Submission Details

The C19orf12 gene is located on chromosome 19 at 19p12 and encodes for a transmembrane glycine zipper-containing mitochondrial protein. This protein is involved in the mitochondrial and lipid metabolism. C19orf12 was first reported in relation to Autosomal Recessive Neurodegeneration with Brain Iron Accumulation (NBIA) in 2011. (Hartig et al 2011, PMID:21981780). Hartig et al first described 25 NBIA cases with homozygous, or compound heterozygous frameshift, or missense variants in C19orf12. A total of 18 NBIA cases were found to have homozygous common founder mutation c.204_214del11 (p.Gly69ArgfsX10) with all individuals having common MRI brain findings of hypointensities in the globus pallidus and substantia nigra, and presenting features including speech, gait difficulties, extrapyramidal features (oromandibular dystonia, generalized dystonia and parkinsonism), spasticity, hyperreflexia, psychiatric symptoms, and optic atrophy. C19orf12 was previously reported in two Malian sisters presenting with spastic paraplegia with gait difficulty, spasticity and peripheral neuropathy without brain abnormalities. (Landoure et al 2013 (PMID: 23857908); Meilleur et al 2009 (PMID: 20039086)). Both disease assertions have overlapping features in the central and peripheral nervous systems, with NBIA individuals having additional MRI brain abnormal findings in globus pallidus/substantia nigra, and ophthalmological features (e.g. Optic atrophy). Monfrini et al first published a case report of a patient with NBIA with novel heterozygous pathogenic variant c.265_266delAT (p.Met89Glyfs*12) in C19orf12 (Monfrini et al 2018, PMID:29295770). This was followed by Gregory et al that published 18 heterozygous cases of C19orf12-related NBIA from 13 families (Gregory et al 2019, PMID:3108752). The individuals with autosomal dominant form of NBIA were clinically similar to individuals with autosomal recessive form of NBIA. Gregory et al proposed that the nonsense truncating variants located in the final exon of C19rf12 impairs the function of the wild-type protein, producing a dominant-negative effect and leading to loss of function (Gregory et al 2019, PMID:3108752). Another proposed dominant disease mechanism was haploinsufficiency (Gregory et al 2019, PMID: 3108752)

Evidence supporting this gene-disease relationship includes case-level and experimental data. Heterozygous variants in C19orf12 (including nonsense and frameshift) were identified in at least 19 patients with clinical features suggestive of Autosomal Dominant Neurodegeneration with Brain Iron Accumulation (NBIA) (Gregory et al 2019, PMID: 3108752; Monfrini et al 2018, PMID:29295770; Rickman et al 2021, PMID:33260061; Fraser et al 2021, PMID:34041867; Yang et al 2022, PMID:35432442). At least 13 unique variants (nonsense and frameshift) have been reported in humans and the information of six unique variants in C19orf12 is available in ClinVar database. This gene-disease association is supported by biochemical function studies, non-human model organism studies, and functional alteration analysis. (Hartig et al 2011, PMID:21981780; Landouré et al 2013, PMID: 23857908; Mori et al 2019, PMID 31548400; Mignani et al 2020, PMID: 33425903; Iuso et al 2014, PMID:24586779; Venco et al 2015, PMID: 26136767; Shao et al 2022, PMID: 35182730). In summary, the C19orf12 gene has a moderate association with Autosomal Dominant Neurodegeneration with Brain Iron Accumulation (NBIA).