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). Evidence supporting this gene-disease relationship includes case-level and experimental data. Biallelic variants in C19orf12 (including nonsense, frameshift, splice, and missense variants, small indel, duplication and deletion) were identified in at least 35 patients with clinical features suggestive of Autosomal Recessive Neurodegeneration with Brain Iron Accumulation (NBIA) (Hartig et al 2011, PMID:21981780; Hogarth et al 2012, PMID:23269600; Deschauer et al 2012, PMID: 22584950; Akçakaya et al 2019, PMID: 31804703; Dezfouli et al 2013, PMID:23166001; Landouré et al 2013, PMID: 23857908). At least 11 unique variants (nonsense, frameshift, splice, and missense variants, small indel, duplication and deletion) have been reported in humans. 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 is definitively associated with Autosomal Recessive Neurodegeneration with Brain Iron Accumulation (NBIA) and Autosomal Recessive Spastic Paraplegia. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.