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17 Jan 2022	Skeletal dysplasia v2.168	DSPP	Michael Oldridge changed review comment from: agree should be demoted to Red. Dentinogenesis imperfecta appears to only affect the teeth, no evidence of OI phenotype in these cases.; to: agree should be demoted to Red. Dentinogenesis imperfecta appears to only affect the teeth, no evidence of OI phenotype in reported cases.
17 Jan 2022	Skeletal dysplasia v2.168	DSPP	Michael Oldridge reviewed gene: DSPP: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Dentinogenesis imperfecta; Mode of inheritance: None
20 Jan 2021	Skeletal dysplasia v2.51	MIA3	Eleanor Williams Phenotypes for gene: MIA3 were changed from short stature; skeletal dysplasia; amelogenesis to short stature; skeletal dysplasia; amelogenesis; dentinogenesis imperfecta; short stature; brachydactyly; Platyspondyly; insulin-dependent diabetes mellitus; sensorineural hearing loss; mild intellectual disability
20 Jan 2021	Skeletal dysplasia v2.50	MIA3	Eleanor Williams reviewed gene: MIA3: Rating: RED; Mode of pathogenicity: None; Publications: 32101163; Phenotypes: dentinogenesis imperfecta, short stature, brachydactyly, Platyspondyly, insulin-dependent diabetes mellitus, sensorineural hearing loss, mild intellectual disability; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
16 Dec 2020	Skeletal dysplasia v2.36	MIA3	Aleš Maver changed review comment from: The MIA3 gene is synonymous with TANGO1 in PMID:32101163. This publication reports a synonymous substitution (NM_001324062.1:c.3621A > G) that results in functionally validated exon eight skipping, leading to a truncated TANGO1/MIA3 protein. The variant was identified in four homozygous affected sibs of a consanguineous family, that presented with severe dentinogenesis imperfecta, short stature, various skeletal abnormalities, insulin-dependent diabetes mellitus, sensorineural hearing loss, and mild intellectual disability. Functional studies in HeLa and U2OS cells revealed that the truncated TANGO1/MIA3 protein is dispersed in the ER and its expression in cells with intact endogenous TANGO1/MIA3 impairs cellular collagen I secretion (PMID:32101163). Sources: Literature; to: The MIA3 gene is synonymous with TANGO1 in PMID:32101163. This publication reports a synonymous substitution (NM_001324062.1:c.3621A > G) that results in functionally validated exon eight skipping, leading to a truncated TANGO1/MIA3 protein. The variant was identified in four homozygous affected sibs of a consanguineous family, that presented with severe dentinogenesis imperfecta, short stature, various skeletal abnormalities, insulin-dependent diabetes mellitus, sensorineural hearing loss, and mild intellectual disability. Functional studies in HeLa and U2OS cells revealed that the truncated TANGO1/MIA3 protein is dispersed in the ER and its expression in cells with intact endogenous TANGO1/MIA3 impairs cellular collagen I secretion (PMID:32101163). Sources: Literature
16 Dec 2020	Skeletal dysplasia v2.36	MIA3	Aleš Maver changed review comment from: The MIA3 gene is synonymous with TANGO1 in PMID:32101163. This publications reports a synonymous substitution (NM_001324062.1:c.3621A > G) that results in functionally validated exon eight skipping, leading to a truncated TANGO1/MIA3 protein. The variant was identified in four homozygous affected sibs of a consanguineous family, that presented with severe dentinogenesis imperfecta, short stature, various skeletal abnormalities, insulin-dependent diabetes mellitus, sensorineural hearing loss, and mild intellectual disability. Functional studies in HeLa and U2OS cells revealed that the truncated TANGO1/MIA3 protein is dispersed in the ER and its expression in cells with intact endogenous TANGO1/MIA3 impairs cellular collagen I secretion (PMID:32101163). Sources: Literature; to: The MIA3 gene is synonymous with TANGO1 in PMID:32101163. This publication reports a synonymous substitution (NM_001324062.1:c.3621A > G) that results in functionally validated exon eight skipping, leading to a truncated TANGO1/MIA3 protein. The variant was identified in four homozygous affected sibs of a consanguineous family, that presented with severe dentinogenesis imperfecta, short stature, various skeletal abnormalities, insulin-dependent diabetes mellitus, sensorineural hearing loss, and mild intellectual disability. Functional studies in HeLa and U2OS cells revealed that the truncated TANGO1/MIA3 protein is dispersed in the ER and its expression in cells with intact endogenous TANGO1/MIA3 impairs cellular collagen I secretion (PMID:32101163). Sources: Literature
