Delineation of C12orf65-related phenotypes: A genotype-phenotype relationship

Ronen Spiegel, Hanna Mandel, Ann Saada, Issy Lerer, Ayala Burger, Avraham Shaag, Stavit A. Shalev, Haneen Jabaly-Habib, Dorit Goldsher, John M. Gomori, Alex Lossos, Orly Elpeleg, Vardiella Meiner

Research output: Contribution to journalArticlepeer-review

26 Scopus citations


C12orf65 participates in the process of mitochondrial translation and has been shown to be associated with a spectrum of phenotypes, including early onset optic atrophy, progressive encephalomyopathy, peripheral neuropathy, and spastic paraparesis.We used whole-genome homozygosity mapping as well as exome sequencing and targeted gene sequencing to identify novel C12orf65 disease-causing mutations in seven affected individuals originating from two consanguineous families. In four family members affected with childhood-onset optic atrophy accompanied by slowly progressive peripheral neuropathy and spastic paraparesis, we identified a homozygous frame shift mutation c.413-417 delAACAA, which predicts a truncated protein lacking the C-terminal portion. In the second family, we studied three affected individuals who presented with early onset optic atrophy, peripheral neuropathy, and spastic gait in addition to moderate intellectual disability. Muscle biopsy in two of the patients revealed decreased activities of the mitochondrial respiratory chain complexes I and IV. In these patients, we identified a homozygous splice mutation, g.21043 T>A (c.282+2 T>A) which leads to skipping of exon 2. Our study broadens the phenotypic spectrum of C12orf65 defects and highlights the triad of optic atrophy, axonal neuropathy and spastic paraparesis as its key clinical features. In addition, a clear genotype-phenotype correlation is anticipated in which deleterious mutations which disrupt the GGQ-containing domain in the first coding exon are expected to result in a more severe phenotype, whereas down-stream C-terminal mutations may result in a more favorable phenotype, typically lacking cognitive impairment.

Original languageEnglish
Pages (from-to)1019-1025
Number of pages7
JournalEuropean Journal of Human Genetics
Issue number8
StatePublished - Aug 2014
Externally publishedYes

Bibliographical note

Funding Information:
We thank the patients and their families for their participation in this study. Dr Z Argov is acknowledged for his advice and guidance. We also thank Mr Pengfei Han from Beijing Genome Institute-Shenzhen for his kind administrative assistance and Ms Batel Benporat-Zimerman and Ms Moria Gamliel for their excellent technical help. This study was sponsored in part by the Israeli MOH grant (#5914) and the Israeli MOH/ERA-Net (#4800).


  • C12orf65 protein
  • Hereditary
  • Optic atrophy
  • Spastic Paraplegia
  • human
  • inherited peripheral neuropathy


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