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| Limb disorders v1.127 | LMBR1 |
Eleanor Williams changed review comment from: Variants within LMBR1 coding sequence: PMID:11090342 - Ianakiev et al - 2001- found a genomic 4- to 6-kb deletion in LMBR1 in 5 unrelated Brazilian families with acheiropody. The deletion led to a trascript lacking exon 4 and introducing a premature stop codon downstream of exon 3. Haplotype analysis confirmed the expectation that a single common ancestral mutation was the cause of all the cases. PMID: 26749485 - Shamseldin et al 2016 - patient with acheiropodia who had a nullizygous deletion of 102 kb spanning LMBR1. The ZRS is a sonic hedgehog (SHH) regulatory region of approx 800bp. It is not thought to affect the expression LMBR1. Variants and duplications affecting the zone of polarizing activity regulatory sequence (ZRS) within intron 5 of the LMBR1 gene: Numerous reports of heterozygous variants in ZRS being associated with preaxial polydactyly/Werner mesomelic syndrome - (PMID: 31395945 - Xu et al 2019 - 1 case, 446T>A ZRS), (PMID: 19847792 Wieczorek et al. (2010) - 2 cases with variants 404G>A and 404G>C ZRS), (PMID: 24965254 Norbnop et al. (2014) - 2 cases, one familial and one sporadic with 406A>G and 404G>A ZRS variants), (PMID: 24777739 - VanderMeer et al. (2014) - 1 case - 5 generation family with a c.402C->T variant (A more severely affected daughter was homozygous for the same mutation)). Other cases listed in OMIM. PMID: 28127823 - Xiang et al 2017 - report 6/102 of patients with preaxial polydactyly type I with variants in a region upstream of the ZRS. Reports of duplications covering parts of the ZRS also being associated with a limb phenotype. PMID: 19847792 - Wieczorek et al. (2010) - report 2 families (families 3 and 4) with duplications (73-kb and 276-kb) affecting the ZRS region. Members of family 3 had Haas type polysyndactyly and family 4 had triphalangeal thumb-polysyndactyly syndrome. PMID: 18178630 - Klopocki et al 2008 - report a large 4-generation pedigree with variable triphalangeal thumb and polysyndactyly, No point mutations found in the LMBR1 gene but array CGH analysis identified a heterozygous 589-kb duplication comprising the ZRS. PMID: 18417549 - Sun et al 2009 - in 6 Han Chinese families with Triphalangeal thumb-polysyndactyly syndrome they identified duplications of ZRS which segregated with the limb phenotypes in all families. PMID: 19291772 - Wu et al 2009 - in a Chinese family with type IV syndactyly and tibial hypoplasia they detected a duplication of between 105 to 115 kb. PMID: 24456159 - Lohan et al 2104 - report on 5 unrelated families with overlapping microduplications encompassing the ZPA regulatory sequence. Larger duplications of the ZRS region (>80 kb) are associated with Haas-type polysyndactyly, whereas smaller duplications (<80 kb) result in a Laurin-Sandrow syndrome phenotype. Summary: > 3 cases where SNVs in the ZRS are found in patients with polydactyly. In >3 cases duplications covering parts of the ZRS were found in patients with a limb phenotype. Currently variants in the ZRS would NOT be reported via WGS. Duplications > 10Kb covering the LMBR1 gene would be picked up as the gene is green.; to: Variants within LMBR1 coding sequence: PMID:11090342 - Ianakiev et al - 2001- found a genomic 4- to 6-kb deletion in LMBR1 in 5 unrelated Brazilian families with acheiropody. The deletion led to a trascript lacking exon 4 and introducing a premature stop codon downstream of exon 3. Haplotype analysis confirmed the expectation that a single common ancestral mutation was the cause of all the cases. PMID: 26749485 - Shamseldin et al 2016 - patient with acheiropodia who had a nullizygous deletion of 102 kb spanning LMBR1. The ZRS (zone of polarizing activity regulatory sequence) is a sonic hedgehog (SHH) regulatory region of approx 800bp. It