Submission Details

The FTH1 gene encodes the ferritin heavy chain. The heavy chain is responsible for ferroxidase activity, and it has also been implicated in iron delivery to the brain predominantly in the neurons (PMID:37660254). Variants in FTH1 have been reported in individuals with the following disease entities: Hemochromatosis type 5 (HFE5) (MIM#0014225) and Neurodegeneration with brain iron accumulation 9(NBIA9) (MIM#0958012). As per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found the two disease entities do not exhibit phenotypic overlap and are inconsistent with a single spectrum of disease while both being autosomal dominantly inherited. Genetic disorders such as neurodegeneration with brain iron accumulation (NBIA), have been linked to disruption of iron homeostasis in the brain has been often present at early age with neurodevelopmental deficits progressing to neurodegeneration. Commonly affected anatomical areas being the basal ganglia, particularly the globus pallidum and substantia nigra. Summary of case- based evidence: Two de novo nonsense heterozygous variants in the last coding exon of FTH1 in five unrelated children were observed with characteristic clinical and imaging findings (PMID:37660254). The variants escape Nonsense Mediated Decay (NMD) and lead to ferritin accumulation on neuropathology, neuroimaging findings consistent with NBIA, and cellular markers of oxidative stress. Also, an additional study observed that distinct neuropathology with ferritin-positive IB, the absence of the variant in the healthy population and the absence of likely pathogenic variants in other genes associated with NBIA, the variant in FTH1(c.409_410del; p.H137Lfs4) is causative for the pathological findings in the patient (PMID:37265023). Summary of experimental evidence: The gene-disease association is supported by experimental studies on patient-derived fibroblasts, assayed for ferritin expression, susceptibility to iron accumulation, and oxidative stress suggesting that variant FTH1 mRNA transcripts escape NMD, and fibroblasts show elevated ferritin protein levels, markers of oxidative stress, and increased susceptibility to iron accumulation. FTH1 pathogenic variants appear to act by a dominant, toxic gain-of-function mechanism. Further, targeted knockdown of mutant FTH1 transcript with antisense oligonucleotides rescues cellular phenotypes and suggests a potential therapeutic strategy for this pediatric neurodegenerative disorder (PMID:37660254). The data support that truncating variants in the last exon of FTH1 cause a disorder in the spectrum of NBIA. Another study on Iron homeostasis in Ferritin knock out mice, suggests that single allele expressing the H subunit is not sufficient for survival when both alleles encoding the L subunit are absent, suggesting the need for some degree of complementation between the subunits as well as a dosage effect (PMID: 25629408). Studies on mutant mouse liver cells with alterations in terminal E-helix abolished the capacity of ferritin to incorporate iron during expression in the cells, probably caused by conformational modification of the hydrophobic channels (PMID:16751596). In summary, there is moderate level of evidence supporting the relationship between FTH1 and susceptibility neurodegeneration with brain iron accumulation (NBIA). This classification was approved by the ClinGen IEM GCEP at the meeting on September 12, 2025 (SOP Version 11).