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| Mendeliome v2.392 | HOXD cluster regulatory region |
Sarah Milton changed review comment from: The HOXD cluster of genes including HOXD1, HOXD3, HOXD4, HOXD8, HOXD9, HOXD10, HOXD11, HOXD12, HOXD13 are involved in embryonic patterning in developing limb buds. Multiple publications report copy number changes in the 2q31 region involving the HOXD cluster resulting in Mesomelic dysplasia, Kantaputra type characterised by marked shortening of the upper and lower limbs and progressive flexion contractures of PIP joints. Copy number changes in affected individuals included deletions, duplications and inversions ranging from 93kb to 1mb, many individuals had more than one structural variant within the region. The proposed molecular mechanism is repositioning of the HOX genes in relation to up and downstream enhancers resulting in misexpression. It should be noted deletions of the HOX gene cluster don't recapitulate the phenotype as it is thought there is compensation from HOXA genes. Functional studies in a mouse model showed inappropriate expression of HOXD13 in the middle segment of limb (ulnar/radius/tibia/fibula) and loss of normal expression in hand/foot, as well as loss of normal HOXD11 expression in the middle segment of the limb. This is thought to occur as each enhancer region normally acts on different precursor cells in normal physiology thus rearranging the region results in misexpression. Note: coordinates used for the above entry were the minimum seen in an affected individual (duplication). Authors of above publications did note if the copy number variant is too large it did not recapitulate the phenotype. Sources: Literature; to: The HOXD cluster of genes including HOXD1, HOXD3, HOXD4, HOXD8, HOXD9, HOXD10, HOXD11, HOXD12, HOXD13 are involved in embryonic patterning in developing limb buds. Multiple publications report copy number changes in the 2q31 region involving the HOXD cluster resulting in Mesomelic dysplasia, Kantaputra type characterised by marked shortening of the upper and lower limbs and progressive flexion contractures of PIP joints. Copy number changes in affected individuals included deletions, duplications and inversions ranging from 93kb to 1mb, many individuals had more than one structural variant within the region. The proposed molecular mechanism is repositioning of the HOX genes in relation to up and downstream enhancers resulting in misexpression. It should be noted deletions of the HOX gene cluster don't recapitulate the phenotype as it is thought there is compensation from HOXA genes. Functional studies in a mouse model showed inappropriate expression of HOXD13 in the middle segment of limb (ulnar/radius/tibia/fibula) and loss of normal expression in hand/foot, as well as loss of normal HOXD11 expression in the middle segment of the limb. This is thought to occur as each enhancer region acts on different precursor cells in normal physiology thus rearranging the region results in misexpression. Note: coordinates used for the above entry were the minimum seen in an affected individual (duplication). Authors of above publications did note if the copy number variant is too large it did not recapitulate the phenotype. Sources: Literature |
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| Mendeliome v2.392 | HOXD cluster regulatory region |
Sarah Milton changed review comment from: The HOXD cluster of genes including HOXD1, HOXD3, HOXD4, HOXD8, HOXD9, HOXD10, HOXD11, HOXD12, HOXD13 are involved in embryonic patterning in developing limb buds. Multiple publications report copy number changes in the 2q31 region involving the HOXD cluster resulting in Mesomelic dysplasia, Kantaputra type characterised by marked shortening of the upper and lower limbs and progressive flexion contractures of PIP joints. Copy number changes in affected individuals included deletions, duplications and inversions ranging from 93kb to 1mb, many individuals had more than one structural variant within the region. The proposed molecular mechanism is repositioning of the HOX genes in relation to up and downstream enhancers resulting in misexpression. It should be noted deletions of the HOX gene cluster don't recapitulate the phenotype as it is thought there is compensation from HOXA genes. Functional studies in a mouse model showed inappropriate expression of HOXD13 in the middle segment of limb (ulnar/radius/tibia/fibula) and loss of normal expression in hand/foot, as well as loss of normal HOXD11 expression in the middle segment of the limb. This is thought to occur as each enhancer region normally acts on different precursor cells but repositioning of genes in the region results in misexpression. Note: coordinates used for the above entry were the minimum seen in an affected individual (duplication). Authors of above publications did note if the copy number variant is too large it did not recapitulate the phenotype. Sources: Literature; to: The HOXD cluster of genes including HOXD1, HOXD3, HOXD4, HOXD8, HOXD9, HOXD10, HOXD11, HOXD12, HOXD13 are involved in embryonic patterning in developing limb buds. Multiple publications report copy number changes in the 2q31 region involving the HOXD cluster resulting in Mesomelic dysplasia, Kantaputra type characterised by marked shortening of the upper and lower limbs and progressive flexion contractures of PIP joints. Copy number