16 Dec 2020	Skeletal dysplasia v2.36	MIA3	Aleš Maver gene: MIA3 was added gene: MIA3 was added to Skeletal dysplasia. Sources: Literature Mode of inheritance for gene: MIA3 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MIA3 were set to 32101163 Phenotypes for gene: MIA3 were set to short stature; skeletal dysplasia; amelogenesis Penetrance for gene: MIA3 were set to unknown Review for gene: MIA3 was set to RED Added comment: The MIA3 gene is synonymous with TANGO1 in PMID:32101163. This publications reports a synonymous substitution (NM_001324062.1:c.3621A > G) that results in functionally validated exon eight skipping, leading to a truncated TANGO1/MIA3 protein. The variant was identified in four homozygous affected sibs of a consanguineous family, that presented with severe dentinogenesis imperfecta, short stature, various skeletal abnormalities, insulin-dependent diabetes mellitus, sensorineural hearing loss, and mild intellectual disability. Functional studies in HeLa and U2OS cells revealed that the truncated TANGO1/MIA3 protein is dispersed in the ER and its expression in cells with intact endogenous TANGO1/MIA3 impairs cellular collagen I secretion (PMID:32101163). Sources: Literature
31 Jul 2019	Skeletal dysplasia v1.192	IFT81	Eleanor Williams changed review comment from: Associated with Short-rib thoracic dysplasia 19 with or without polydactyly (#617895) in OMIM PMID: 27666822 - Duran et al 2016 - 2 cases. Family 1 - male infant (R98-443) with features consistent with Asphyxiating thoracic dystrophy (ATD). The radiographic abnormalities included midface hypoplasia, dolichocephaly, a prominent occiput , short ribs, handlebar clavicles and short, curved appendicular bones, with the upper limbs particularly abnormally shaped. There was no polydactyly on either the hands or feet. They identified compound heterozygosity for two variants: p.Leu29Phe and p.Arg512. Family 2 - fetus (R13-147A) suspected to have SRPS by prenatal ultrasonography. Postnatal radiographs showed dolichocephaly, a prominent occiput, midface hypoplasia, a very small thorax with shortened horizontal ribs, markedly short long bones with rounded metaphyses and marked hypoplasia of the radii, ulnae, tibiae and fibulae. Other radiographic features included small iliac bones and postaxial polydactyly of all extremities. They identified compound heterozygosity for variants in IFT81: p.Leu262 and p.Leu435del). Cultured chondrocytes from one patient showed decreased levels of transcript. Mutant cells produced elongated cilia, had altered hedgehog signaling, had increased post-translation modification of tubulin, and showed evidence of destabilization of additional anterograde transport complex components PMID: 26275418 - Perrault et al 2015 - identified a homozygous mutation in IFT81 affecting an obligatory donor splice site in an individual with nephronophthisis and polydactyly (c.1188+1G-A). The variant has been classified as a VUS in OMIM as its contribution to nephronophthisis-related ciliopathy has not be confirmed. Only candidate gene sequencing of IFT-B complex proteins was found. A variant in IFT81 (c.2015_2019delACCGG) was also found in a second unrelated child with retinal dystrophy and intellectual disability (no skeletal phenotype) suggestive of a ciliopathy however 9 additional rare homozygous variants were found and so this variant has also been classified as a VUS in OMIM. PMID: 28460050 - Dharmat et al 2017 - Compound heterozygous mutations in IFT81 were identified in a nonsyndromic Cone rod dystrophy proband. PMID: 30080953 - Pettersson et al 2018 - a homozygous tandem duplication of exon 9 and 10 in IFT81 in a boy with Jeune syndrome, or short-rib thoracic dysplasia (SRTD). The duplication was predicted to disrupt the ORF and cause a truncation of the peptide sequence. He had narrow thorax, short arms, brachydactyly and short stature. Western blot analysis did not detect any wild-type IFT81 protein in fibroblasts from the patient with the IFT81 duplication, but only a shorter isoform of IFT81 that was also present in the normal control samples. Summary - 2 cases with SNVs and strong skeletal phenotype, one with some functional data. 3rd case with polydactyly the only skeletal component of the phenotype. 