title: Delineation of C12orf65-related phenotypes: a genotype-phenotype relationship.
abstract: 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.
authors.affiliation: 1] Genetic Institute, Emek Medical Center, Afula, Israel [2] Rappaport School of Medicine, Technion, Haifa, Israel.
authors.forename: Ronen
authors.initials: R
authors.lastname: Spiegel
authors.affiliation: 1] Rappaport School of Medicine, Technion, Haifa, Israel [2] Metabolic Unit, Rambam Medical Center, Haifa, Israel.
authors.forename: Hanna
authors.initials: H
authors.lastname: Mandel
authors.affiliation: Department of Genetics and Metabolic Diseases, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Ann
authors.initials: A
authors.lastname: Saada
authors.affiliation: Department of Genetics and Metabolic Diseases, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Issy
authors.initials: I
authors.lastname: Lerer
authors.affiliation: Department of Genetics and Metabolic Diseases, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Ayala
authors.initials: A
authors.lastname: Burger
authors.affiliation: Monique and Jacques Roboh Department of Genetic Research, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Avraham
authors.initials: A
authors.lastname: Shaag
authors.affiliation: 1] Genetic Institute, Emek Medical Center, Afula, Israel [2] Rappaport School of Medicine, Technion, Haifa, Israel.
authors.forename: Stavit A
authors.initials: SA
authors.lastname: Shalev
authors.affiliation: Department of Ophthalmology, Emek Medical Center, Afula, Israel.
authors.forename: Haneen
authors.initials: H
authors.lastname: Jabaly-Habib
authors.affiliation: Department of Radiology, Rambam Medical Center, Haifa, Israel.
authors.forename: Dorit
authors.initials: D
authors.lastname: Goldsher
authors.affiliation: Department of Radiology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: John M
authors.initials: JM
authors.lastname: Gomori
authors.affiliation: Department of Neurology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Alex
authors.initials: A
authors.lastname: Lossos
authors.affiliation: Monique and Jacques Roboh Department of Genetic Research, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Orly
authors.initials: O
authors.lastname: Elpeleg
authors.affiliation: Department of Genetics and Metabolic Diseases, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Vardiella
authors.initials: V
authors.lastname: Meiner
mesh_terms: D000293:Adolescent; D000328:Adult; D017398:Alternative Splicing; D000595:Amino Acid Sequence; D001921:Brain / Q000473:pathology; D002648:Child; D003241:Consanguinity; D004252:DNA Mutational Analysis; D003576:Electron Transport Complex IV / Q000378:metabolism; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D024101:Mitochondrial Proteins / Q000235:genetics*; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D009896:Optic Atrophy / Q000235:genetics; D010375:Pedigree; D010454:Peptide Termination Factors / Q000235:genetics*; D010641:Phenotype; D055815:Young Adult
chemical_list: D003576:Electron Transport Complex IV; D024101:Mitochondrial Proteins; D010454:Peptide Termination Factors; C551030:MTRFR protein, human