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Skeletal dysplasia v2.145 | COL9A3 | Arina Puzriakova Phenotypes for gene: COL9A3 were changed from MED; multiple epiphyseal dysplasia; Epiphyseal dysplasia, multiple, with myopathy; Stickler syndrome type VI; multiple epiphyseal dysplasia 3, with or without myopathy - 600969; Multiple Epiphyseal Dysplasia, Dominant; Mutiple Epiphyseal Dysplasia to Epiphyseal dysplasia, multiple, 3, with or without myopathy, OMIM:600969 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Skeletal dysplasia v2.144 | COL9A2 | Arina Puzriakova Phenotypes for gene: COL9A2 were changed from Epiphyseal dysplasia, multiple, 2 600204; Stickler syndrome, type V 614284; Stickler syndrome, type V, 614284; {Intervertebral disc disease, susceptibility to}, 603932 to Stickler syndrome, type V, OMIM:614284; Epiphyseal dysplasia, multiple, 2, OMIM:600204 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Skeletal dysplasia v2.143 | COL9A1 | Arina Puzriakova Added comment: Comment on mode of inheritance: MOI should be updated from 'Monoallelic' to 'Both mono- and biallelic' at the next GMS panel update. COL9A1 is associated with two relevant disorders as they both include epiphyseal dysplasia - one of which shows biallelic inheritance (Stickler syndrome, type IV, OMIM:614134) while the other is associated with monoallelic inheritance (Epiphyseal dysplasia, multiple, 6, OMIM:614135) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Skeletal dysplasia v2.142 | COL9A1 | Arina Puzriakova Phenotypes for gene: COL9A1 were changed from Stickler syndrome, type IV 614134; Epiphyseal dysplasia, multiple, 6 614135 to Stickler syndrome, type IV, OMIM:614134; Epiphyseal dysplasia, multiple, 6, OMIM:614135 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Skeletal dysplasia v2.141 | COL11A1 | Arina Puzriakova Phenotypes for gene: COL11A1 were changed from Stickler syndrome, type II 604841; Marshall syndrome 154780; Fibrochondrogenesis 1 228520 to Stickler syndrome, type II, OMIM:604841; Marshall syndrome, OMIM:154780; Fibrochondrogenesis 1, OMIM:228520 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Skeletal dysplasia v2.107 | FLNA | Arina Puzriakova Phenotypes for gene: FLNA were changed from Terminal osseous dysplasia 300244; Otopalatodigital syndrome, type II -304120; Otopalatodigital syndrome, type II 304120 XLD; Otopalatodigital syndrome, type I -311300; Melnick Needles syndrome 309350; Frontometaphyseal dysplasia 305620; Frontometaphyseal dysplasia 305620 XLR; Osteodysplasty Melnick Needles 309350 XLD to Frontometaphyseal dysplasia 1, OMIM:305620; Melnick-Needles syndrome, OMIM:309350; Otopalatodigital syndrome, type I, OMIM:311300; Otopalatodigital syndrome, type II, OMIM:304120; Terminal osseous dysplasia, OMIM:300244 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Skeletal dysplasia v2.79 | ICK | Arina Puzriakova Phenotypes for gene: ICK were changed from Endocrine-cerebroosteodysplasia 612651 to Endocrine-cerebroosteodysplasia, OMIM:612651; Endocrine-cerebro-osteodysplasia syndrome, MONDO:0012980 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Skeletal dysplasia v1.326 | MKKS | Eleanor Williams Phenotypes for gene: MKKS were changed from to Polydactyly; Bardet-Biedl syndrome 6, 605231; McKusick-Kaufman syndrome, 236700 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Skeletal dysplasia v1.274 | SLC34A1 | Eleanor Williams Added comment: Comment on list classification: Changing rating from red to green. Including genes that are green on the Hypophosphataemia or rickets panel (panel ID:482, version 2.1) as green on the Skeletal dysplasia panel on the advice of Prof Lyn Chitty. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Skeletal dysplasia v1.273 | SLC34A1 |
Eleanor Williams gene: SLC34A1 was added gene: SLC34A1 was added to Skeletal dysplasia. Sources: Other Mode of inheritance for gene: SLC34A1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: SLC34A1 were set to 12324554; 9560283; 25050900 Phenotypes for gene: SLC34A1 were set to Nephrolithiasis/osteoporosis, hypophosphatemic, 1, 612286 Review for gene: SLC34A1 was set to GREEN Added comment: Adding genes that are green on the Hypophosphataemia or rickets panel Sources: Other |
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Skeletal dysplasia v1.272 | CYP2R1 | Eleanor Williams Added comment: Comment on list classification: Changing rating from red to green. Including genes that are green on the Hypophosphataemia or rickets panel (panel ID:482, version 2.1) as green on the Skeletal dysplasia panel on the advice of Prof Lyn Chitty. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Skeletal dysplasia v1.271 | CYP2R1 |
