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27 Jan 2025	Skeletal dysplasia v7.15	BTRC	Eleanor Williams gene: BTRC was added gene: BTRC was added to Skeletal dysplasia. Sources: Literature Mode of inheritance for gene: BTRC was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: BTRC were set to 19584065; 18067070; 12913067; 16681918; 27600068; 30622331; 35908152; 36928426; 18392654 Phenotypes for gene: BTRC were set to Split-hand/foot malformation 3, gene duplication syndrome, OMIM:246560; split hand-foot malformation 3, MONDO:0009525 Mode of pathogenicity for gene: BTRC was set to Other Review for gene: BTRC was set to AMBER Added comment: In OMIM Split-hand/foot malformation 3, gene duplication syndrome (OMIM:246560) is linked to a duplication at 10q24q25 inherited in an autosomal dominant manner and is characterized by the absence of central digits. Gene2Phenotype and ClinGen do not list this gene associated with any phenotype. Multiple publications have reported patients with SHFM3 and rearrangements covering a 500 kb region encompassing five genes of the locus (LBX1, BTRC, POLL, DPCD, and a partial portion of FBXW4) but excluding the neighbouring FGF8 e.g. PMID: 12913067 (2003), PMID: 16681918 (2006). Subsequent reports have reported various re-arrangements involving different sets of genes in the region. Examples are: PMID: 27600068 Li et al 2015 - mapped the breakpoints of cases with duplications in the 10q24 region with and without a SHFM3 phenotype and concluded that the critical region responsible for the SHFM phenotypes is most likely located at exon 1 of BTRC gene, which is duplicated in all cases with SHFM phenotypes. PMID: 30622331 Holder-Espinasse et al 2019 - used array CGH or qPCR to analyse 32 new index cases of 10q24 duplication (22 SHFM including 3 with preaxial polydactyly, 7 monodactylies and 3 patients presenting overlapping phenotypes). 17 cases were familial and 15 occurred de novo. Studies in 4 families showed that the duplication segregated with the phenotype. All cases tested by array-CGH had duplication of at least BTRC and POLL genes. Seven cases had duplication of LBX1 gene as well and 12 patients had duplications comprising the FBXW4 gene (although partially for cases 24 and 27). PMID: 35908152 - Qui et al 2022 - using trio clinical exome sequencing, a 120 kb microduplication containing only BTRC were identified in a Chinese family affected with SHFM3. The duplication co-segregated with SHFM phenotypes in the family. Transcription levels of BTRC mRNA in lymphocytes of the proband was significantly higher than in the healthy control. PMID: 36928426 Cova et al 2023 - show that the Lbx1/Fgf8 locus consists of two separate, but interacting, regulatory domains. By re-engineering a human SHFM3-associated duplication in mice they observed ectopic interactions between the Fgf8 apical ectodermal ridge (AER) enhancers and two other genes in the locus, Lbx1 and Btrc. The same ectopic interactions were present in fibroblasts from a SHFM3 affected individual with duplication. In mice with the duplication a limb malformation was not observed. They also report a case of SHFM3 malformation associated with an inversion encompassing the DPDC, POLL and FBXW4 genes which when re-engineered in mice results in increased expression of genes, Lbx1 and Btrc, in an Fgf8-like pattern in the apical ectodermal ridge. Mice with the inversion were observed to have a digit phenotype. In conclusion, point mutations in BTRC in association with SHFM3 have not been reported. It appears that changed expression of gene BTRC is related to the phenotype, but that expression levels can be impacted by both duplication of the region itself and inversion of other nearby regions, likely by disruption of regulatory domains. Sources: Literature
27 Jan 2025	Skeletal dysplasia v7.14	FBXW4	Eleanor Williams Phenotypes for gene: FBXW4 were changed from Split-hand/foot malformation 3 syndrome, OMIM:246560; split hand-foot malformation 3, MONDO:0009525 to Split-hand/foot malformation 3, gene duplication syndrome, OMIM:246560; split hand-foot malformation 3, MONDO:0009525
