Biallelic variants in OGDH encoding oxoglutarate dehydrogenase lead to a neurodevelopmental disorder characterized by global developmental delay, movement disorder, and metabolic abnormalities

Authors

Ella F Whittle
Madison Chilian
Ehsan Ghayoor Karimiani
Helga Progri
Daniela Buhas
Melis Kose
Rebecca D Ganetzky
Mehran Beiraghi Toosi
Paria Najarzadeh Torbati
Reza Shervin Badv
Ivan Shelihan
Hui Yang
Houda Zghal Elloumi
Sukyeong Lee
Yalda Jamshidi
Alan M Pittman
Henry Houlden
Erika Ignatius
Shamima Rahman
Reza Maroofian
Wan Hee Yoon
Christopher J Carroll

Publication Date

2-1-2023

Journal

Genetics in Medicine

DOI

10.1016/j.gim.2022.11.001

PMID

36520152

PMCID

PMC9905285

PubMedCentral® Posted Date

2-25-2023

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Animals, Humans, Drosophila melanogaster, HEK293 Cells, Ketoglutarate Dehydrogenase Complex, Movement Disorders, Neurodevelopmental Disorders, α-ketoglutarate dehydrogenase deficiency, Mitochondria, Neurodevelopmental disease, OGDH, Oxoglutarate dehydrogenase

Abstract

PURPOSE: This study aimed to establish the genetic cause of a novel autosomal recessive neurodevelopmental disorder characterized by global developmental delay, movement disorder, and metabolic abnormalities.

METHODS: We performed a detailed clinical characterization of 4 unrelated individuals from consanguineous families with a neurodevelopmental disorder. We used exome sequencing or targeted-exome sequencing, cosegregation, in silico protein modeling, and functional analyses of variants in HEK293 cells and Drosophila melanogaster, as well as in proband-derived fibroblast cells.

RESULTS: In the 4 individuals, we identified 3 novel homozygous variants in oxoglutarate dehydrogenase (OGDH) (NM_002541.3), which encodes a subunit of the tricarboxylic acid cycle enzyme α-ketoglutarate dehydrogenase. In silico homology modeling predicts that c.566C>T:p.(Pro189Leu) and c.890C>A:p.(Ser297Tyr) variants interfere with the structure and function of OGDH. Fibroblasts from individual 1 showed that the p.(Ser297Tyr) variant led to a higher degradation rate of the OGDH protein. OGDH protein with p.(Pro189Leu) or p.(Ser297Tyr) variants in HEK293 cells showed significantly lower levels than the wild-type protein. Furthermore, we showed that expression of Drosophila Ogdh (dOgdh) carrying variants homologous to p.(Pro189Leu) or p.(Ser297Tyr), failed to rescue developmental lethality caused by loss of dOgdh. SpliceAI, a variant splice predictor, predicted that the c.935G>A:p.(Arg312Lys)/p.(Phe264_Arg312del) variant impacts splicing, which was confirmed through a mini-gene assay in HEK293 cells.

CONCLUSION: We established that biallelic variants in OGDH cause a neurodevelopmental disorder with metabolic and movement abnormalities.

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