Eleanor Williams gene: CYP2R1 was added gene: CYP2R1 was added to Skeletal dysplasia. Sources: Other Mode of inheritance for gene: CYP2R1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CYP2R1 were set to 22855339; 15128933; 28548312; 25942481 Phenotypes for gene: CYP2R1 were set to Rickets due to defect in vitamin D 25-hydroxylation, 600081 Review for gene: CYP2R1 was set to GREEN Added comment: Adding genes that are green on the Hypophosphataemia or rickets panel Sources: Other |
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Skeletal dysplasia v1.270 | VDR | Eleanor Williams Added comment: Comment on list classification: Changing rating from red to green. Including genes that are green on the Hypophosphataemia or rickets panel (panel ID:482, version 2.1) as green on the Skeletal dysplasia panel on the advice of Prof Lyn Chitty | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Skeletal dysplasia v1.269 | VDR | Eleanor Williams Phenotypes for gene: VDR were changed from to Rickets, vitamin D-resistant, type IIA, 277440 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Skeletal dysplasia v1.204 | TMEM67 |
Eleanor Williams changed review comment from: Associated with several phenotypes in OMIM but ?RHYNS syndrome (#609884) is the main disease phenotype that has a skeletal component. Polydactyly may also be seen in Meckel syndrome 3 (#607361). RHYNS syndrome - 1 case: PMID: 9375913 - Di Rocco et al. (1997) - 1 case. 17.5-year-old boy with short stature, severe bone-age retardation and exhibited mild signs of skeletal dysplasia, including generalized osteopenia, epiphyseal hypoplasia, hypoplastic iliac bones with irregular acetabular margins, and thin tubular bones. He later developed nephronophthisis. Brancati et al. (2018) (PMID: 29891882) re-assessed this patient at age 38 years and reported he exhibited short stature and severe generalized osteoporosis. Skeletal survey showed moderately shortened long bones, bowed radii, short femoral neck, brachydactyly of the hands and feet with more severe involvement of middle phalanges, distal phalanx of the thumbs, and metacarpals, moderately thickened calvarium, and rotoscoliosis. Compound heterozygous variants in TMEM67 were identified, one inherited from each of his parents. PMID: 11391657 - Hedera and Gorski (2001) described 2 brothers, who had early onset retinitis pigmentosa, short stature with GH deficiency, mild facial asymmetry, and acromelic shortening of the distal extremities. They suggest this phenotype is consistent with RHYNS syndrome but no genome analysis was done. Meckel syndrome 3 - 3 out of 22 cases show polydactyly: PMID: 16415887 - Smith et al. 2006 - detected 5 different homozygous mutations in the TMEM67 in 5 consanguineous families with Meckel syndrome. The mutations were not found in over 120 ethnically matched normal control chromosomes. Polydactyly was observed in 2 out of the 5 families. PMID: 17377820 - Consugar et al. 2007 - identified 7 novel pathogenic mutations in the TMEM67 gene in 5 of 17 families with a clinical diagnosis of Meckel syndrome. All cases were compound heterogygous. Polydactyly is reported in 1 family.; to: Associated with several phenotypes in OMIM but ?RHYNS syndrome (#609884) is the main disease phenotype that has a skeletal component. Polydactyly may also be seen in Meckel syndrome 3 (#607361). RHYNS syndrome - 1 case: PMID: 9375913 - Di Rocco et al. (1997) - 1 case. 17.5-year-old boy with short stature, severe bone-age retardation and exhibited mild signs of skeletal dysplasia, including generalized osteopenia, epiphyseal hypoplasia, hypoplastic iliac bones with irregular acetabular margins, and thin tubular bones. He later developed nephronophthisis. Brancati et al. (2018) (PMID: 29891882) re-assessed this patient at age 38 years and reported he exhibited short stature and severe generalized osteoporosis. Skeletal survey showed moderately shortened long bones, bowed radii, short femoral neck, brachydactyly of the hands and feet with more severe involvement of middle phalanges, distal phalanx of the thumbs, and metacarpals, moderately thickened calvarium, and rotoscoliosis. Compound heterozygous variants in TMEM67 were identified, one inherited from each of his parents. PMID: 11391657 - Hedera and Gorski (2001) described 2 brothers, who had early onset retinitis pigmentosa, short stature with GH deficiency, mild facial asymmetry, and acromelic shortening of the distal extremities. They suggest this phenotype is consistent with RHYNS syndrome but no genome analysis was done. Meckel syndrome 3 - 3 out of 22 cases show polydactyly: PMID: 16415887 - Smith et al. 2006 - detected 5 different homozygous mutations in the TMEM67 in 5 consanguineous families with Meckel syndrome. The mutations were not found in over 120 ethnically matched normal control chromosomes. Polydactyly was observed in 2 out of the 5 families. PMID: 17377820 - Consugar et al. 2007 - identified 7 novel pathogenic mutations in the TMEM67 gene in 5 of 17 families with a clinical diagnosis of Meckel syndrome. All cases were compound heterogygous. Polydactyly is reported in 1 family. |