is not thought to affect the expression LMBR1. Variants and duplications affecting the ZRS within intron 5 of the LMBR1 gene: Numerous reports of heterozygous variants in ZRS being associated with preaxial polydactyly/Werner mesomelic syndrome - (PMID: 31395945 - Xu et al 2019 - 1 case, 446T>A ZRS), (PMID: 19847792 Wieczorek et al. (2010) - 2 cases with variants 404G>A and 404G>C ZRS), (PMID: 24965254 Norbnop et al. (2014) - 2 cases, one familial and one sporadic with 406A>G and 404G>A ZRS variants), (PMID: 24777739 - VanderMeer et al. (2014) - 1 case - 5 generation family with a c.402C->T variant (A more severely affected daughter was homozygous for the same mutation)). Other cases listed in OMIM. PMID: 28127823 - Xiang et al 2017 - report 6/102 of patients with preaxial polydactyly type I with variants in a region upstream of the ZRS. Reports of duplications covering parts of the ZRS also being associated with a limb phenotype. PMID: 19847792 - Wieczorek et al. (2010) - report 2 families (families 3 and 4) with duplications (73-kb and 276-kb) affecting the ZRS region. Members of family 3 had Haas type polysyndactyly and family 4 had triphalangeal thumb-polysyndactyly syndrome. PMID: 18178630 - Klopocki et al 2008 - report a large 4-generation pedigree with variable triphalangeal thumb and polysyndactyly, No point mutations found in the LMBR1 gene but array CGH analysis identified a heterozygous 589-kb duplication comprising the ZRS. PMID: 18417549 - Sun et al 2009 - in 6 Han Chinese families with Triphalangeal thumb-polysyndactyly syndrome they identified duplications of ZRS which segregated with the limb phenotypes in all families. PMID: 19291772 - Wu et al 2009 - in a Chinese family with type IV syndactyly and tibial hypoplasia they detected a duplication of between 105 to 115 kb. PMID: 24456159 - Lohan et al 2104 - report on 5 unrelated families with overlapping microduplications encompassing the ZPA regulatory sequence. Larger duplications of the ZRS region (>80 kb) are associated with Haas-type polysyndactyly, whereas smaller duplications (<80 kb) result in a Laurin-Sandrow syndrome phenotype. Summary: > 3 cases where SNVs in the ZRS are found in patients with polydactyly. In >3 cases duplications covering parts of the ZRS were found in patients with a limb phenotype. Currently variants in the ZRS would NOT be reported via WGS. Duplications > 10Kb covering the LMBR1 gene would be picked up as the gene is green. |
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| Limb disorders v1.127 | LMBR1 |
Eleanor Williams changed review comment from: Variants within LMBR1 coding sequence: PMID:11090342 - Ianakiev et al - 2001- found a genomic 4- to 6-kb deletion in LMBR1 in 5 unrelated Brazilian families with acheiropody. The deletion led to a trascript lacking exon 4 and introducing a premature stop codon downstream of exon 3. Haplotype analysis confirmed the expectation that a single common ancestral mutation was the cause of all the cases. PMID: 26749485 - Shamseldin et al 2016 - patient with acheiropodia who had a nullizygous deletion of 102 kb spanning LMBR1. The ZRS is a sonic hedgehog (SHH) regulatory region of approx 800bp. It is not thought to affect the expression LMBR1. Variants and duplications affecting the zone of polarizing activity regulatory sequence (ZRS) within intron 5 of the LMBR1 gene: Numerous reports of heterozygous variants in ZRS being associated with preaxial polydactyly/Werner mesomelic syndrome - (PMID: 31395945 - Xu et al 2019 - 1 case, 446T>A ZRS), (PMID: 19847792 Wieczorek et al. (2010) - 2 cases with variants 404G>A and 404G>C ZRS), (PMID: 24965254 Norbnop et al. (2014) - 2 cases, one familial and one sporadic with 406A>G and 404G>A ZRS variants), (PMID: 24777739 - VanderMeer et al. (2014) - 1 case - 5 generation family with a c.402C->T variant (A more severely affected daughter