27 Jan 2025	Skeletal dysplasia v7.13	FBXW4	Eleanor Williams Publications for gene: FBXW4 were set to 19584065; 18067070
27 Jan 2025	Skeletal dysplasia v7.12	FBXW4	Eleanor Williams Source was removed from FBXW4.
27 Jan 2025	Skeletal dysplasia v7.11	FBXW4	Eleanor Williams Tag currently-ngs-unreportable was removed from gene: FBXW4.
27 Jan 2025	Skeletal dysplasia v7.11	FBXW4	Eleanor Williams Classified gene: FBXW4 as Amber List (moderate evidence)
27 Jan 2025	Skeletal dysplasia v7.11	FBXW4	Eleanor Williams Added comment: Comment on list classification: Promoting to amber. There is some evidence from both patient cases and mouse models that disruptions within this gene can result in a split-hand/foot malformation phenotype. However, it is not clear exactly which disruptions are causative since duplications frequently span more than this gene.
27 Jan 2025	Skeletal dysplasia v7.11	FBXW4	Eleanor Williams Gene: fbxw4 has been classified as Amber List (Moderate Evidence).
27 Jan 2025	Skeletal dysplasia v7.10	FBXW4	Eleanor Williams Phenotypes for gene: FBXW4 were changed from Split-hand/foot malformation 3 syndrome 246560 to Split-hand/foot malformation 3 syndrome, OMIM:246560; split hand-foot malformation 3, MONDO:0009525
27 Jan 2025	Skeletal dysplasia v7.9	FBXW4	Eleanor Williams Mode of inheritance for gene: FBXW4 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
27 Jan 2025	Skeletal dysplasia v7.8	FBXW4	Eleanor Williams changed review comment from: In OMIM Split-hand/foot malformation 3, gene duplication syndrome (OMIM:246560) is linked to a duplication at 10q24q25 inherited in an autosomal dominant manner and is characterized by the absence of central digits. Multiple publications have reported patients with SHFM3 and rearrangements covering a 500 kb region encompassing five genes of the locus (LBX1, BTRC, POLL, DPCD, and a partial portion of FBXW4) but excluding the neighbouring FGF8 e.g. PMID: 12913067 (2003), PMID: 16681918 (2006). Subsequent reports have reported various re-arrangements involving different sets of genes in the region. Examples are: PMID: 27600068 Li et al 2015 - mapped the breakpoints of cases with duplications in the 10q24 region with and without a SHFM3 phenotype and concluded that the critical region responsible for the SHFM phenotypes is most likely located at exon 1 of BTRC gene, which is duplicated in all cases with SHFM phenotypes. PMID: 30622331 Holder-Espinasse et al 2019 - used array CGH or qPCR to analyse 32 new index cases of 10q24 duplication (22 SHFM including 3 with preaxial polydactyly, 7 monodactylies and 3 patients presenting overlapping phenotypes). 17 cases were familial and 15 occurred de novo. Studies in 4 families showed that the duplication segregated with the phenotype. All cases tested by array-CGH had duplication of at least BTRC and POLL genes. Seven cases had duplication of LBX1 gene as well and 12 patients had duplications comprising the FBXW4 gene (although partially for cases 24 and 27). PMID: 35908152 - Qui et al 2022 - using trio clinical exome sequencing, a 120 kb microduplication containing only BTRC were identified in a Chinese family affected with SHFM3. The duplication co-segregated with SHFM phenotypes in the family. Transcription levels of BTRC mRNA in lymphocytes of the proband was significantly higher than in the healthy control. PMID: 36928426 Cova et al 2023 - show that the Lbx1/Fgf8 locus consists of two separate, but interacting, regulatory domains. By re-engineering a human SHFM3-associated duplication in mice they observed ectopic interactions between the Fgf8 apical ectodermal ridge (AER) enhancers and two other genes in the locus, Lbx1 and Btrc. The same ectopic interactions were present in fibroblasts from a SHFM3 affected individual with duplication. In mice with the duplication a limb malformation was not observed. They also report a case of SHFM3 malformation associated with an inversion encompassing the DPDC, POLL and FBXW4 genes which when re-engineered in mice results in increased expression of genes, Lbx1 and Btrc, in an Fgf8-like pattern in the apical ectodermal ridge. Mice with the inversion were observed to have a digit phenotype. Mouse model: PMID: 18392654 - Friedli et al 2008 - show that in Dactylaplasia mice which show a digital phenotype both Dac1j and Dac2j alleles are caused by insertions of MusD retroelements either within or close to the gene Fbxw4. They propose that both mutations result in complex alterations of gene regulation. In conclusion, point mutations in FBXW4 in association with SHFM3 have not been reported. It appears that changed expression of gene BTRC is related to the phenotype, but that expression levels can be impacted by both duplication of the region itself and inversion of other nearby regions, by disruption of regulatory domains.; to: In OMIM Split-hand/foot malformation 3, gene duplication syndrome (OMIM:246560) is linked to a duplication at 10q24q25 inherited in an autosomal dominant manner and is characterized by the absence of central digits. In Gene2Phenotype the association of FBXW4 with SHFM3 has been rated limited. ClinGen report no evidence for haplo or triplosensitivity in relation to SHFM3 but this has not been re-assessed since 2014. Multiple publications have reported patients with SHFM3 and rearrangements covering a 500 kb region encompassing five genes of the locus (LBX1, BTRC, POLL, DPCD, and a partial portion of FBXW4) but excluding the neighbouring FGF8 e.g. PMID: 12913067 (2003), PMID: 16681918 (2006). Subsequent reports have reported various re-arrangements involving different sets of genes in the region. Examples are: PMID: 27600068 Li et al 2015 - mapped the breakpoints of cases with duplications in the 10q24 region with and without a SHFM3 phenotype and concluded that the critical region responsible for the SHFM phenotypes is most likely located at exon 1 of BTRC gene, which is duplicated in all cases with SHFM phenotypes. PMID: 30622331 Holder-Espinasse et al 2019 - used array CGH or qPCR to analyse 32 new index cases of 10q24 duplication (22 SHFM including 3 with preaxial polydactyly, 7 monodactylies and 3 patients presenting overlapping phenotypes). 17 cases were familial and 15 occurred de novo. Studies in 4 families showed that the duplication segregated with the phenotype. All cases tested by array-CGH had duplication of at least BTRC and POLL genes. Seven cases had duplication of LBX1 gene as well and 12 patients had duplications comprising the FBXW4 gene (although partially for cases 24 and 27). PMID: 35908152 - Qui et al 2022 - using trio clinical exome sequencing, a 120 kb microduplication containing only BTRC were identified in a Chinese family affected with SHFM3. The duplication co-segregated with SHFM phenotypes in the family. Transcription levels of BTRC mRNA in lymphocytes of the proband was significantly higher than in the healthy control. PMID: 36928426 Cova et al 2023 - show that the Lbx1/Fgf8 locus consists of two separate, but interacting, regulatory domains. By re-engineering a human SHFM3-associated duplication in mice they observed ectopic interactions between the Fgf8 apical ectodermal ridge (AER) enhancers and two other genes in the locus, Lbx1 and Btrc. The same ectopic interactions were present in fibroblasts from a SHFM3 affected individual with duplication. In mice with the duplication a limb malformation was not observed. They also report a case of SHFM3 malformation associated with an inversion encompassing the DPDC, POLL and FBXW4 genes which when re-engineered in mice results in increased expression of genes, Lbx1 and Btrc, in an Fgf8-like pattern in the apical ectodermal ridge. Mice with the inversion were observed to have a digit phenotype. Mouse model: PMID: 18392654 - Friedli et al 2008 - show that in Dactylaplasia mice which show a digital phenotype both Dac1j and Dac2j alleles are caused by insertions of MusD retroelements either within or close to the gene Fbxw4. They propose that both mutations result in complex alterations of gene regulation. In conclusion, point mutations in FBXW4 in association with SHFM3 have not been reported. It appears that changed expression of gene BTRC is related to the phenotype, but that expression levels can be impacted by both duplication of the region itself and inversion of other nearby regions which include FBXW4, likely by disruption of regulatory domains.