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Skeletal dysplasia v1.202 | ICK | Eleanor Williams commented on gene: ICK: Added new-gene-name tag, new approved HGNC gene symbol for ICK is CILK1 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Skeletal dysplasia v1.202 | ICK | Eleanor Williams Tag new-gene-name tag was added to gene: ICK. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Skeletal dysplasia v1.192 | B9D1 |
Eleanor Williams changed review comment from: Associated with ?Meckel syndrome 9 (#614209) and Joubert syndrome 27 (#617120) in OMIM. Gene2Phenotype reports a probable association with MECKEL SYNDROME 9. PMID: 24886560 - Romani et al 2014 - report mutations in B9D1 in two patients, a 9-year-old boy (COR363) and a 7-year-old girl (COR346), both presenting with pure JS. The mutations (cG467A; p.R156Q homo, and cA95G; p.Y32C, c.520-522delGTG; p.V175del) were inherited from heterozygous healthy parents, were not reported in public databases, and affected highly conserved residues. Missense mutations were predicted as pathogenic by prediction web tools. Neither patient showed polydactyly or orofacial features although patient COR363's facial dysmorphisms included a triangular face, retrognatism, accentuated philtrum and big ears, and patient COR346's dysmorphic facial features included frontal bossing, macrostomia, thick lips and low-set ears. PMID: 21493627 - Hopp et al 2011 - In family M456 with Meckel syndrome (MKS), a splice-donor site change in B9D1 was detected in a fetus (c.505+2T>C). Sanger sequencing revealed likely hemizygosity of this variant, with a de novo deletion of the B9D1 locus in the fetus. The deletion spans 1.713 Mb at chromosome 17p11.2, including the complete B9D1 locus. Additionally, 18 other genes were deleted. The authors also identified a novel change in a second MKS gene, CEP290. Sanger sequencing showed that the heterozygous variant, p.R2210C, was inherited from the mother. Polydactyly, that is typical in MKS, was not noted but the fetus had bilateral club feet and shortened limbs.; to: Associated with ?Meckel syndrome 9 (#614209) and Joubert syndrome 27 (#617120) in OMIM. Gene2Phenotype reports a probable association with MECKEL SYNDROME 9. PMID: 24886560 - Romani et al 2014 - report mutations in B9D1 in two unrelated patients, a 9-year-old boy (COR363) and a 7-year-old girl (COR346), both presenting with pure JS. The mutations (cG467A; p.R156Q homo, and cA95G; p.Y32C, c.520-522delGTG; p.V175del) were inherited from heterozygous healthy parents, were not reported in public databases, and affected highly conserved residues. Missense mutations were predicted as pathogenic by prediction web tools. Neither patient showed polydactyly or orofacial features although patient COR363's facial dysmorphisms included a triangular face, retrognatism, accentuated philtrum and big ears, and patient COR346's dysmorphic facial features included frontal bossing, macrostomia, thick lips and low-set ears. PMID: 21493627 - Hopp et al 2011 - In family M456 with Meckel syndrome (MKS), a splice-donor site change in B9D1 was detected in a fetus (c.505+2T>C). Sanger sequencing revealed likely hemizygosity of this variant, with a de novo deletion of the B9D1 locus in the fetus. The deletion spans 1.713 Mb at chromosome 17p11.2, including the complete B9D1 locus. Additionally, 18 other genes were deleted. The authors also identified a novel change in a second MKS gene, CEP290. Sanger sequencing showed that the heterozygous variant, p.R2210C, was inherited from the mother. Polydactyly, that is typical in MKS, was not noted but the fetus had bilateral club feet and shortened limbs. |
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Skeletal dysplasia v1.177 | MATN3 |
Eleanor Williams changed review comment from: Associated with Spondyloepimetaphyseal dysplasia (#608728) and Epiphyseal dysplasia, multiple, 5 (#607078) in OMIM. Epiphyseal dysplasia: PMID: 11479597 - Chapman et al. 2001 - 1 family - 2 different missense mutations (V194D and R121W) identified. Suggested it might be a dominant negative mode of action. PMID: 14729835 - Jackson et al. 2004 - in 7 families with multiple epiphyseal dysplasia they identified 4 novel mutations and 1 recurrent mutation ( R121W). Spondyloepimetaphyseal Dysplasia: PMID: 15121775 - Borochowitz et al. 2004 - report a large consanguineous Arab Muslim family with autosomal recessive spondyloepimetaphyseal dysplasia with a homozygous missense mutation in MATN3. Animal studies - PMID: 16199550 - Otten et al. 2005 - mice with point mutations corresponding to human disease-causing mutations were created and found that transcripts for two of mutation were poorly expressed and protein trafficking was reduced. PMID: 16287128 - Cotterill et al. 2005 - experiments with wild type and mutant protein expressed in Chinese hamster ovaries showed intracellular retention of the mutant protein.; to: Associated with Spondyloepimetaphyseal