4th case with tandem duplication of 2 exons. ; to: Associated with Short-rib thoracic dysplasia 19 with or without polydactyly (#617895) in OMIM PMID: 27666822 - Duran et al 2016 - 2 cases. Family 1 - male infant (R98-443) with features consistent with Asphyxiating thoracic dystrophy (ATD). The radiographic abnormalities included midface hypoplasia, dolichocephaly, a prominent occiput , short ribs, handlebar clavicles and short, curved appendicular bones, with the upper limbs particularly abnormally shaped. There was no polydactyly on either the hands or feet. They identified compound heterozygosity for two variants: p.Leu29Phe and p.Arg512. Family 2 - fetus (R13-147A) suspected to have SRPS by prenatal ultrasonography. Postnatal radiographs showed dolichocephaly, a prominent occiput, midface hypoplasia, a very small thorax with shortened horizontal ribs, markedly short long bones with rounded metaphyses and marked hypoplasia of the radii, ulnae, tibiae and fibulae. Other radiographic features included small iliac bones and postaxial polydactyly of all extremities. They identified compound heterozygosity for variants in IFT81: p.Leu262 and p.Leu435del). Cultured chondrocytes from one patient showed decreased levels of transcript. Mutant cells produced elongated cilia, had altered hedgehog signaling, had increased post-translation modification of tubulin, and showed evidence of destabilization of additional anterograde transport complex components PMID: 26275418 - Perrault et al 2015 - identified a homozygous mutation in IFT81 affecting an obligatory donor splice site in an individual with nephronophthisis and polydactyly (c.1188+1G-A). The variant has been classified as a VUS in OMIM as its contribution to nephronophthisis-related ciliopathy has not be confirmed. Only candidate gene sequencing of IFT-B complex proteins was found. A variant in IFT81 (c.2015_2019delACCGG) was also found in a second unrelated child with retinal dystrophy and intellectual disability (no skeletal phenotype) suggestive of a ciliopathy however 9 additional rare homozygous variants were found and so this variant has also been classified as a VUS in OMIM. PMID: 28460050 - Dharmat et al 2017 - Compound heterozygous mutations in IFT81 were identified in a nonsyndromic Cone rod dystrophy proband. PMID: 30080953 - Pettersson et al 2018 - a homozygous tandem duplication of exon 9 and 10 in IFT81 in a boy with Jeune syndrome, or short-rib thoracic dysplasia (SRTD). The duplication was predicted to disrupt the ORF and cause a truncation of the peptide sequence. He had narrow thorax, short arms, brachydactyly and short stature. Western blot analysis did not detect any wild-type IFT81 protein in fibroblasts from the patient with the IFT81 duplication, but only a shorter isoform of IFT81 that was also present in the normal control samples. Summary - 2 cases with SNVs and strong skeletal phenotype, one with some functional data. 3rd case with polydactyly the only skeletal component of the phenotype and the variant classified as a VUS. 4th case with tandem duplication of 2 exons which is predicted to result in a truncated protein.
31 Jul 2019	Skeletal dysplasia v1.192	IFT81	Eleanor Williams changed review comment from: Associated with Short-rib thoracic dysplasia 19 with or without polydactyly (#617895) in OMIM PMID: 27666822 - Duran et al 2016 - 2 cases. Family 1 - male infant (R98-443) with features consistent with Asphyxiating thoracic dystrophy (ATD). The radiographic abnormalities included midface hypoplasia, dolichocephaly, a prominent occiput , short ribs, handlebar clavicles and short, curved appendicular bones, with the upper limbs particularly abnormally shaped. There was no polydactyly on either the hands or feet. They identified compound heterozygosity for two variants: p.Leu29Phe and p.Arg512. Family 2 - fetus (R13-147A) suspected to have SRPS by prenatal ultrasonography. Postnatal radiographs showed dolichocephaly, a prominent occiput, midface hypoplasia, a very small thorax with shortened horizontal ribs, markedly short long bones with rounded metaphyses and marked hypoplasia of the radii, ulnae, tibiae and fibulae. Other radiographic features included small iliac bones and postaxial polydactyly of all extremities. They identified compound heterozygosity for variants in IFT81: p.Leu262 and p.Leu435del). Cultured chondrocytes from one patient showed decreased levels of