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| Rare syndromic craniosynostosis or isolated multisuture synostosis v3.4 | ASXL3 |
Rebecca Tooze gene: ASXL3 was added gene: ASXL3 was added to Craniosynostosis. Sources: Literature Mode of inheritance for gene: ASXL3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Review for gene: ASXL3 was set to AMBER Added comment: • A de novo c.3033dup; p.(Leu1012Serfs*23) was identified in a patient with metopic synostosis within the Norwegian cohort (Tønne et al., 2021). • A six-year-old with microcephaly, autism, global developmental delay, and metopic craniosynostosis was found on exome sequencing to harbour a heterozygous two base pair de novo deletion, c.1897_1898delCA; p.(Gln633Valfs*13) in ASXL3 (Dinwiddie et al., 2013). • A heterozygous de novo single nucleotide variant (c.3039+1G>A; p.(?)) in the invariant “GT” splice donor site of exon 11 was identified in an individual with a prominent forehead, thick eyebrows, long lashes, exotropia, depressed nasal ridge, thin upper lip vermillion, hirsutism, microcephaly, bilateral camptodactyly of third, fourth and fifth fingers, deep palmar creases, and small hands and feet. Craniosynostosis is not confirmed (Hori et al., 2016). Two cases of loss-of-function variants in ASXL3; only one has radiologically confirmed craniosynostosis. Sources: Literature |
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| Rare syndromic craniosynostosis or isolated multisuture synostosis v3.1 | BCL11B |
Helen Lord changed review comment from: 36275064 Zhao et al, 2022, 25 month old Chinese boy with a novel fs variant in the BCL11B gene by WES and confirmed de novo by parental sanger sequencing c.2346_2361del. Patient shown to have frontal and right coronal synostosis on 3D-CT scan. Table 1 - comparing the clinical features of the 6 patients with BCCLB variants reported in the literature with craniosynostosis. The other 5 identifed variants were all missense, 1 de novo and the other 4 inherited. The truncation is predicted to lack the last three C2HH zinc finger domains (ZnF4-6). As BCL11B is a transcriptional activator, the premature stop-codon sequence of BCL11B may affect the proteins function in binding to it's target DNA and it's interactions with target proteins. 310673176 Goos et al, 2019 c.7C>A p.(Arg3Ser) de novo variant identified in a male patient with bicoronal synostosis, raised ICP, variant identified by WGS trio analysis. Bcl11b is expressed in cranila sutures and Bcl11b-/- mice exhibit craniofacial abnormalities including craniosynostosis. Co immunoprecipitation analyses reveled that the amino acid substitrution abolished the ability of BCL11B to interact with both the NuRD and PRC2 complexes. Crystal structures of RBBP4 in complex with the AA fragments of FOG-2, BCL11A and SALL4 showed that the motif residues Arg-3, Arg-4 and Lys-5 co-ordinated to the acidic core and surface of RBBP4, suggesting that the Arg-3 contributes to the ionic coordination, stabilising its interaction with RBBP4 and closely related RBBP7. introduced the c.7C>A mutation into the germline of C57BL/6 mice using CRISPR-Cas9 genome editing. Het mice were born at Mendelian ratios survivied into adulthood without gross anatomical abnormalities and bred normally. However, examination of calvarial sutures by micro-CT revealed these mice exhibited variable and partial bilateral osteogenic fusion of the coronal suture that was accomponied by narrowing of the sagittal and lambdoid sutires by ~50% at P0. Other calvarial and facial sutures in these het mice were indistinguishable from those of wt mice. Hom mutant mice recapitulated perinatal lethality of Bcl11b-/- mice due to apparant respoiratiry insufficiency, as well as multisuture synostosis at P0 involving the coeronla (bilateral), interfrontal, sagittal, interparietal and temporal sutures; however, in marked contrast to Bcl11b-/-mice or those lacking BCL11B in cells derived from the neural crest, the Bcl11b R3S hom mice did not exhibit fusion of facial sutures. 