dysplasia (#608728) and Epiphyseal dysplasia, multiple, 5 (#607078) in OMIM. Epiphyseal dysplasia: PMID: 11479597 - Chapman et al. 2001 - 1 family - 2 different missense mutations (V194D and R121W) identified. Suggested it might be a dominant negative mode of action. PMID: 14729835 - Jackson et al. 2004 - in 7 families with multiple epiphyseal dysplasia they identified 4 novel mutations and 1 recurrent mutation ( R121W). PMID: PMID: 30080953 - Pettersson et al 2018 - in a 17‐year‐old girl born to healthy, nonconsanguineous parents of Caucasian origin who was diagnosed with multiple epiphyseal dysplasia they identified a heterozygous intragenic duplication within MATN3, affecting exons 2–5 by custom array‐CGH. Spondyloepimetaphyseal Dysplasia: PMID: 15121775 - Borochowitz et al. 2004 - report a large consanguineous Arab Muslim family with autosomal recessive spondyloepimetaphyseal dysplasia with a homozygous missense mutation in MATN3. Animal studies - PMID: 16199550 - Otten et al. 2005 - mice with point mutations corresponding to human disease-causing mutations were created and found that transcripts for two of mutation were poorly expressed and protein trafficking was reduced. PMID: 16287128 - Cotterill et al. 2005 - experiments with wild type and mutant protein expressed in Chinese hamster ovaries showed intracellular retention of the mutant protein. |
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Skeletal dysplasia v1.177 | MATN3 |
Eleanor Williams changed review comment from: Associated with Spondyloepimetaphyseal dysplasia (#608728) and Epiphyseal dysplasia, multiple, 5 (#607078) in OMIM. Epiphyseal dysplasia including: PMID: 11479597 - Chapman et al. 2001 - 1 family - 2 different missense mutations (V194D and R121W) identified. Suggested it might be a dominant negative mode of action. PMID: 14729835 - Jackson et al. 2004 - in 7 families with multiple epiphyseal dysplasia they identified 4 novel mutations and 1 recurrent mutation ( R121W). Spondyloepimetaphyseal Dysplasia: PMID: 15121775 - Borochowitz et al. 2004 - report a large consanguineous Arab Muslim family with autosomal recessive spondyloepimetaphyseal dysplasia with a homozygous missense mutation in MATN3. Animal studies - PMID: 16199550 - Otten et al. 2005 - mice with point mutations corresponding to human disease-causing mutations were created and found that transcripts for two of mutation were poorly expressed and protein trafficking was reduced. PMID: 16287128 - Cotterill et al. 2005 - experiments with wild type and mutant protein expressed in Chinese hamster ovaries showed intracellular retention of the mutant protein.; to: Associated with Spondyloepimetaphyseal dysplasia (#608728) and Epiphyseal dysplasia, multiple, 5 (#607078) in OMIM. Epiphyseal dysplasia: PMID: 11479597 - Chapman et al. 2001 - 1 family - 2 different missense mutations (V194D and R121W) identified. Suggested it might be a dominant negative mode of action. PMID: 14729835 - Jackson et al. 2004 - in 7 families with multiple epiphyseal dysplasia they identified 4 novel mutations and 1 recurrent mutation ( R121W). Spondyloepimetaphyseal Dysplasia: PMID: 15121775 - Borochowitz et al. 2004 - report a large consanguineous Arab Muslim family with autosomal recessive spondyloepimetaphyseal dysplasia with a homozygous missense mutation in MATN3. Animal studies - PMID: 16199550 - Otten et al. 2005 - mice with point mutations corresponding to human disease-causing mutations were created and found that transcripts for two of mutation were poorly expressed and protein trafficking was reduced. PMID: 16287128 - Cotterill et al. 2005 - experiments with wild type and mutant protein expressed in Chinese hamster ovaries showed intracellular retention of the mutant protein. |
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Skeletal dysplasia v1.177 | MATN3 |
Eleanor Williams commented on gene: MATN3: Associated with Spondyloepimetaphyseal dysplasia (#608728) and Epiphyseal dysplasia, multiple, 5 (#607078) in OMIM. Epiphyseal dysplasia including: PMID: 11479597 - Chapman et al. 2001 - 1 family - 2 different missense mutations (V194D and R121W) identified. Suggested it might be a dominant negative mode of action. PMID: 14729835 - Jackson et al. 2004 - in 7 families with multiple epiphyseal dysplasia they identified 4 novel mutations and 1 recurrent mutation ( R121W). Spondyloepimetaphyseal Dysplasia: PMID: 15121775 - Borochowitz et al. 2004 - report a large consanguineous Arab Muslim family with autosomal recessive spondyloepimetaphyseal dysplasia with a homozygous missense mutation in MATN3. Animal studies - PMID: 16199550 - Otten et al. 2005 - mice with point mutations corresponding to human disease-causing mutations were created and found that transcripts for two of mutation were poorly expressed and protein trafficking was reduced. PMID: 16287128 - Cotterill et al. 2005 - experiments with wild type and mutant protein expressed in Chinese hamster ovaries showed intracellular retention of the mutant protein. |
