Evaluating the association of biallelic OGDHL variants with significant phenotypic heterogeneity

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Abstract
Background: Biallelic variants inOGDHL, 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 secondOGDHLpatient 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 biallelicOGDHLvariants. We used CRISPR/Cas9 to generate zebrafish knockouts ofogdhl,ogdhparalogs, anddhtkd1to 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 anogdhlzebrafish 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 ofOGDHLas 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: biallelicOGDHLvariants lead to a highly variable monogenic disorder, variants inOGDHLare 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”.
Funding Information
  • Deutsche Forschungsgemeinschaft (469177153)
  • Wellcome Trust
  • University College London Hospitals Biomedical Research Centre

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