34900871 Gaillard et al, 2021, 4 patients with BCL11B variants Patient A: c.2000G>A p.(Gly667Glu) het left sided congernital diaphragmatic hernia (CDH) and progressive sagittal synostosis. Maternally inherited. Patient B: c.1744G>A p.(Gly582Ser) het sagittal and bilambdoid synostosis. Paternally inherited. Patient C: c.2018C>G p.(Pro673Arg) het left unicoronal synostosis. Maternally inherited. Patient D: c.1265C>T p.(Pro422Leu) het sagittal synostosis. Maternally inherited. Of notes the parents also carrying these variants were phenotypically normal; this could suggest incomplete penetrance, simialr to other craniosynostosis syndromes such as TCF12 and SMAD6. 36512050 Chaisrisawadisuk et al, 2022: 2 month old female with left coronal and sagittal synostosis on CT scan, found to have a de novo 14q32.12-q32.31 deletion (blood karyotpe and microarray) - the most likely candidate genes are YY1 and BCL11B for causing craniosynostosis in this patient. 36470856 Eto et al, 2022: 5 year old Japense boy - CT scan at 10 months revelaed partial early fusion of sagittal and lambda sutures - trio exome analysis identified a de novo het fs variant c.2439_2452dup p.(His818fs). Case reported in Oxford Molecular genetics laboratory: 14q32.2 - 1.5Mb del: 14q32.2(99,052,763_100,591,634). Patient has unicoronal synostosis and intellectual disability - parental testing not yet undertaken. 4 cases of de novo BCL11B variants in patients with craniosynostosis, although for one of these patients two candidate genes that could be responsible for phenotype. 4 cases where missense variant inherited from an unaffected parents - suggests non-penetrance associated feature. Sources: Expert list; to: 36275064 Zhao et al, 2022, 25 month old Chinese boy with a novel fs variant in the BCL11B gene by WES and confirmed de novo by parental sanger sequencing c.2346_2361del. Patient shown to have frontal and right coronal synostosis on 3D-CT scan. Table 1 - comparing the clinical features of the 6 patients with BCCLB variants reported in the literature with craniosynostosis. The other 5 identifed variants were all missense, 1 de novo and the other 4 inherited. The truncation is predicted to lack the last three C2HH zinc finger domains (ZnF4-6). As BCL11B is a transcriptional activator, the premature stop-codon sequence of BCL11B may affect the proteins function in binding to it's target DNA and it's interactions with target proteins. 31067316 Goos et al, 2019 c.7C>A p.(Arg3Ser) de novo variant identified in a male patient with bicoronal synostosis, raised ICP, variant identified by WGS trio analysis. Bcl11b is expressed in cranila sutures and Bcl11b-/- mice exhibit craniofacial abnormalities including craniosynostosis. Co immunoprecipitation analyses reveled that the amino acid substitrution abolished the ability of BCL11B to interact with both the NuRD and PRC2 complexes. Crystal structures of RBBP4 in complex with the AA fragments of FOG-2, BCL11A and SALL4 showed that the motif residues Arg-3, Arg-4 and Lys-5 co-ordinated to the acidic core and surface of RBBP4, suggesting that the Arg-3 contributes to the ionic coordination, stabilising its interaction with RBBP4 and closely related RBBP7. introduced the c.7C>A mutation into the germline of C57BL/6 mice using CRISPR-Cas9 genome editing. Het mice were born at Mendelian ratios survivied into adulthood without gross anatomical abnormalities and bred normally. However, examination of calvarial sutures by micro-CT revealed these mice exhibited variable and partial bilateral osteogenic fusion of the coronal suture that was accomponied by narrowing of the sagittal and lambdoid sutires by ~50% at P0. Other calvarial and facial sutures in these het mice were indistinguishable from those of wt mice. Hom mutant mice recapitulated perinatal lethality of Bcl11b-/- mice due to apparant respoiratiry insufficiency, as well as multisuture synostosis at P0 involving the coeronla (bilateral), interfrontal, sagittal, interparietal and temporal sutures; however, in marked contrast to Bcl11b-/-mice or those lacking BCL11B in cells derived from the neural crest, the Bcl11b R3S hom mice did not exhibit fusion of facial sutures. 