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Skeletal dysplasia v1.168 | TMEM67 |
Eleanor Williams changed review comment from: Associated with several phenotypes in OMIM but ?RHYNS syndrome (#609884) is the main disease phenotype that has a skeletal component. Polydactyly may also be seen in Meckel syndrome 3 (#607361). RHYNS syndrome - 1 case PMID: 9375913 - Di Rocco et al. (1997) - 1 case. 17.5-year-old boy with short stature, severe bone-age retardation and exhibited mild signs of skeletal dysplasia, including generalized osteopenia, epiphyseal hypoplasia, hypoplastic iliac bones with irregular acetabular margins, and thin tubular bones. He later developed nephronophthisis. Brancati et al. (2018) (PMID: 29891882) re-assessed this patient at age 38 years and reported he exhibited short stature and severe generalized osteoporosis. Skeletal survey showed moderately shortened long bones, bowed radii, short femoral neck, brachydactyly of the hands and feet with more severe involvement of middle phalanges, distal phalanx of the thumbs, and metacarpals, moderately thickened calvarium, and rotoscoliosis. Compound heterozygous variants in TMEM67 were identified, one inherited from each of his parents. PMID: 11391657 - Hedera and Gorski (2001) described 2 brothers, who had early onset retinitis pigmentosa, short stature with GH deficiency, mild facial asymmetry, and acromelic shortening of the distal extremities. They suggest this phenotype is consistent with RHYNS syndrome but no genome analysis was done. Meckel syndrome 3 PMID: 16415887 - Smith et al. 2006 - detected 5 different homozygous mutations in the TMEM67 in 5 consanguineous families with Meckel syndrome. The mutations were not found in over 120 ethnically matched normal control chromosomes. Polydactyly was observed in 2 out of the 5 families. PMID: 17377820 - Consugar et al. 2007 - identified 7 novel pathogenic mutations in the TMEM67 gene in 5 of 17 families with a clinical diagnosis of Meckel syndrome. All cases were compound heterogygous. Polydactyly is reported in 1 family.; to: Associated with several phenotypes in OMIM but ?RHYNS syndrome (#609884) is the main disease phenotype that has a skeletal component. Polydactyly may also be seen in Meckel syndrome 3 (#607361). RHYNS syndrome - 1 case: PMID: 9375913 - Di Rocco et al. (1997) - 1 case. 17.5-year-old boy with short stature, severe bone-age retardation and exhibited mild signs of skeletal dysplasia, including generalized osteopenia, epiphyseal hypoplasia, hypoplastic iliac bones with irregular acetabular margins, and thin tubular bones. He later developed nephronophthisis. Brancati et al. (2018) (PMID: 29891882) re-assessed this patient at age 38 years and reported he exhibited short stature and severe generalized osteoporosis. Skeletal survey showed moderately shortened long bones, bowed radii, short femoral neck, brachydactyly of the hands and feet with more severe involvement of middle phalanges, distal phalanx of the thumbs, and metacarpals, moderately thickened calvarium, and rotoscoliosis. Compound heterozygous variants in TMEM67 were identified, one inherited from each of his parents. PMID: 11391657 - Hedera and Gorski (2001) described 2 brothers, who had early onset retinitis pigmentosa, short stature with GH deficiency, mild facial asymmetry, and acromelic shortening of the distal extremities. They suggest this phenotype is consistent with RHYNS syndrome but no genome analysis was done. Meckel syndrome 3 - 3 out of 22 cases show polydactyly: PMID: 16415887 - Smith et al. 2006 - detected 5 different homozygous mutations in the TMEM67 in 5 consanguineous families with Meckel syndrome. The mutations were not found in over 120 ethnically matched normal control chromosomes. Polydactyly was observed in 2 out of the 5 families. PMID: 17377820 - Consugar et al. 2007 - identified 7 novel pathogenic mutations in the TMEM67 gene in 5 of 17 families with a clinical diagnosis of Meckel syndrome. All cases were compound heterogygous. Polydactyly is reported in 1 family. |
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Skeletal dysplasia v1.168 | TMEM67 |
