Leigh syndrome in a patient with a novel C12orf65 pathogenic variant: case report and literature review.

Eduardo Perrone,Simone Brasil De O Iglesias,Cecília Micheletti,Juliana S Silva,Luiza Do A Virmond,Viviane Nakano,Marco Antonio Curiati,Maria Fernanda Milanezi,Manuella G Oliveira,Ariane Falconi,Marina De França B Silva,Maria De Fatima F Soares,Thiago R Cavole,Carmen Silvia C Mendes

doi:10.1590/1678-4685-gmb-2018-0271

Eduardo Perrone, Simone Brasil De O Iglesias + Show 12 more

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https://doi.org/10.1590/1678-4685-gmb-2018-0271

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Abstract

Leigh syndrome is an early onset progressive disorder caused by defects in mitochondrial oxidative phosphorylation. Pathogenic variants in nuclear and mitochondrial genes are associated with the syndrome. Homozygous pathogenic variants in the C12orf65 gene impair the mitochondrial oxidative phosphorylation system. We describe a new case of Leigh syndrome caused by a novel pathogenic variant of the C12orf65 gene resulting in the lack of the Gly-Gly-Gln (GGQ) domain in the predicted protein, and review clinical and molecular data from previously reported patients. Our study supports that the phenotype caused by C12orf65 gene variants is heterogeneous and varies from spastic paraparesis to Leigh syndrome. Loss-of-function variants are more likely to cause the disease, and variants affecting the GGQ domain tend to be associated with more severe phenotypes, reinforcing a possible genotype-phenotype correlation.

Highlights

Leigh syndrome is an early-onset progressive neurodegenerative disorder associated with defects of mitochondrial oxidative phosphorylation and is the most common distinct phenotype among oxidative phosphorylation disorders in children
The nuclear C12orf65 gene at chromosome 12q24.31 comprises three exons, with 501 base pairs in its protein-coding exons 2 and 3. It encodes a soluble mitochondrial matrix protein related to the family of class I peptide chain release factors (RFs), which interacts with the large ribosomal subunit to release the polypeptide chain from the P-site-bound peptidyl-tRNA (Huynen et al, 2012; Kogure et al, 2012)
We identified a novel homozygous 14 bp frameshift deletion in exon 2 of the C12orf65 gene: c.207_220del; p.Pro70Asnfs*28 (NM_152269), which was validated by Sanger sequencing, the sequence, being aligned with CRISP-ID (Figure S1)

Summary

Introduction

Leigh syndrome is an early-onset progressive neurodegenerative disorder associated with defects of mitochondrial oxidative phosphorylation and is the most common distinct phenotype among oxidative phosphorylation disorders in children. We describe a 2-year-old female patient with Leigh syndrome and a novel frameshift deletion pathogenic variant of the C12orf65 gene. We evaluated the variants in the homozygous state, because the parents of the proband were consanguineous, and prioritized genes based on phenotypic databases, such as the Online Mendelian Inheritance in Man. The variant identified as pathogenic was confirmed by Sanger sequencing.

Results

Conclusion