34900871 Gaillard et al, 2021, 4 patients with BCL11B variants Patient A: c.2000G>A p.(Gly667Glu) het left sided congernital diaphragmatic hernia (CDH) and progressive sagittal synostosis. Maternally inherited. Patient B: c.1744G>A p.(Gly582Ser) het sagittal and bilambdoid synostosis. Paternally inherited. Patient C: c.2018C>G p.(Pro673Arg) het left unicoronal synostosis. Maternally inherited. Patient D: c.1265C>T p.(Pro422Leu) het sagittal synostosis. Maternally inherited. Of notes the parents also carrying these variants were phenotypically normal; this could suggest incomplete penetrance, simialr to other craniosynostosis syndromes such as TCF12 and SMAD6. 36512050 Chaisrisawadisuk et al, 2022: 2 month old female with left coronal and sagittal synostosis on CT scan, found to have a de novo 14q32.12-q32.31 deletion (blood karyotpe and microarray) - the most likely candidate genes are YY1 and BCL11B for causing craniosynostosis in this patient. 36470856 Eto et al, 2022: 5 year old Japense boy - CT scan at 10 months revelaed partial early fusion of sagittal and lambda sutures - trio exome analysis identified a de novo het fs variant c.2439_2452dup p.(His818fs). Case reported in Oxford Molecular genetics laboratory: 14q32.2 - 1.5Mb del: 14q32.2(99,052,763_100,591,634). Patient has unicoronal synostosis and intellectual disability - parental testing not yet undertaken. 4 cases of de novo BCL11B variants in patients with craniosynostosis, although for one of these patients two candidate genes that could be responsible for phenotype. 4 cases where missense variant inherited from an unaffected parents - suggests non-penetrance associated feature. Sources: Expert list |
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| Rare syndromic craniosynostosis or isolated multisuture synostosis v3.1 | BCL11B |
Helen Lord gene: BCL11B was added gene: BCL11B was added to Craniosynostosis. Sources: Expert list Mode of inheritance for gene: BCL11B was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: BCL11B were set to 36275064; 310673176; 34900871; 36512050; 36470856 Phenotypes for gene: BCL11B were set to Craniosynostosis and global developmental delay Review for gene: BCL11B was set to GREEN Added comment: 36275064 Zhao et al, 2022, 25 month old Chinese boy with a novel fs variant in the BCL11B gene by WES and confirmed de novo by parental sanger sequencing c.2346_2361del. Patient shown to have frontal and right coronal synostosis on 3D-CT scan. Table 1 - comparing the clinical features of the 6 patients with BCCLB variants reported in the literature with craniosynostosis. The other 5 identifed variants were all missense, 1 de novo and the other 4 inherited. The truncation is predicted to lack the last three C2HH zinc finger domains (ZnF4-6). As BCL11B is a transcriptional activator, the premature stop-codon sequence of BCL11B may affect the proteins function in binding to it's target DNA and it's interactions with target proteins. 310673176 Goos et al, 2019 c.7C>A p.