Combined oxidative phosphorylation deficiency 35 (COXPD 35) is a very rare autosomal recessive disorder caused by homozygous or compound heterozygous mutations in the TRIT1 gene on chromosome 1p34. Only six cases of COXPD 35 and six allelic variants of TRIT1 gene mutations have been reported worldwide.
Case description: We describe two siblings who presented with similar clinical features including severe intellectual disability and epilepsy with onset of symptom in early infancy.
The whole exome sequencing results revealed a compound heterozygous novel variant, c.979G > A (p.Glu327Lys) and c.682 + 2 T > C, on TRIT1 exon 8 and intron 5, respectively, which was confirmed by Sanger sequencing. Protein structure analysis revealed that the p.Glu327Lys variant disrupts the conformation and electrostatic charge of the zinc-finger motif in the tRNA isopentenyltransferase (IPT), impairing binding of the mutant IPT to specific DNA sequences.
This is the first report of two Korean siblings with COXPD 35 with two novel variants in TRIT1. This study will help to understand the various phenotypic spectra in patients with COXPD 35 and to expand knowledge on the mechanisms of the disease based on genetic features.
Abbreviations:ASD (atrial septal defect), COXPD (combined oxidative phosphorylation deficiency), EEG (electroencephalogram), HSF (human splicing finder), IPT (isopentenyltransferase), LP (likely pathogenic), MRI (magnetic resonance imaging), PVWM (periventricular white matter around temporal horn), VSD (ventricular septal defect), VUS (variant of uncertain significance), WES (whole-exome sequencing), WT (wild-type)
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Published online: September 15, 2020
Accepted: August 30, 2020
Received in revised form: August 24, 2020
Received: April 21, 2020
© 2020 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.