Sproul, Duncan and Wray, Naomi R and Deary, Ian J and McRae, Allan F and Visscher, Peter M},
  issn         = {1756-994X},
  journal      = {Genome Medicine},
  number       = {1},
  publisher    = {Springer Nature},
  title        = {{Genotype effects contribute to variation in longitudinal methylome patterns in older people}},
  doi          = {10.1186/s13073-018-0585-7},
  volume       = {10},
  year         = {2018},
}