transcript. Mutant cells produced elongated cilia, had altered hedgehog signaling, had increased post-translation modification of tubulin, and showed evidence of destabilization of additional anterograde transport complex components PMID: 26275418 - Perrault et al 2015 - identified a homozygous mutation in IFT81 affecting an obligatory donor splice site in an individual with nephronophthisis and polydactyly. The variant has been classified as a VUS in OMIM as its contribution to nephronophthisis-related ciliopathy has not be confirmed. PMID: 28460050 - Dharmat et al 2017 - Compound heterozygous mutations in IFT81 were identified in a nonsyndromic Cone rod dystrophy proband. PMID: 30080953 - Pettersson et al 2018 - a homozygous tandem duplication of exon 9 and 10 in IFT81 in a boy with Jeune syndrome, or short-rib thoracic dysplasia (SRTD). The duplication was predicted to disrupt the ORF and cause a truncation of the peptide sequence. He had narrow thorax, short arms, brachydactyly and short stature. Western blot analysis did not detect any wild-type IFT81 protein in fibroblasts from the patient with the IFT81 duplication, but only a shorter isoform of IFT81 that was also present in the normal control samples. Summary - 2 cases with SNVs and strong skeletal phenotype, one with some functional data. 3rd case with polydactyly the only skeletal component of the phenotype. 4th case with tandem duplication of 2 exons. ; to: Associated with Short-rib thoracic dysplasia 19 with or without polydactyly (#617895) in OMIM PMID: 27666822 - Duran et al 2016 - 2 cases. Family 1 - male infant (R98-443) with features consistent with Asphyxiating thoracic dystrophy (ATD). The radiographic abnormalities included midface hypoplasia, dolichocephaly, a prominent occiput , short ribs, handlebar clavicles and short, curved appendicular bones, with the upper limbs particularly abnormally shaped. There was no polydactyly on either the hands or feet. They identified compound heterozygosity for two variants: p.Leu29Phe and p.Arg512. Family 2 - fetus (R13-147A) suspected to have SRPS by prenatal ultrasonography. Postnatal radiographs showed dolichocephaly, a prominent occiput, midface hypoplasia, a very small thorax with shortened horizontal ribs, markedly short long bones with rounded metaphyses and marked hypoplasia of the radii, ulnae, tibiae and fibulae. Other radiographic features included small iliac bones and postaxial polydactyly of all extremities. They identified compound heterozygosity for variants in IFT81: p.Leu262 and p.Leu435del). Cultured chondrocytes from one patient showed decreased levels of transcript. Mutant cells produced elongated cilia, had altered hedgehog signaling, had increased post-translation modification of tubulin, and showed evidence of destabilization of additional anterograde transport complex components PMID: 26275418 - Perrault et al 2015 - identified a homozygous mutation in IFT81 affecting an obligatory donor splice site in an individual with nephronophthisis and polydactyly (c.1188+1G-A). The variant has been classified as a VUS in OMIM as its contribution to nephronophthisis-related ciliopathy has not be confirmed. Only candidate gene sequencing of IFT-B complex proteins was found. A variant in IFT81 (c.2015_2019delACCGG) was also found in a second unrelated child with retinal dystrophy and intellectual disability (no skeletal phenotype) suggestive of a ciliopathy however 9 additional rare homozygous variants were found and so this variant has also been classified as a VUS in OMIM. PMID: 28460050 - Dharmat et al 2017 - Compound heterozygous mutations in IFT81 were identified in a nonsyndromic Cone rod dystrophy proband. PMID: 30080953 - Pettersson et al 2018 - a homozygous tandem duplication of exon 9 and 10 in IFT81 in a boy with Jeune syndrome, or short-rib thoracic dysplasia (SRTD). The duplication was predicted to disrupt the ORF and cause a truncation of the peptide sequence. He had narrow thorax, short arms, brachydactyly and short stature. Western blot analysis did not detect any wild-type IFT81 protein in fibroblasts from the patient with the IFT81 duplication, but only a shorter isoform of IFT81 that was also present in the normal control samples. Summary - 2 cases with SNVs and strong skeletal phenotype, one with some functional data. 3rd case with polydactyly the only skeletal component of the phenotype. 4th case with tandem duplication of 2 exons.