Eleanor Williams commented on gene: TMEM67: Associated with several phenotypes in OMIM but ?RHYNS syndrome (#609884) is the main disease phenotype that has a skeletal component. Polydactyly may also be seen in Meckel syndrome 3 (#607361). RHYNS syndrome - 1 case PMID: 9375913 - Di Rocco et al. (1997) - 1 case. 17.5-year-old boy with short stature, severe bone-age retardation and exhibited mild signs of skeletal dysplasia, including generalized osteopenia, epiphyseal hypoplasia, hypoplastic iliac bones with irregular acetabular margins, and thin tubular bones. He later developed nephronophthisis. Brancati et al. (2018) (PMID: 29891882) re-assessed this patient at age 38 years and reported he exhibited short stature and severe generalized osteoporosis. Skeletal survey showed moderately shortened long bones, bowed radii, short femoral neck, brachydactyly of the hands and feet with more severe involvement of middle phalanges, distal phalanx of the thumbs, and metacarpals, moderately thickened calvarium, and rotoscoliosis. Compound heterozygous variants in TMEM67 were identified, one inherited from each of his parents. PMID: 11391657 - Hedera and Gorski (2001) described 2 brothers, who had early onset retinitis pigmentosa, short stature with GH deficiency, mild facial asymmetry, and acromelic shortening of the distal extremities. They suggest this phenotype is consistent with RHYNS syndrome but no genome analysis was done. Meckel syndrome 3 PMID: 16415887 - Smith et al. 2006 - detected 5 different homozygous mutations in the TMEM67 in 5 consanguineous families with Meckel syndrome. The mutations were not found in over 120 ethnically matched normal control chromosomes. Polydactyly was observed in 2 out of the 5 families. PMID: 17377820 - Consugar et al. 2007 - identified 7 novel pathogenic mutations in the TMEM67 gene in 5 of 17 families with a clinical diagnosis of Meckel syndrome. All cases were compound heterogygous. Polydactyly is reported in 1 family. |
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Skeletal dysplasia v1.166 | ICK |
Eleanor Williams commented on gene: ICK: Mouse model data PMID: 24853502 - Moon et al 2014 - Ick null mouse embryos displayed cleft palate, hydrocephalus, polydactyly, and delayed skeletal development, closely resembling ECO syndrome phenotypes. PMID: 24797473 - Chaya et al 2014 - ICK−/− mice died around birth probably because of respiratory failure. ICK−/− mice exhibited preaxial polydactyly in both fore and hind limbs. All four limbs were severely shortened in the ICK−/− mice at E18.5 PMID: 28380258 - Tong et al 2017 - created an Ick R272Q knock-in mouse model that recapitulates ECO pathological phenotypes. Their report focusses on the respiratory phenotype, but they report that mice displayed essential ECO pathological features such as polydactyly and shortened limbs. |
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Skeletal dysplasia v1.166 | ICK |
Eleanor Williams changed review comment from: PMID: 19185282 - Lahiry et al. (2009) - in 6 affected infants with Endocrine-Cerebroosteodysplasia of Old Order Amish pedigree a homozygous mutation was identified in the ICK gene. The phenotype was severe, involved several organ systems, and resulted in fetal or neonatal death. PMID: 27069622 Oud et al. (2016) - a Turkish fetus with Endocrine-Cerebroosteodysplasia was found to be homozygous for a missense mutation in the ICK gene that segregated fully with disease in the family and was not found in Turkish controls or public variant databases PMID: 27466187 Paige Taylor et al (2016) - identified homozygosity for a missense mutation, p.E80K, in Intestinal Cell Kinase, ICK, in one short rib polydactyly syndromes family.; to: PMID: 19185282 - Lahiry et al. (2009) - in 6 affected infants with Endocrine-Cerebroosteodysplasia of Old Order Amish pedigree a homozygous mutation (R272Q) was identified in the ICK gene. The phenotype was severe, involved several organ systems, and resulted in fetal or neonatal death. PMID: 27069622 Oud et al. (2016) - a Turkish fetus with Endocrine-Cerebroosteodysplasia was found to be homozygous for a missense mutation (G120C) in the ICK gene that segregated fully with disease in the family and was not found in Turkish controls or public variant databases PMID: 27466187 Paige Taylor et al (2016) - identified homozygosity for a missense mutation, p.E80K, in Intestinal Cell Kinase, ICK, in one short rib polydactyly syndromes family. |
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Skeletal dysplasia v1.166 | B9D1 |
Eleanor Williams commented on gene: B9D1: Associated with ?Meckel syndrome 9 (#614209) and Joubert syndrome 27 (#617120) in OMIM. Gene2Phenotype reports a probable association with MECKEL SYNDROME 9. PMID: 24886560 - Romani et al 2014 - report mutations in B9D1 in two patients, a 9-year-old boy (COR363) and a 7-year-old girl (COR346), both presenting with pure JS. The mutations (cG467A; p.R156Q homo, and cA95G; p.Y32C, c.520-522delGTG; p.V175del) were inherited from heterozygous healthy parents, were not reported in public databases, and affected highly conserved residues. Missense mutations were predicted as pathogenic by prediction web tools. Neither patient showed polydactyly or orofacial features although patient COR363's facial dysmorphisms included a triangular face, retrognatism, accentuated philtrum and big ears, and patient COR346's dysmorphic facial features included frontal bossing, macrostomia, thick lips and low-set ears. PMID: 21493627 - Hopp et al 2011 - In family M456 with Meckel syndrome (MKS), a splice-donor site change in B9D1 was detected in a fetus (c.505+2T>C). Sanger sequencing revealed likely hemizygosity of this variant, with a de novo deletion of the B9D1 locus in the fetus. The deletion spans 1.713 Mb at chromosome 17p11.2, including the complete B9D1 locus. Additionally, 18 other genes were deleted. The authors also identified a novel change in a second MKS gene, CEP290. Sanger sequencing showed that the heterozygous variant, p.R2210C, was inherited from the mother. Polydactyly, that is typical in MKS, was not noted but the fetus had bilateral club feet and shortened limbs. |
