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| Limb disorders v2.78 | IHH | Arina Puzriakova Phenotypes for gene: IHH were changed from Acrocapitofemoral dysplasia 607778; Brachydactyly, type A1 112500; syndactyly and craniosynostosis; F syndrome to Acrocapitofemoral dysplasia, OMIM:607778; Brachydactyly, type A1, OMIM:112500 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Limb disorders v1.137 | EPHA4 |
Eleanor Williams changed review comment from: EPHA4 not associated with any phenotype in OMIM or Gene2Phenotype. PMID: 25959774 - Lupiáñez et al 2015 - studied limb abnormalities in 3 sets of families: Group 1 - 3 unrelated families with a dominantly inherited novel type of brachydactyly, characterized by short digits predominantly on the preaxial (radial) side resulting in stub thumbs, short index fingers and a cutaneous web between the first and second fingers. aCGH revealed heterozygous deletions of 1.75–1.9 Mb on chromosome 2q35–36 in all three affected families. All three deletions include the EPHA4 gene along with a large portion of its surrounding TAD and extend into the non-coding part of the adjacent PAX3 TAD (topologically associated domain), thereby removing the predicted boundary between the EPHA4 and PAX3 TADs. Mutant mice with a deletion corresponding to the human disease alleles recapitulated the phenotype observed in patients. Group 2 - 2 unrelated families with F-syndrome, a limb malformation syndrome characterized by severe and complex syndactyly, often involving the first and second fingers, and polydactyly of the feet. By whole genome sequencing they detected a ~1.1 Mb heterozygous inversion in family F1 and a ~1.4 Mb heterozygous duplication, arranged in direct tandem orientation, in family F2. The telomeric breakpoints were located 1.4 Mb away from the EPHA4 gene within the gene desert in the case of the inversion, and 1.2 Mb in the case of the duplication. Heterozygous as well as homozygous newborn mice generated via tetraploid aggregation died shortly after birth of unknown cause and did not show overt limb phenotypes or other morphological defects Group 3 - a family that carries a heterozygous ~900 kb duplication in chromosomal region 2q35 that results in severe polysyndactyly and craniofacial abnormalities. The phenotype is reminiscent of the doublefoot (Dbf) mouse mutant, which also features massive polysyndactyly and was shown to be caused by a ~600 kb deletion affecting the same region (Babbs et al., 2008) Using 4C-seq they show that In wild-type distal limbs, there was minimal interaction of Pax3, Wnt6 and Ihh with non-coding sequences in the Epha4 TAD. In contrast, all three genes showed substantial interaction with the Epha4 TAD in the mutants. Similar results were found using patient fibroblasts. Genomic re-arrangements in the Epha4 TAD can result in limb abnormalities. It maybe best to represent these as regions of gain or loss in PanelApp; to: EPHA4 not associated with any phenotype in OMIM or Gene2Phenotype. PMID: 25959774 - Lupiáñez et al 2015 - studied limb abnormalities in 3 sets of families: Group 1 - 3 unrelated families with a dominantly inherited novel type of brachydactyly, characterized by short digits predominantly on the preaxial (radial) side resulting in stub thumbs, short index fingers and a cutaneous web between the first and second fingers. aCGH revealed heterozygous deletions of 1.75–1.9 Mb on chromosome 2q35–36 in all three affected families. All three deletions include the EPHA4 gene along with a large portion of its surrounding TAD and extend into the non-coding part of the adjacent PAX3 TAD (topologically associated domain), thereby removing the predicted boundary between the EPHA4 and PAX3 TADs. Mutant mice with a deletion corresponding to the human disease alleles recapitulated the phenotype observed in patients. They detected a significant upregulation of Pax3 in DelB/+ limbs in mice, and DelB/+ (brachydactyly-like deletion) mice showed strong misexpression of Pax3 in the distal anterior part of the autopod, in a pattern resembling endogenous Epha4 expression. Group 2 - 2 unrelated families with F-syndrome, a limb malformation syndrome characterized by severe and complex syndactyly, often involving the first and second fingers, and polydactyly of the feet. By whole genome sequencing they detected a ~1.1 Mb heterozygous inversion in family F1 and a ~1.4 Mb heterozygous duplication, arranged in direct tandem orientation, in family F2. The telomeric breakpoints were located 1.4 Mb