31 Jul 2019	Skeletal dysplasia v1.192	IFT81	Eleanor Williams changed review comment from: Associated with Short-rib thoracic dysplasia 19 with or without polydactyly (#617895) in OMIM PMID: 27666822 - Duran et al 2016 - 2 cases. Family 1 - male infant (R98-443) with features consistent with Asphyxiating thoracic dystrophy (ATD). The radiographic abnormalities included midface hypoplasia, dolichocephaly, a prominent occiput , short ribs, handlebar clavicles and short, curved appendicular bones, with the upper limbs particularly abnormally shaped. There was no polydactyly on either the hands or feet. They identified compound heterozygosity for two variants: p.Leu29Phe and p.Arg512. Family 2 - fetus (R13-147A) suspected to have SRPS by prenatal ultrasonography. Postnatal radiographs showed dolichocephaly, a prominent occiput, midface hypoplasia, a very small thorax with shortened horizontal ribs, markedly short long bones with rounded metaphyses and marked hypoplasia of the radii, ulnae, tibiae and fibulae. Other radiographic features included small iliac bones and postaxial polydactyly of all extremities. They identified compound heterozygosity for variants in IFT81: p.Leu262 and p.Leu435del). Cultured chondrocytes from one patient showed decreased levels of transcript. Mutant cells produced elongated cilia, had altered hedgehog signaling, had increased post-translation modification of tubulin, and showed evidence of destabilization of additional anterograde transport complex components PMID: 26275418 - Perrault et al 2015 - identified a homozygous mutation in IFT81 affecting an obligatory donor splice site in an individual with nephronophthisis and polydactyly. The variant has been classified as a VUS in OMIM as its contribution to nephronophthisis-related ciliopathy has not be confirmed. PMID: 28460050 - Dharmat et al 2017 - Compound heterozygous mutations in IFT81 were identified in a nonsyndromic Cone rod dystrophy proband. PMID: 30080953 - Pettersson et al 2018 - a homozygous tandem duplication of exon 9 and 10 in IFT81 in a boy with Jeune syndrome, or short-rib thoracic dysplasia (SRTD). He had narrow thorax, short arms, brachydactyly and short stature. Western blot analysis did not detect any wild-type IFT81 protein in fibroblasts from the patient with the IFT81 duplication, but only a shorter isoform of IFT81 that was also present in the normal control samples. Summary - 2 cases with SNVs and strong skeletal phenotype, one with some functional data. 3rd case with polydactyly the only skeletal component of the phenotype. 4th case with tandem duplication of 2 exons. ; to: Associated with Short-rib thoracic dysplasia 19 with or without polydactyly (#617895) in OMIM PMID: 27666822 - Duran et al 2016 - 2 cases. Family 1 - male infant (R98-443) with features consistent with Asphyxiating thoracic dystrophy (ATD). The radiographic abnormalities included midface hypoplasia, dolichocephaly, a prominent occiput , short ribs, handlebar clavicles and short, curved appendicular bones, with the upper limbs particularly abnormally shaped. There was no polydactyly on either the hands or feet. They identified compound heterozygosity for two variants: p.Leu29Phe and p.Arg512. Family 2 - fetus (R13-147A) suspected to have SRPS by prenatal ultrasonography. Postnatal radiographs showed dolichocephaly, a prominent occiput, midface hypoplasia, a very small thorax with shortened horizontal ribs, markedly short long bones with rounded metaphyses and marked hypoplasia of the radii, ulnae, tibiae and fibulae. Other radiographic features included small iliac bones and postaxial polydactyly of all extremities. They identified compound heterozygosity for variants in IFT81: p.Leu262 and p.Leu435del). Cultured chondrocytes from one patient showed decreased levels of transcript. Mutant cells produced elongated cilia, had altered hedgehog signaling, had increased post-translation modification of tubulin, and showed evidence of destabilization of additional anterograde transport complex components PMID: 26275418 - Perrault et al 2015 - identified a homozygous mutation in IFT81 affecting an obligatory donor splice site in an individual with nephronophthisis and polydactyly. The variant has been classified as a VUS in OMIM as its contribution to nephronophthisis-related ciliopathy has not be confirmed. PMID: 28460050 - Dharmat et al 2017 - Compound heterozygous mutations in IFT81 were identified in a nonsyndromic Cone rod dystrophy proband. PMID: 30080953 - Pettersson et al 2018 - a homozygous tandem duplication of exon 9 and 10 in IFT81 in a boy with Jeune syndrome, or short-rib thoracic dysplasia (SRTD). The duplication was predicted to disrupt the ORF and cause a truncation of the peptide sequence. He had narrow thorax, short arms, brachydactyly and short stature. Western blot analysis did not detect any wild-type IFT81 protein in fibroblasts from the patient with the IFT81 duplication, but only a shorter isoform of IFT81 that was also present in the normal control samples. Summary - 2 cases with SNVs and strong skeletal phenotype, one with some functional data. 3rd case with polydactyly the only skeletal component of the phenotype. 4th case with tandem duplication of 2 exons.