was homozygous for the same mutation)). Other cases listed in OMIM. PMID: 28127823 - Xiang et al 2017 - report 6/102 of patients with preaxial polydactyly type I with variants in a region upstream of the ZRS. Reports of duplications covering parts of the ZRS also being associated with a limb phenotype. PMID: 19847792 - Wieczorek et al. (2010) - report 2 families (families 3 and 4) with duplications (73-kb and 276-kb) affecting the ZRS region. Members of family 3 had Haas type polysyndactyly and family 4 had triphalangeal thumb-polysyndactyly syndrome. PMID: 18178630 - Klopocki et al 2008 - report a large 4-generation pedigree with variable triphalangeal thumb and polysyndactyly, No point mutations found in the LMBR1 gene but array CGH analysis identified a heterozygous 589-kb duplication comprising the ZRS. PMID: 18417549 - Sun et al 2009 - in 6 Han Chinese families with Triphalangeal thumb-polysyndactyly syndrome they identified duplications of ZRS which segregated with the limb phenotypes in all families. PMID: 19291772 - Wu et al 2009 - in a Chinese family with type IV syndactyly and tibial hypoplasia they detected a duplication of between 105 to 115 kb. Summary: > 3 cases where SNVs in the ZRS are found in patients with polydactyly. In >3 cases duplications covering parts of the ZRS were found in patients with a limb phenotype. Currently variants in the ZRS would NOT be reported via WGS. Duplications > 10Kb covering the LMBR1 gene would be picked up as the gene is green.; to: Variants within LMBR1 coding sequence: PMID:11090342 - Ianakiev et al - 2001- found a genomic 4- to 6-kb deletion in LMBR1 in 5 unrelated Brazilian families with acheiropody. The deletion led to a trascript lacking exon 4 and introducing a premature stop codon downstream of exon 3. Haplotype analysis confirmed the expectation that a single common ancestral mutation was the cause of all the cases. PMID: 26749485 - Shamseldin et al 2016 - patient with acheiropodia who had a nullizygous deletion of 102 kb spanning LMBR1. The ZRS is a sonic hedgehog (SHH) regulatory region of approx 800bp. It is not thought to affect the expression LMBR1. Variants and duplications affecting the zone of polarizing activity regulatory sequence (ZRS) within intron 5 of the LMBR1 gene: Numerous reports of heterozygous variants in ZRS being associated with preaxial polydactyly/Werner mesomelic syndrome - (PMID: 31395945 - Xu et al 2019 - 1 case, 446T>A ZRS), (PMID: 19847792 Wieczorek et al. (2010) - 2 cases with variants 404G>A and 404G>C ZRS), (PMID: 24965254 Norbnop et al. (2014) - 2 cases, one familial and one sporadic with 406A>G and 404G>A ZRS variants), (PMID: 24777739 - VanderMeer et al. (2014) - 1 case - 5 generation family with a c.402C->T variant (A more severely affected daughter was homozygous for the same mutation)). Other cases listed in OMIM. PMID: 28127823 - Xiang et al 2017 - report 6/102 of patients with preaxial polydactyly type I with variants in a region upstream of the ZRS. Reports of duplications covering parts of the ZRS also being associated with a limb phenotype. PMID: 19847792 - Wieczorek et al. (2010) - report 2 families (families 3 and 4) with duplications (73-kb and 276-kb) affecting the ZRS region. Members of family 3 had Haas type polysyndactyly and family 4 had triphalangeal thumb-polysyndactyly syndrome. PMID: 18178630 - Klopocki et al 2008 - report a large 4-generation pedigree with variable triphalangeal thumb and polysyndactyly, No point mutations found in the LMBR1 gene but array CGH analysis identified a heterozygous 589-kb duplication comprising the ZRS. PMID: 18417549 - Sun et al 2009 - in 6 Han Chinese families with Triphalangeal thumb-polysyndactyly syndrome they identified duplications of ZRS which segregated with the limb phenotypes in all families. PMID: 19291772 - Wu et al 2009 - in a Chinese family with type IV syndactyly