27 Jan 2025	Skeletal dysplasia v7.8	FBXW4	Eleanor Williams changed review comment from: In OMIM Split-hand/foot malformation 3, gene duplication syndrome (OMIM:246560) is linked to a duplication at 10q24q25 inherited in an autosomal dominant manner and is characterized by the absence of central digits. Multiple publications have reported patients with SHFM3 and rearrangements covering a 500 kb region encompassing five genes of the locus (LBX1, BTRC, POLL, DPCD, and a partial portion of FBXW4) but excluding the neighbouring FGF8 e.g. PMID: 12913067 (2003), PMID: 16681918 (2006). Subsequent reports have reported various duplications involving different sets of genes: PMID: 27600068 Li et al 2015 - mapped the breakpoints of cases with duplications in the 10q24 region with and without a SHFM3 phenotype and concluded that the critical region responsible for the SHFM phenotypes is most likely located at exon 1 of BTRC gene, which is duplicated in all cases with SHFM phenotypes. PMID: 30622331 Holder-Espinasse et al 2019 - used array CGH or qPCR to analyse 32 new index cases of 10q24 duplication (22 SHFM including 3 with preaxial polydactyly, 7 monodactylies and 3 patients presenting overlapping phenotypes). 17 cases were familial and 15 occurred de novo. Studies in 4 families showed that the duplication segregated with the phenotype. All cases tested by array-CGH had duplication of at least BTRC and POLL genes. Seven cases had duplication of LBX1 gene as well and 12 patients had duplications comprising the FBXW4 gene (although partially for cases 24 and 27). PMID: 35908152 - Qui et al 2022 - using trio clinical exome sequencing, a 120 kb microduplication containing only BTRC were identified in a Chinese family affected with SHFM3. The duplication co-segregated with SHFM phenotypes in the family. Transcription levels of BTRC mRNA in lymphocytes of the proband was significantly higher than that in the healthy control. PMID: 36928426 Cova et al 2023 - show that the Lbx1/Fgf8 locus consists of two separate, but interacting, regulatory domains. By re-engineering a human SHFM3-associated duplication in mice they observed ectopic interactions between the Fgf8 apical ectodermal ridge (AER) enhancers and two other genes in the locus, Lbx1 and Btrc. The same ectopic interactions were present in fibroblasts from a SHFM3 affected individual with duplication. In mice with the duplication a limb malformation was not observed. They also report a case of SHFM3 malformation associated with an inversion encompassing the DPDC, POLL and FBXW4 genes which when re-engineered in mice results in increased expression of genes, Lbx1 and Btrc, in an Fgf8-like pattern in the apical ectodermal ridge. Mice with the inversion were observed to have a digit phenotype. Mouse model: PMID: 18392654 - Friedli et al 2008 - show that in Dactylaplasia mice which show a digital phenotype both Dac1j and Dac2j alleles are caused by insertions of MusD retroelements either within or close to the gene Fbxw4. They propose that both mutations result in complex alterations of gene regulation. In conclusion, point mutations in FBXW4 in association with SHFM3 have not been reported. It appears that expression of gene BTRC is related to the phenotype, but that expression levels can be impacted by both duplication of the region itself and inversion of other nearby regions, by disruption of regulatory domains.; to: In OMIM Split-hand/foot malformation 3, gene duplication syndrome (OMIM:246560) is linked to a duplication at 10q24q25 inherited in an autosomal dominant manner and is characterized by the absence of central digits. Multiple publications have reported patients with SHFM3 and rearrangements covering a 500 kb region encompassing five genes of the locus (LBX1, BTRC, POLL, DPCD, and a partial portion of FBXW4) but excluding the neighbouring FGF8 e.g. PMID: 12913067 (2003), PMID: 16681918 (2006). Subsequent reports have reported various re-arrangements involving different sets of genes in the region. Examples are: PMID: 27600068 Li et al 2015 - mapped the breakpoints of cases with duplications in the 10q24 region with and without a SHFM3 phenotype and concluded that the critical region responsible for the SHFM phenotypes is most likely located at exon 1 of BTRC gene, which is duplicated in all cases with SHFM phenotypes. PMID: 30622331 Holder-Espinasse et al 2019 - used array CGH or qPCR to analyse 32 new index cases of 10q24 duplication (22 SHFM including 3 with preaxial polydactyly, 7 monodactylies and 3 patients presenting overlapping phenotypes). 