31 Jul 2019	Skeletal dysplasia v1.192	MMP9	Eleanor Williams changed review comment from: Associated with Metaphyseal anadysplasia 2 (613073) in OMIM PMID: 19615667 - Lausch et al 2009 - 1 family. In a recessive kindred, family E, MMP13 was normal, but a c.21T>A transversion in exon 1 altered the start codon of MMP9, substituting methionine with lysine. The variant segregated with the disease in the family. PMID: 28342220 - Sharony et al 2017 - 1 family. Two affected sib fetuses with early sonographic evidence of long bone shortening and postnatally no metaphyseal changes. Whole-exome sequencing revealed homozygous mutation in MMP9 in both fetuses. NM_004994: c.[559C>T], p.(L187F). PMID: 24781753 - Li et al 2015 - 0 families. 2 brothers with short stature and mixed epiphyseal and metaphyseal dysplasia. Identified a homozygous C>T transition mutation in exon 2 of MMP13 (c.325C>T, p.(R109). So not in MMP9. Only 2 cases reported, 3rd had variant in MMP13 not MMP9. Mouse model - PMID: 9590175 - Vu et al. 1998 - report that homozygous mice with a null mutation in the MMP-9/gelatinase B gene exhibit an abnormal pattern of skeletal growth plate vascularization and ossification.; to: Associated with Metaphyseal anadysplasia 2 (613073) in OMIM PMID: 19615667 - Lausch et al 2009 - 1 family. In a recessive kindred, family E, MMP13 was normal, but a c.21T>A transversion in exon 1 altered the start codon of MMP9, substituting methionine with lysine. The variant segregated with the disease in the family. PMID: 28342220 - Sharony et al 2017 - 1 family. Two affected sib fetuses with early sonographic evidence of long bone shortening and postnatally no metaphyseal changes. Whole-exome sequencing revealed homozygous mutation in MMP9 in both fetuses. NM_004994: c.[559C>T], p.(L187F). PMID: 24781753 - Li et al 2015 - 0 families. 2 brothers with short stature and mixed epiphyseal and metaphyseal dysplasia. Identified a homozygous C>T transition mutation in exon 2 of MMP13 (c.325C>T, p.(R109). So not in MMP9. Summary: only 2 cases reported, 3rd had variant in MMP13 not MMP9. Mouse model - PMID: 9590175 - Vu et al. 1998 - report that homozygous mice with a null mutation in the MMP-9/gelatinase B gene exhibit an abnormal pattern of skeletal growth plate vascularization and ossification.
17 Jul 2019	Skeletal dysplasia v1.182	MMP9	Eleanor Williams changed review comment from: Associated with Metaphyseal anadysplasia 2 (613073) in OMIM PMID: 19615667 - Lausch et al 2009 - 1 family. In a recessive kindred, family E, MMP13 was normal, but a c.21T>A transversion in exon 1 altered the start codon of MMP9, substituting methionine with lysine. The variant segregated with the disease in the family. PMID: 28342220 - Sharony et al 2017 - 1 family. Two affected sib fetuses with early sonographic evidence of long bone shortening and postnatally no metaphyseal changes. Whole-exome sequencing revealed homozygous mutation in MMP9 in both fetuses. NM_004994: c.[559C>T], p.(L187F). PMID: 24781753 - Li et al 2015 - 0 families. 2 brothers with short stature and mixed epiphyseal and metaphyseal dysplasia. Identified a homozygous C>T transition mutation in exon 2 of MMP13 (c.325C>T, p.(R109). So not in MMP9. Only 2 cases reported, 3rd had variant in MMP13 not MMP9.; to: Associated with Metaphyseal anadysplasia 2 (613073) in OMIM PMID: 19615667 - Lausch et al 2009 - 1 family. In a recessive kindred, family E, MMP13 was normal, but a c.21T>A transversion in exon 1 altered the start codon of MMP9, substituting methionine with lysine. The variant segregated with the disease in the family. PMID: 28342220 - Sharony et al 2017 - 1 family. Two affected sib fetuses with early sonographic evidence of long bone shortening and postnatally no metaphyseal changes. Whole-exome sequencing revealed homozygous mutation in MMP9 in both fetuses. NM_004994: c.[559C>T], p.(L187F). PMID: 24781753 - Li et al 2015 - 0 families. 2 brothers with short stature and mixed epiphyseal and metaphyseal dysplasia. Identified a homozygous C>T transition mutation in exon 2 of MMP13 (c.325C>T, p.(R109). So not in MMP9. Only 2 cases reported, 3rd had variant in MMP13 not MMP9. Mouse model - PMID: 9590175 - Vu et al. 1998 - report that homozygous mice with a null mutation in the MMP-9/gelatinase B gene exhibit an abnormal pattern of skeletal growth plate vascularization and ossification.