and tibial hypoplasia they detected a duplication of between 105 to 115 kb. PMID: 24456159 - Lohan et al 2104 - report on 5 unrelated families with overlapping microduplications encompassing the ZPA regulatory sequence. Larger duplications of the ZRS region (>80 kb) are associated with Haas-type polysyndactyly, whereas smaller duplications (<80 kb) result in a Laurin-Sandrow syndrome phenotype. Summary: > 3 cases where SNVs in the ZRS are found in patients with polydactyly. In >3 cases duplications covering parts of the ZRS were found in patients with a limb phenotype. Currently variants in the ZRS would NOT be reported via WGS. Duplications > 10Kb covering the LMBR1 gene would be picked up as the gene is green. |
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| Limb disorders v1.127 | SHH | Eleanor Williams changed review comment from: Variants and duplications in the ZRS region within intron LMBR1 which affect the expression of SHH have been reviewed in gene LMBR1 on this panel.; to: Variants and duplications in the regulatory ZRS region within intron LMBR1 which affect the expression of SHH have been reviewed in gene LMBR1 on this panel. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Limb disorders v1.127 | SHH | Eleanor Williams commented on gene: SHH: Variants and duplications in the ZRS region within intron LMBR1 which affect the expression of SHH have been reviewed in gene LMBR1 on this panel. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Limb disorders v1.127 | LMBR1 |
Eleanor Williams changed review comment from: Variants within the zone of polarizing activity regulatory sequence (ZRS) within intron 5 of the LMBR1 gene are thought to lead to Preaxial polydactyly. The ZRS is a sonic hedgehog (SHH) regulatory region. It is not thought to affect the expression LMBR1. PMID: 31395945 - Xu et al 2019 - large 4 generation family with isolated preaxial polydactyly. A novel 446T>A ZRS) variant segregates with all PPD I–affected individuals. A knockin mouse with this ZRS variant exhibited PPD I phenotype accompanying ectopic and excess expression of Shh. PMID: 19847792 Wieczorek et al. (2010) - report 2 families (Turkish and Brazilian) with Werner mesomelic syndrome (hypo- or aplasia of the tibiae in addition to the preaxial polydactyly (PPD) of the hands and feet ) with variants in the ZRS region (404G>A and 404G>C). Two other families (families 3 and 4) were reported with duplications (73-kb and 276-kb) affecting the ZRS region. Members of family 3 had Haas type polysyndactyly and family 4 had triphalangeal thumb-polysyndactyly syndrome. PMID: 24965254 Norbnop et al. (2014) - report 2 Thai cases of Werner mesomelic syndrome, one familial with a heterozygous 406A>G variant in the ZRS and one sporadic with a heterozygous 404G>A ZRS mutation. PMID: 24777739 - VanderMeer et al. (2014) - large 5-generation Mexican kindred where affect individuals (with isolated triphalangeal thumb, or preaxial polydactyly with triphalangeal thumbs) were heterozygous for a c.402C->T variant in ZRS region of LMBR1. A more severely affected daughter was homozygous for the same mutation. Summary: > 3 cases where variants in the ZRS are found in patients with polydactyly. In 2 cases duplications covering parts of the ZRS were found in patients with polydactyly. Currently variants in the ZRS would NOT be reported via WGS. Duplications > 10Kb covering the LMBR1 gene would be picked up as the gene is green.; to: Variants within LMBR1 coding sequence: PMID:11090342 - Ianakiev et al - 2001- found a genomic 4- to 6-kb deletion in LMBR1 in 5 unrelated Brazilian families with acheiropody. The deletion led to a trascript lacking exon 4 and introducing a premature stop codon downstream of exon 3. Haplotype analysis confirmed the expectation that a single common ancestral mutation was the cause of all the cases. PMID: 26749485 - Shamseldin