17 cases were familial and 15 occurred de novo. Studies in 4 families showed that the duplication segregated with the phenotype. All cases tested by array-CGH had duplication of at least BTRC and POLL genes. Seven cases had duplication of LBX1 gene as well and 12 patients had duplications comprising the FBXW4 gene (although partially for cases 24 and 27). PMID: 35908152 - Qui et al 2022 - using trio clinical exome sequencing, a 120 kb microduplication containing only BTRC were identified in a Chinese family affected with SHFM3. The duplication co-segregated with SHFM phenotypes in the family. Transcription levels of BTRC mRNA in lymphocytes of the proband was significantly higher than in the healthy control. PMID: 36928426 Cova et al 2023 - show that the Lbx1/Fgf8 locus consists of two separate, but interacting, regulatory domains. By re-engineering a human SHFM3-associated duplication in mice they observed ectopic interactions between the Fgf8 apical ectodermal ridge (AER) enhancers and two other genes in the locus, Lbx1 and Btrc. The same ectopic interactions were present in fibroblasts from a SHFM3 affected individual with duplication. In mice with the duplication a limb malformation was not observed. They also report a case of SHFM3 malformation associated with an inversion encompassing the DPDC, POLL and FBXW4 genes which when re-engineered in mice results in increased expression of genes, Lbx1 and Btrc, in an Fgf8-like pattern in the apical ectodermal ridge. Mice with the inversion were observed to have a digit phenotype. Mouse model: PMID: 18392654 - Friedli et al 2008 - show that in Dactylaplasia mice which show a digital phenotype both Dac1j and Dac2j alleles are caused by insertions of MusD retroelements either within or close to the gene Fbxw4. They propose that both mutations result in complex alterations of gene regulation. In conclusion, point mutations in FBXW4 in association with SHFM3 have not been reported. It appears that changed expression of gene BTRC is related to the phenotype, but that expression levels can be impacted by both duplication of the region itself and inversion of other nearby regions, by disruption of regulatory domains.
27 Jan 2025	Skeletal dysplasia v7.8	FBXW4	Eleanor Williams changed review comment from: In OMIM Split-hand/foot malformation 3, gene duplication syndrome (OMIM:246560) is linked to a duplication at 10q24q25 inherited in an autosomal dominant manner and is characterized by the absence of central digits. Multiple publications have reported patients with SHFM3 and rearrangements covering a 500 kb region encompassing five genes of the locus (LBX1, BTRC, POLL, DPCD, and a partial portion of FBXW4) but excluding the neighbouring FGF8 e.g. PMID: 12913067 (2003), PMID: 16681918 (2006). Subsequent reports have reported various duplications involving different sets of genes: PMID: 27600068 Li et al 2015 - mapped the breakpoints of cases with duplications in the 10q24 region with and without a SHFM3 phenotype and concluded that the critical region responsible for the SHFM phenotypes is most likely located at exon 1 of BTRC gene, which is duplicated in all cases with SHFM phenotypes. PMID: 30622331 Holder-Espinasse et al 2019 - used array CGH or qPCR to analyse 32 new index cases of 10q24 duplication (22 SHFM including 3 with preaxial polydactyly, 7 monodactylies and 3 patients presenting overlapping phenotypes). 17 cases were familial and 15 occurred de novo. Studies in 4 families showed that the duplication segregated with the phenotype. All cases tested by array-CGH had duplication of at least BTRC and POLL genes. Seven cases had duplication of LBX1 gene as well and 12 patients had duplications comprising the FBXW4 gene (although partially for cases 24 and 27). PMID: 35908152 - Qui et al 2022 - using trio clinical exome sequencing, a 120 kb microduplication containing only BTRC were identified in a Chinese family affected with SHFM3. The duplication co-segregated with SHFM phenotypes in the family. Transcription levels of BTRC mRNA in lymphocyte of the proband was significantly higher than that in the healthy control. PMID: 36928426 Cova et al 2023 - show that the Lbx1/Fgf8 locus consists of two separate, but interacting, regulatory domains. By re-engineering a human SHFM3-associated duplication in mice they observed ectopic interactions between the Fgf8 apical ectodermal ridge (AER) enhancers and two other genes in the locus, Lbx1 and Btrc. The same ectopic interactions were present in fibroblasts from