16 Jul 2019	Skeletal dysplasia v1.167	IFT81	Eleanor Williams changed review comment from: Associated with Short-rib thoracic dysplasia 19 with or without polydactyly (#617895) in OMIM PMID: 27666822 - Duran et al 2016 - 2 cases. Family 1 - male infant (R98-443) with features consistent with Asphyxiating thoracic dystrophy (ATD). The radiographic abnormalities included midface hypoplasia, dolichocephaly, a prominent occiput , short ribs, handlebar clavicles and short, curved appendicular bones, with the upper limbs particularly abnormally shaped. There was no polydactyly on either the hands or feet. They identified compound heterozygosity for two variants: p.Leu29Phe and p.Arg512. Family 2 - fetus (R13-147A) suspected to have SRPS by prenatal ultrasonography. Postnatal radiographs showed dolichocephaly, a prominent occiput, midface hypoplasia, a very small thorax with shortened horizontal ribs, markedly short long bones with rounded metaphyses and marked hypoplasia of the radii, ulnae, tibiae and fibulae. Other radiographic features included small iliac bones and postaxial polydactyly of all extremities. They identified compound heterozygosity for variants in IFT81: p.Leu262 and p.Leu435del). Cultured chondrocytes from one patient showed decreased levels of transcript. Mutant cells produced elongated cilia, had altered hedgehog signaling, had increased post-translation modification of tubulin, and showed evidence of destabilization of additional anterograde transport complex components PMID: 26275418 - Perrault et al 2015 - identified a homozygous mutation in IFT81 affecting an obligatory donor splice site in an individual with nephronophthisis and polydactyly. The variant has been classified as a VUS in OMIM as its contribution to nephronophthisis-related ciliopathy has not be confirmed. PMID: 28460050 - Dharmat et al 2017 - Compound heterozygous mutations in IFT81 were identified in a nonsyndromic Cone rod dystrophy proband. Summary - 2 cases, one with some functional data. 3rd case with polydactyly the only skeletal component of the phenotype; to: Associated with Short-rib thoracic dysplasia 19 with or without polydactyly (#617895) in OMIM PMID: 27666822 - Duran et al 2016 - 2 cases. Family 1 - male infant (R98-443) with features consistent with Asphyxiating thoracic dystrophy (ATD). The radiographic abnormalities included midface hypoplasia, dolichocephaly, a prominent occiput , short ribs, handlebar clavicles and short, curved appendicular bones, with the upper limbs particularly abnormally shaped. There was no polydactyly on either the hands or feet. They identified compound heterozygosity for two variants: p.Leu29Phe and p.Arg512. Family 2 - fetus (R13-147A) suspected to have SRPS by prenatal ultrasonography. Postnatal radiographs showed dolichocephaly, a prominent occiput, midface hypoplasia, a very small thorax with shortened horizontal ribs, markedly short long bones with rounded metaphyses and marked hypoplasia of the radii, ulnae, tibiae and fibulae. Other radiographic features included small iliac bones and postaxial polydactyly of all extremities. They identified compound heterozygosity for variants in IFT81: p.Leu262 and p.Leu435del). Cultured chondrocytes from one patient showed decreased levels of transcript. Mutant cells produced elongated cilia, had altered hedgehog signaling, had increased post-translation modification of tubulin, and showed evidence of destabilization of additional anterograde transport complex components PMID: 26275418 - Perrault et al 2015 - identified a homozygous mutation in IFT81 affecting an obligatory donor splice site in an individual with nephronophthisis and polydactyly. The variant has been classified as a VUS in OMIM as its contribution to nephronophthisis-related ciliopathy has not be confirmed. PMID: 28460050 - Dharmat et al 2017 - Compound heterozygous mutations in IFT81 were identified in a nonsyndromic Cone rod dystrophy proband. PMID: 30080953 - Pettersson et al 2018 - a homozygous tandem duplication of exon 9 and 10 in IFT81 in a boy with Jeune syndrome, or short-rib thoracic dysplasia (SRTD). He had narrow thorax, short arms, brachydactyly and short stature. Western blot analysis did not detect any wild-type IFT81 protein in fibroblasts from the patient with the IFT81 duplication, but only a shorter isoform of IFT81 that was also present in the normal control samples. Summary - 2 cases with SNVs and strong skeletal phenotype, one with some functional data. 3rd case with polydactyly the only skeletal component of the phenotype. 4th case with tandem duplication of 2 exons.