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Skeletal dysplasia v1.154 | ICK |
Eleanor Williams commented on gene: ICK: PMID: 19185282 - Lahiry et al. (2009) - in 6 affected infants with Endocrine-Cerebroosteodysplasia of Old Order Amish pedigree a homozygous mutation was identified in the ICK gene. The phenotype was severe, involved several organ systems, and resulted in fetal or neonatal death. PMID: 27069622 Oud et al. (2016) - a Turkish fetus with Endocrine-Cerebroosteodysplasia was found to be homozygous for a missense mutation in the ICK gene that segregated fully with disease in the family and was not found in Turkish controls or public variant databases PMID: 27466187 Paige Taylor et al (2016) - identified homozygosity for a missense mutation, p.E80K, in Intestinal Cell Kinase, ICK, in one short rib polydactyly syndromes family. |
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Skeletal dysplasia v1.153 | CYP27B1 | Eleanor Williams Added phenotypes Vitamin D-dependent rickets, type I 264700 for gene: CYP27B1 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Skeletal dysplasia v1.153 | COL9A2 | Eleanor Williams Added phenotypes Epiphyseal dysplasia, multiple, 2 600204; Stickler syndrome, type V 614284; Stickler syndrome, type V, 614284; {Intervertebral disc disease, susceptibility to}, 603932 for gene: COL9A2 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Skeletal dysplasia v1.153 | FLNA | Eleanor Williams Added phenotypes Terminal osseous dysplasia 300244; Melnick Needles syndrome 309350; Frontometaphyseal dysplasia 305620; Otopalatodigital syndrome, type II -304120; Otopalatodigital syndrome, type I -311300 for gene: FLNA | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Skeletal dysplasia v1.153 | PHEX | Eleanor Williams Added phenotypes Hypophosphatemic rickets, X-linked dominant 307800 for gene: PHEX | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Skeletal dysplasia v1.153 | FGF23 | Eleanor Williams Added phenotypes Hypophosphatemic rickets, autosomal dominant 193100 for gene: FGF23 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Skeletal dysplasia v1.153 | DMP1 | Eleanor Williams Added phenotypes Hypophosphatemic rickets, AR, 241520 for gene: DMP1 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Skeletal dysplasia v1.153 | SLC34A3 | Eleanor Williams Added phenotypes Hypophosphatemic rickets with hypercalciuria 241530 for gene: SLC34A3 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Skeletal dysplasia v1.153 | COL11A2 | Eleanor Williams Added phenotypes Stickler syndrome, type III 184840; Otospondylomegaepiphyseal dysplasia 215150; Fibrochondrogenesis 2 614524? for gene: COL11A2 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Skeletal dysplasia v1.153 | COL11A1 | Eleanor Williams Added phenotypes Stickler syndrome, type II 604841; Marshall syndrome 154780; Fibrochondrogenesis 1 228520 for gene: COL11A1 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Skeletal dysplasia v1.153 | COL9A1 | Eleanor Williams Added phenotypes Stickler syndrome, type IV 614134; Epiphyseal dysplasia, multiple, 6 614135 for gene: COL9A1 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Skeletal dysplasia v1.153 | ICK | Eleanor Williams Added phenotypes Endocrine-cerebroosteodysplasia 612651 for gene: ICK | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Skeletal dysplasia v1.153 | CLCN5 | Eleanor Williams Added phenotypes Proteinuria, low molecular weight, with hypercalciuric nephrocalcinosis 308990; Dent disease 300009; Nephrolithiasis, type I 310468; Hypophosphatemic rickets 300554 for gene: CLCN5 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Skeletal dysplasia v1.153 | ENPP1 | Eleanor Williams Added phenotypes Hypophosphatemic rickets, autosomal recessive, 2 613312; Cole disease 615522 for gene: ENPP1 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Skeletal dysplasia v1.153 | COL2A1 | Eleanor Williams Added phenotypes Epiphyseal dysplasia, multiple, with myopia and deafness 132450; Spondyloepiphyseal dysplasia, Stanescu type 616583; Stickler sydrome, type I, nonsyndromic ocular 609508; Achondrogenesis, type II or hypochondrogenesis 200610; Kniest dysplasia 156550; Legg-Calve-Perthes disease 150600; Otospondylomegaepiphyseal dysplasia 215150; Stickler syndrome, type I 108300; SMED Strudwick type 184250; Spondyloperipheral dysplasia 271700; Platyspondylic