a SHFM3 affected individual with duplication. In mice with the duplication a limb malformation was not observed. They also report a case of SHFM3 malformation associated with an inversion encompassing the DPDC, POLL and FBXW4 genes which when re-engineered in mice results in increased expression of genes, Lbx1 and Btrc, in an Fgf8-like pattern in the apical ectodermal ridge. Mice with the inversion were observed to have a digit phenotype. Mouse model: PMID: 18392654 - Friedli et al 2008 - show that in Dactylaplasia mice which show a digital phenotype both Dac1j and Dac2j are caused by insertions of MusD retroelements either within or close to the gene Fbxw4. They propose that both mutations result in complex alterations of gene regulation. In conclusion, point mutations in FBXW4 in association with SHFM3 have not been reported. It appears that expression of gene BTRC is related to the phenotype, but that expression levels can be impacted by both duplication of the region itself and inversion of other nearby regions, by disruption of regulatory domains.; to: In OMIM Split-hand/foot malformation 3, gene duplication syndrome (OMIM:246560) is linked to a duplication at 10q24q25 inherited in an autosomal dominant manner and is characterized by the absence of central digits. Multiple publications have reported patients with SHFM3 and rearrangements covering a 500 kb region encompassing five genes of the locus (LBX1, BTRC, POLL, DPCD, and a partial portion of FBXW4) but excluding the neighbouring FGF8 e.g. PMID: 12913067 (2003), PMID: 16681918 (2006). Subsequent reports have reported various duplications involving different sets of genes: PMID: 27600068 Li et al 2015 - mapped the breakpoints of cases with duplications in the 10q24 region with and without a SHFM3 phenotype and concluded that the critical region responsible for the SHFM phenotypes is most likely located at exon 1 of BTRC gene, which is duplicated in all cases with SHFM phenotypes. PMID: 30622331 Holder-Espinasse et al 2019 - used array CGH or qPCR to analyse 32 new index cases of 10q24 duplication (22 SHFM including 3 with preaxial polydactyly, 7 monodactylies and 3 patients presenting overlapping phenotypes). 17 cases were familial and 15 occurred de novo. Studies in 4 families showed that the duplication segregated with the phenotype. All cases tested by array-CGH had duplication of at least BTRC and POLL genes. Seven cases had duplication of LBX1 gene as well and 12 patients had duplications comprising the FBXW4 gene (although partially for cases 24 and 27). PMID: 35908152 - Qui et al 2022 - using trio clinical exome sequencing, a 120 kb microduplication containing only BTRC were identified in a Chinese family affected with SHFM3. The duplication co-segregated with SHFM phenotypes in the family. Transcription levels of BTRC mRNA in lymphocytes of the proband was significantly higher than that in the healthy control. PMID: 36928426 Cova et al 2023 - show that the Lbx1/Fgf8 locus consists of two separate, but interacting, regulatory domains. By re-engineering a human SHFM3-associated duplication in mice they observed ectopic interactions between the Fgf8 apical ectodermal ridge (AER) enhancers and two other genes in the locus, Lbx1 and Btrc. The same ectopic interactions were present in fibroblasts from a SHFM3 affected individual with duplication. In mice with the duplication a limb malformation was not observed. They also report a case of SHFM3 malformation associated with an inversion encompassing the DPDC, POLL and FBXW4 genes which when re-engineered in mice results in increased expression of genes, Lbx1 and Btrc, in an Fgf8-like pattern in the apical ectodermal ridge. Mice with the inversion were observed to have a digit phenotype. Mouse model: PMID: 18392654 - Friedli et al 2008 - show that in Dactylaplasia mice which show a digital phenotype both Dac1j and Dac2j alleles are caused by insertions of MusD retroelements either within or close to the gene Fbxw4. They propose that both mutations result in complex alterations of gene regulation. In conclusion, point mutations in FBXW4 in association with SHFM3 have not been reported. It appears that expression of gene BTRC is related to the phenotype, but that expression levels can be impacted by both duplication of the region itself and inversion of other nearby regions, by disruption of regulatory domains.
27 Jan 2025	Skeletal dysplasia v7.8	FBXW4	Eleanor Williams commented on gene: FBXW4
10 Apr 2017	Skeletal dysplasia	FBXW4	Sarah Leigh classified FBXW4 as red