16 Jul 2019	Skeletal dysplasia v1.167	IFT81	Eleanor Williams commented on gene: IFT81: Associated with Short-rib thoracic dysplasia 19 with or without polydactyly (#617895) in OMIM PMID: 27666822 - Duran et al 2016 - 2 cases. Family 1 - male infant (R98-443) with features consistent with Asphyxiating thoracic dystrophy (ATD). The radiographic abnormalities included midface hypoplasia, dolichocephaly, a prominent occiput , short ribs, handlebar clavicles and short, curved appendicular bones, with the upper limbs particularly abnormally shaped. There was no polydactyly on either the hands or feet. They identified compound heterozygosity for two variants: p.Leu29Phe and p.Arg512*. Family 2 - fetus (R13-147A) suspected to have SRPS by prenatal ultrasonography. Postnatal radiographs showed dolichocephaly, a prominent occiput, midface hypoplasia, a very small thorax with shortened horizontal ribs, markedly short long bones with rounded metaphyses and marked hypoplasia of the radii, ulnae, tibiae and fibulae. Other radiographic features included small iliac bones and postaxial polydactyly of all extremities. They identified compound heterozygosity for variants in IFT81: p.Leu262 and p.Leu435del). Cultured chondrocytes from one patient showed decreased levels of transcript. Mutant cells produced elongated cilia, had altered hedgehog signaling, had increased post-translation modification of tubulin, and showed evidence of destabilization of additional anterograde transport complex components PMID: 26275418 - Perrault et al 2015 - identified a homozygous mutation in IFT81 affecting an obligatory donor splice site in an individual with nephronophthisis and polydactyly. The variant has been classified as a VUS in OMIM as its contribution to nephronophthisis-related ciliopathy has not be confirmed. PMID: 28460050 - Dharmat et al 2017 - Compound heterozygous mutations in IFT81 were identified in a nonsyndromic Cone rod dystrophy proband. Summary - 2 cases, one with some functional data. 3rd case with polydactyly the only skeletal component of the phenotype
08 May 2019	Skeletal dysplasia v1.159	MMP9	Eleanor Williams commented on gene: MMP9: Associated with Metaphyseal anadysplasia 2 (613073) in OMIM PMID: 19615667 - Lausch et al 2009 - 1 family. In a recessive kindred, family E, MMP13 was normal, but a c.21T>A transversion in exon 1 altered the start codon of MMP9, substituting methionine with lysine. The variant segregated with the disease in the family. PMID: 28342220 - Sharony et al 2017 - 1 family. Two affected sib fetuses with early sonographic evidence of long bone shortening and postnatally no metaphyseal changes. Whole-exome sequencing revealed homozygous mutation in MMP9 in both fetuses. NM_004994: c.[559C>T], p.(L187F). PMID: 24781753 - Li et al 2015 - 0 families. 2 brothers with short stature and mixed epiphyseal and metaphyseal dysplasia. Identified a homozygous C>T transition mutation in exon 2 of MMP13 (c.325C>T, p.(R109*). So not in MMP9. Only 2 cases reported, 3rd had variant in MMP13 not MMP9.
06 May 2019	Skeletal dysplasia v1.153	NOG	Eleanor Williams Added phenotypes Symphalangism, proximal, 1A 185800; Brachydactyly, type B2 611377; Tarsal-carpal coalition syndrome 186570; Stapes ankylosis with broad thumb and toes 184460; Multiple synostoses syndrome 1 186500 for gene: NOG
06 Mar 2019	Skeletal dysplasia v1.147	NOG	Tracy Lester reviewed gene: NOG: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Brachydactyly, type B2 611377, Multiple synostoses syndrome 1 186500, Stapes ankylosis with broad thumb and toes 184460, Symphalangism, proximal, 1A 185800, Tarsal-carpal coalition syndrome 186570; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
06 Mar 2019	Skeletal dysplasia v1.146	NOG	Eleanor Williams reviewed gene: NOG: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
06 Mar 2019	Skeletal dysplasia v1.145	NOG	Eleanor Williams Source NHS GMS was added to NOG. Rating Changed from Green List (high evidence) to Green List (high evidence)