skeletal dysplasia, Torrance type 151210; Czech dysplasia 609162; SED congenita 183900; Osteoarthritis with mild chondrodysplasia 604864; Avascular necrosis of the femoral head 608805 for gene: COL2A1 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Skeletal dysplasia v1.147 | SLC34A3 | Tracy Lester reviewed gene: SLC34A3: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Hypophosphatemic rickets with hypercalciuria 241530; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Skeletal dysplasia v1.147 | PHEX | Tracy Lester reviewed gene: PHEX: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Hypophosphatemic rickets, X-linked dominant 307800; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Skeletal dysplasia v1.147 | ICK | Tracy Lester reviewed gene: ICK: Rating: AMBER; Mode of pathogenicity: ; Publications: 27069622, 19185282; Phenotypes: Endocrine-cerebroosteodysplasia 612651; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Skeletal dysplasia v1.147 | FLNA | Tracy Lester reviewed gene: FLNA: Rating: GREEN; Mode of pathogenicity: Other - please provide details in the comments; Publications: ; Phenotypes: Melnick Needles syndrome 309350, Otopalatodigital syndrome, type I -311300, Otopalatodigital syndrome, type II -304120, Frontometaphyseal dysplasia 305620, Terminal osseous dysplasia 300244; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males); Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Skeletal dysplasia v1.147 | FGF23 | Tracy Lester reviewed gene: FGF23: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Hypophosphatemic rickets, autosomal dominant 193100; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Skeletal dysplasia v1.147 | ENPP1 | Tracy Lester reviewed gene: ENPP1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Cole disease 615522, Hypophosphatemic rickets, autosomal recessive, 2 613312; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Skeletal dysplasia v1.147 | DMP1 | Tracy Lester reviewed gene: DMP1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Hypophosphatemic rickets, AR, 241520; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Skeletal dysplasia v1.147 | CYP27B1 | Tracy Lester reviewed gene: CYP27B1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Vitamin D-dependent rickets, type I 264700; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Skeletal dysplasia v1.147 | COL9A2 | Tracy Lester reviewed gene: COL9A2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Stickler syndrome, type V 614284, Epiphyseal dysplasia, multiple, 2 600204, {Intervertebral disc disease, susceptibility to}, 603932, Stickler syndrome, type V, 614284; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Skeletal dysplasia v1.147 | COL9A1 | Tracy Lester reviewed gene: COL9A1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Epiphyseal dysplasia, multiple, 6 614135, Stickler syndrome, type IV 614134; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Skeletal dysplasia v1.147 | COL2A1 | Tracy Lester reviewed gene: COL2A1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Achondrogenesis, type II or hypochondrogenesis 200610, Avascular necrosis of the femoral head 608805, Czech dysplasia 609162, Epiphyseal dysplasia, multiple, with myopia and deafness 132450, Kniest dysplasia 156550, Legg-Calve-Perthes disease 150600, Osteoarthritis with mild chondrodysplasia 604864, Otospondylomegaepiphyseal dysplasia 215150, Platyspondylic skeletal dysplasia, Torrance type 151210, SED congenita 183900, SMED Strudwick type 184250, Spondyloepiphyseal dysplasia, Stanescu type 616583, Spondyloperipheral dysplasia 271700, Stickler sydrome, type I, nonsyndromic ocular 609508, Stickler syndrome, type I 108300; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Skeletal dysplasia v1.147 | COL11A2 | Tracy Lester reviewed gene: COL11A2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Fibrochondrogenesis 2 614524?, Otospondylomegaepiphyseal dysplasia 215150, Stickler syndrome, type III 184840; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Skeletal dysplasia v1.147 | COL11A1 | Tracy Lester reviewed gene: COL11A1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Fibrochondrogenesis 1 228520, Marshall syndrome 154780, Stickler syndrome, type II 604841; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Skeletal dysplasia v1.147 | CLCN5 | Tracy Lester reviewed gene: CLCN5: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Dent disease 300009, Hypophosphatemic rickets 300554, Nephrolithiasis, type I 310468, Proteinuria, low molecular weight, with hypercalciuric nephrocalcinosis 308990; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Skeletal dysplasia v1.146 | ICK | Eleanor Williams reviewed gene: ICK: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Skeletal dysplasia v1.145 | ICK |
Eleanor Williams Source NHS GMS was added to ICK. Rating Changed from Green List (high evidence) to Green List (high evidence) |