changes in affected individuals included deletions, duplications and inversions ranging from 93kb to 1mb, many individuals had more than one structural variant within the region. The proposed molecular mechanism is repositioning of the HOX genes in relation to up and downstream enhancers resulting in misexpression. It should be noted deletions of the HOX gene cluster don't recapitulate the phenotype as it is thought there is compensation from HOXA genes. Functional studies in a mouse model showed inappropriate expression of HOXD13 in the middle segment of limb (ulnar/radius/tibia/fibula) and loss of normal expression in hand/foot, as well as loss of normal HOXD11 expression in the middle segment of the limb. This is thought to occur as each enhancer region normally acts on different precursor cells in normal physiology thus rearranging the region results in misexpression. Note: coordinates used for the above entry were the minimum seen in an affected individual (duplication). Authors of above publications did note if the copy number variant is too large it did not recapitulate the phenotype. Sources: Literature |
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| Mendeliome v2.392 | HOXD cluster regulatory region |
Sarah Milton Region: HOXD cluster regulatory region was added Region: HOXD cluster regulatory region was added to Mendeliome. Sources: Literature regulatory region tags were added to Region: HOXD cluster regulatory region. Mode of inheritance for Region: HOXD cluster regulatory region was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for Region: HOXD cluster regulatory region were set to 20648051; 36990510; 34408147; 31591517; 20577005; 29517766 Phenotypes for Region: HOXD cluster regulatory region were set to Mesomelic dysplasia, Kantaputra type, MIM#156232 Review for Region: HOXD cluster regulatory region was set to GREEN Added comment: The HOXD cluster of genes including HOXD1, HOXD3, HOXD4, HOXD8, HOXD9, HOXD10, HOXD11, HOXD12, HOXD13 are involved in embryonic patterning in developing limb buds. Multiple publications report copy number changes in the 2q31 region involving the HOXD cluster resulting in Mesomelic dysplasia, Kantaputra type characterised by marked shortening of the upper and lower limbs and progressive flexion contractures of PIP joints. Copy number changes in affected individuals included deletions, duplications and inversions ranging from 93kb to 1mb, many individuals had more than one structural variant within the region. The proposed molecular mechanism is repositioning of the HOX genes in relation to up and downstream enhancers resulting in misexpression. It should be noted deletions of the HOX gene cluster don't recapitulate the phenotype as it is thought there is compensation from HOXA genes. Functional studies in a mouse model showed inappropriate expression of HOXD13 in the middle segment of limb (ulnar/radius/tibia/fibula) and loss of normal expression in hand/foot, as well as loss of normal HOXD11 expression in the middle segment of the limb. This is thought to occur as each enhancer region normally acts on different precursor cells but repositioning of genes in the region results in misexpression. Note: coordinates used for the above entry were the minimum seen in an affected individual (duplication). Authors of above publications did note if the copy number variant is too large it did not recapitulate the phenotype. Sources: Literature |
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| Mendeliome v2.0 | HOXD12 | Gene migrated from ENSG00000170178 to ENSG00000170178 (gene set migration) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1762 | HOXD12 | Zornitza Stark Marked gene: HOXD12 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1762 | HOXD12 | Zornitza Stark Gene: hoxd12 has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1762 | HOXD12 | Zornitza Stark Classified gene: HOXD12 as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1762 | HOXD12 | Zornitza Stark Gene: hoxd12 has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1761 | HOXD12 | Zornitza Stark reviewed gene: HOXD12: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Clubfoot (non-syndromic) MONDO:0007342; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1758 | HOXD12 |
Sangavi Sivagnanasundram gene: HOXD12 was added gene: HOXD12 was added to Mendeliome. Sources: Other Mode of inheritance for gene: HOXD12 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: HOXD12 were set to 38663984 Phenotypes for gene: HOXD12 were set to Clubfoot (non-syndromic) MONDO:0007342 Mode of pathogenicity for gene: HOXD12 was set to Other Review for gene: HOXD12 was set to GREEN Added comment: Novel gene-disease association with non-syndromic clubfoot. 10 variants in HOXD12 have been reported in individuals with clubfoot (variants are predominantly missense variants however one rare deletion has been reported). PMID: 38663984 Around 9 individuals from 4 unrelated families have been reported with clubfoot and the variants were shown to segregate. N-terminal region and C-terminal homeobox domain of HOXD12 are known to be clusters for pathogenic variants related to clubfoot. Loss of function variants are less likely to contribute to clubfoot pathogenesis therefore mechanism of disease is suggested as dominant negative but is not confirmed. Sources: Other |
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