away from the EPHA4 gene within the gene desert in the case of the inversion, and 1.2 Mb in the case of the duplication. Heterozygous as well as homozygous newborn mice generated via tetraploid aggregation died shortly after birth of unknown cause and did not show overt limb phenotypes or other morphological defects Group 3 - a family that carries a heterozygous ~900 kb duplication in chromosomal region 2q35 that results in severe polysyndactyly and craniofacial abnormalities. The phenotype is reminiscent of the doublefoot (Dbf) mouse mutant, which also features massive polysyndactyly and was shown to be caused by a ~600 kb deletion affecting the same region (Babbs et al., 2008) Using 4C-seq they show that In wild-type distal limbs, there was minimal interaction of Pax3, Wnt6 and Ihh with non-coding sequences in the Epha4 TAD. In contrast, all three genes showed substantial interaction with the Epha4 TAD in the mutants. Similar results were found using patient fibroblasts. Genomic re-arrangements in the Epha4 TAD can result in limb abnormalities. It maybe best to represent these as regions of gain or loss in PanelApp |
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| Limb disorders v1.129 | IHH | Eleanor Williams Phenotypes for gene: IHH were changed from Acrocapitofemoral dysplasia 607778; Brachydactyly, type A1 112500; syndactyly and craniosynostosis to Acrocapitofemoral dysplasia 607778; Brachydactyly, type A1 112500; syndactyly and craniosynostosis; F syndrome | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Limb disorders v1.128 | IHH | Eleanor Williams Publications for gene: IHH were set to 21167467 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Limb disorders v1.127 | IHH | Eleanor Williams commented on gene: IHH | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Limb disorders v1.56 | EPHA4 |
Eleanor Williams commented on gene: EPHA4: EPHA4 not associated with any phenotype in OMIM or Gene2Phenotype. PMID: 25959774 - Lupiáñez et al 2015 - studied limb abnormalities in 3 sets of families: Group 1 - 3 unrelated families with a dominantly inherited novel type of brachydactyly, characterized by short digits predominantly on the preaxial (radial) side resulting in stub thumbs, short index fingers and a cutaneous web between the first and second fingers. aCGH revealed heterozygous deletions of 1.75–1.9 Mb on chromosome 2q35–36 in all three affected families. All three deletions include the EPHA4 gene along with a large portion of its surrounding TAD and extend into the non-coding part of the adjacent PAX3 TAD (topologically associated domain), thereby removing the predicted boundary between the EPHA4 and PAX3 TADs. Mutant mice with a deletion corresponding to the human disease alleles recapitulated the phenotype observed in patients. Group 2 - 2 unrelated families with F-syndrome, a limb malformation syndrome characterized by severe and complex syndactyly, often involving the first and second fingers, and polydactyly of the feet. By whole genome sequencing they detected a ~1.1 Mb heterozygous inversion in family F1 and a ~1.4 Mb heterozygous duplication, arranged in direct tandem orientation, in family F2. The telomeric breakpoints were located 1.4 Mb away from the EPHA4 gene within the gene desert in the case of the inversion, and 1.2 Mb in the case of the duplication. Heterozygous as well as homozygous newborn mice generated via tetraploid aggregation died shortly after birth of unknown cause and did not show overt limb phenotypes or other morphological defects Group 3 - a family that carries a heterozygous ~900 kb duplication in chromosomal region 2q35 that results in severe polysyndactyly and craniofacial abnormalities. The phenotype is reminiscent of the doublefoot (Dbf) mouse mutant, which also features massive polysyndactyly and was shown to be caused by a ~600 kb deletion affecting the same region (Babbs et al., 2008) Using 4C-seq they show that In wild-type distal limbs, there was minimal interaction of Pax3, Wnt6 and Ihh with non-coding sequences in the Epha4 TAD. In contrast, all three genes showed substantial interaction with the Epha4 TAD in the mutants. Similar results were found using patient fibroblasts. Genomic re-arrangements in the Epha4 TAD can result in limb abnormalities. It maybe best to represent these as regions of gain or loss in PanelApp |
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| Limb disorders | IHH | Ellen McDonagh Added gene to panel | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||