HJV was first reported in relation to autosomal recessive hemochromatosis type 2A in 2004 (Papanikolaou G et al. PMID:14647275). The disease is characterized by an early onset (usually 20s-30s) of iron overload resulting in cardiomyopathy, diabetes and hypogonadism. Eleven unique variants (6 missense, 4 nonsense and 1 frameshift) that have been reported in 17 probands in 3 publications (PMIDs: 14647275, 14982873, 40587672) are included in this curation. Several more missense and frameshift variants are reported in the literature. Four affected segregations from two families are scored in this curation (PMID:14647275) and more families are reported. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity appears to be loss of function. This gene-disease relationship is also supported by animal models, expression studies, and a protein association assay (PMIDs: 19252486, 16075059, 24309898, 25970244, 14647275). Expression studies demonstrate specific expression of HJV in the liver and small intestine (PMIDs:14647275, 24309898, 25970244). An assay demonstrates a direct association of HJV with BMP6, which has been previously curated by this GCEP to be implicated in the phenotype (CCID:008849; PMID:19252486). Two different mouse models, one that knocks out HJV with a targeted vector and one that administers HJV.Fc, have shown that without functional* HJV* mice demonstrate iron accumulation in the liver resulting in a hematological and histopathological phenotype that is similar to that of humans (PMIDs:19252486, 16075059). There may be more experimental evidence available in the literature, but the maximum score for experimental evidence (6 pts.) has been reached.
In summary, there is definitive evidence supporting the relationship between HJV and autosomal recessive hemochromatosis type 2A. This evidence has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen General Inborn Errors of Metabolism GCEP on the meeting date July 11, 2025 (SOP Version 11).
HJV was first reported in relation to autosomal recessive hemochromatosis type 2A in 2004 (Papanikolaou G et al. PMID:14647275). The disease is characterized by an early onset (usually 20s-30s) of iron overload resulting in cardiomyopathy, diabetes and hypogonadism. Eleven unique variants (6 missense, 4 nonsense and 1 frameshift) that have been reported in 17 probands in 3 publications (PMIDs: 14647275, 14982873, 40587672) are included in this curation. Several more missense and frameshift variants are reported in the literature. Four affected segregations from two families are scored in this curation (PMID:14647275) and more families are reported. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity appears to be loss of function. This gene-disease relationship is also supported by animal models, expression studies, and a protein association assay (PMIDs: 19252486, 16075059, 24309898, 25970244, 14647275). Expression studies demonstrate specific expression of HJV in the liver and small intestine (PMIDs:14647275, 24309898, 25970244). An assay demonstrates a direct association of HJV with BMP6, which has been previously curated by this GCEP to be implicated in the phenotype (CCID:008849; PMID:19252486). Two different mouse models, one that knocks out HJV with a targeted vector and one that administers HJV.Fc, have shown that without functional HJV mice demonstrate iron accumulation in the liver resulting in a hematological and histopathological phenotype that is similar to that of humans (PMIDs:19252486, 16075059). There may be more experimental evidence available in the literature, but the maximum score for experimental evidence (6 pts.) has been reached.
In summary, there is definitive evidence supporting the relationship between HJV and autosomal recessive hemochromatosis type 2A. This evidence has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen General Inborn Errors of Metabolism GCEP on the meeting date July 11, 2025 (SOP Version 11).
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