FTH1

Inheritance Pattern: AD

Disease ID:MONDO:0014225

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0958012

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0958012

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0014225

Submitter: ClinGen

The FTH1 gene codes for the ferritin heavy chain. Synthesis of both heavy H- type and light L- type ferritin subunits is controlled by a common cytosolic protein known as iron regulatory protein (IRP), which binds to the iron-responsive element (IRE) in the 5′-UTR of the H- and L-ferritin mRNAs (PMID:11389486). The H subunit is known to generate a ferroxidase activity that is essential for the incorporation of iron into the ferritin molecule, contributing to the maintenance of the redox status of the cells by removing Fe (II). Improperly coordinated Fe (II) has the potential to convert hydrogen peroxide and superoxide into the highly toxic hydroxyl radical, which can attack proteins, lipids, and DNA causing oxidation, fragmentation and crosslinking leading to their loss of function. 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. Summary of case- based evidence: One variant in the IRE region of H-subunit mRNA has been reported in association with hemochromatosis type 5 in three members of a Japanese family affected with dominantly inherited iron overload (PMID:11389486). Summary of experimental evidence: This gene-disease association is supported by experimental evidence from the study on an iron-uptake assay using the COS-1 transfectants, which suggests the A49U mutation of H subunit would affect not only its own translation but also that of the L subunit and that the decrease in H subunit not only impaired iron uptake into the ferritin molecule but also caused iron accumulation in the cytosol, possibly because of the decrease in ferroxidase activity (PMID:11389486). The iron storage function of ferritin plays a major role in preventing iron-mediated cell and tissue damage. (PMID: 19492434). Study on H-ferritin gene–knockout mice showed early embryonic lethality due to massive iron deposition (PMID: 11468145). The studies on kinetics of iron oxidation and uptake of ferritin purified from human liver and of the engineered mutant H-chain observed that the deletion at the carboxyl terminus prevents the formation of a stable iron core suggesting that the ferritin H-chain has an iron oxidation site which is separated from the sites of iron transfer and hydrolysis (PMID:3192527). A study on Hydroxyl radical spin-trapping experiments showed that H-chain ferritin greatly attenuates hydroxyl radical generation from the Fenton reaction and that the ferroxidase site is responsible for this activity. The presence of wild-type human H-chain ferritin HuHF during Fe2+ oxidation by H2O2 greatly decreases the amount of OH- radical produced from Fenton chemistry whereas the ferroxidase site mutant 222 (H62K + H65G) and human L-chain ferritin (HuLF) lack this activity. This data relates to the pathogenesis mechanism in the patients as well where the ferroxidase activity of H-ferritin is lost and there is increase in the serum iron levels (PMID:16519538). In summary, there is limited evidence supporting the relationship between FTH1 and susceptibility to Hemochromatosis type 5. This classification was approved by the ClinGen IEM GCEP at the meeting on August 8, 2025 (SOP Version 11).

Inheritance Pattern: AD

Disease ID:MONDO:0014225

Submitter: PanelApp Australia

Inheritance Pattern: Unknown

Disease ID:MONDO:0014225

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0014225

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0014225

Submitter: Genomics England PanelApp

Inheritance Pattern: AD

Disease ID:MONDO:0958012

Submitter: ClinGen

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).