et al 2016 - patient with acheiropodia who had a nullizygous deletion of 102 kb spanning LMBR1. The ZRS is a sonic hedgehog (SHH) regulatory region of approx 800bp. It is not thought to affect the expression LMBR1. Variants and duplications affecting the zone of polarizing activity regulatory sequence (ZRS) within intron 5 of the LMBR1 gene: Numerous reports of heterozygous variants in ZRS being associated with preaxial polydactyly/Werner mesomelic syndrome - (PMID: 31395945 - Xu et al 2019 - 1 case, 446T>A ZRS), (PMID: 19847792 Wieczorek et al. (2010) - 2 cases with variants 404G>A and 404G>C ZRS), (PMID: 24965254 Norbnop et al. (2014) - 2 cases, one familial and one sporadic with 406A>G and 404G>A ZRS variants), (PMID: 24777739 - VanderMeer et al. (2014) - 1 case - 5 generation family with a c.402C->T variant (A more severely affected daughter was homozygous for the same mutation)). Other cases listed in OMIM. PMID: 28127823 - Xiang et al 2017 - report 6/102 of patients with preaxial polydactyly type I with variants in a region upstream of the ZRS. Reports of duplications covering parts of the ZRS also being associated with a limb phenotype. PMID: 19847792 - Wieczorek et al. (2010) - report 2 families (families 3 and 4) with duplications (73-kb and 276-kb) affecting the ZRS region. Members of family 3 had Haas type polysyndactyly and family 4 had triphalangeal thumb-polysyndactyly syndrome. PMID: 18178630 - Klopocki et al 2008 - report a large 4-generation pedigree with variable triphalangeal thumb and polysyndactyly, No point mutations found in the LMBR1 gene but array CGH analysis identified a heterozygous 589-kb duplication comprising the ZRS. PMID: 18417549 - Sun et al 2009 - in 6 Han Chinese families with Triphalangeal thumb-polysyndactyly syndrome they identified duplications of ZRS which segregated with the limb phenotypes in all families. PMID: 19291772 - Wu et al 2009 - in a Chinese family with type IV syndactyly and tibial hypoplasia they detected a duplication of between 105 to 115 kb. Summary: > 3 cases where SNVs in the ZRS are found in patients with polydactyly. In >3 cases duplications covering parts of the ZRS were found in patients with a limb phenotype. Currently variants in the ZRS would NOT be reported via WGS. Duplications > 10Kb covering the LMBR1 gene would be picked up as the gene is green. |
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| Limb disorders v0.275 | SHH | Eleanor Williams Marked gene: SHH as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Limb disorders v0.275 | SHH | Eleanor Williams Gene: shh has been classified as Red List (Low Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Limb disorders v0.271 | SHH |
Eleanor Williams Mode of inheritance for gene SHH was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Added phenotypes Preaxial polydactyly; Polydactyly for gene: SHH Publications for gene SHH were changed from 12032320; 12837695; 25782671 to 25782671; 12837695; 12032320 |
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| Limb disorders v0.270 | SHH | Louise Daugherty reviewed gene: SHH: Rating: RED; Mode of pathogenicity: ; Publications: 12032320, 12837695, 25782671; Phenotypes: Preaxial polydactyly, Polydactyly; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Limb disorders v0.146 | SHH | Eleanor Williams commented on gene: SHH | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Limb disorders | SHH | Rachel Jones reviewed SHH | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Limb disorders | SHH | Sarah Leigh edited their review of SHH | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Limb disorders | SHH | Ellen McDonagh classified SHH as Red List (low evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Limb disorders | SHH | Dimitris Polychronopoulos Added gene to panel | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||