(Arg3Ser) de novo variant identified in a male patient with bicoronal synostosis, raised ICP, variant identified by WGS trio analysis. Bcl11b is expressed in cranila sutures and Bcl11b-/- mice exhibit craniofacial abnormalities including craniosynostosis. Co immunoprecipitation analyses reveled that the amino acid substitrution abolished the ability of BCL11B to interact with both the NuRD and PRC2 complexes. Crystal structures of RBBP4 in complex with the AA fragments of FOG-2, BCL11A and SALL4 showed that the motif residues Arg-3, Arg-4 and Lys-5 co-ordinated to the acidic core and surface of RBBP4, suggesting that the Arg-3 contributes to the ionic coordination, stabilising its interaction with RBBP4 and closely related RBBP7. introduced the c.7C>A mutation into the germline of C57BL/6 mice using CRISPR-Cas9 genome editing. Het mice were born at Mendelian ratios survivied into adulthood without gross anatomical abnormalities and bred normally. However, examination of calvarial sutures by micro-CT revealed these mice exhibited variable and partial bilateral osteogenic fusion of the coronal suture that was accomponied by narrowing of the sagittal and lambdoid sutires by ~50% at P0. Other calvarial and facial sutures in these het mice were indistinguishable from those of wt mice. Hom mutant mice recapitulated perinatal lethality of Bcl11b-/- mice due to apparant respoiratiry insufficiency, as well as multisuture synostosis at P0 involving the coeronla (bilateral), interfrontal, sagittal, interparietal and temporal sutures; however, in marked contrast to Bcl11b-/-mice or those lacking BCL11B in cells derived from the neural crest, the Bcl11b R3S hom mice did not exhibit fusion of facial sutures. 34900871 Gaillard et al, 2021, 4 patients with BCL11B variants Patient A: c.2000G>A p.(Gly667Glu) het left sided congernital diaphragmatic hernia (CDH) and progressive sagittal synostosis. Maternally inherited. Patient B: c.1744G>A p.(Gly582Ser) het sagittal and bilambdoid synostosis. Paternally inherited. Patient C: c.2018C>G p.(Pro673Arg) het left unicoronal synostosis. Maternally inherited. Patient D: c.1265C>T p.(Pro422Leu) het sagittal synostosis. Maternally inherited. Of notes the parents also carrying these variants were phenotypically normal; this could suggest incomplete penetrance, simialr to other craniosynostosis syndromes such as TCF12 and SMAD6. 36512050 Chaisrisawadisuk et al, 2022: 2 month old female with left coronal and sagittal synostosis on CT scan, found to have a de novo 14q32.12-q32.31 deletion (blood karyotpe and microarray) - the most likely candidate genes are YY1 and BCL11B for causing craniosynostosis in this patient. 36470856 Eto et al, 2022: 5 year old Japense boy - CT scan at 10 months revelaed partial early fusion of sagittal and lambda sutures - trio exome analysis identified a de novo het fs variant c.2439_2452dup p.(His818fs). Case reported in Oxford Molecular genetics laboratory: 14q32.2 - 1.5Mb del: 14q32.2(99,052,763_100,591,634). Patient has unicoronal synostosis and intellectual disability - parental testing not yet undertaken. 4 cases of de novo BCL11B variants in patients with craniosynostosis, although for one of these patients two candidate genes that could be responsible for phenotype. 4 cases where missense variant inherited from an unaffected parents - suggests non-penetrance associated feature. Sources: Expert list |
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| Rare syndromic craniosynostosis or isolated multisuture synostosis v1.123 | RUNX2 |
Eleanor Williams changed review comment from: Loss of functional mutations associated with CLEIDOCRANIAL DYSPLASIA in Gene2Phenotype (confirmed). In OMIM loss of function mutations are associated with several phenotypes including Cleidocranial dysplasia. A heterozygous duplication of some exons of RUNX2 is associated with Metaphyseal dysplasia with maxillary hypoplasia with or without brachydactyly . However, craniosynostosis is not listed as a feature of this disorder (PMID: 23290074, 25311905, 29891876 CNV EVIDENCE: PMID: 20683987 - Mefford et al 2010 - Evaluated 186 individuals with single-suture craniosynostosis for submicroscopic deletions and duplications using whole-genome array CGH. They identified a heterozygous inverted 1.1 Mb duplication including the entire sequence of RUNX2, MIR586, and some of CLIC5 and SUPT3H in two affected cousins (1007 and 1019) with metopic synostosis and hypodontia. The duplication was inherited from the mother of one individual and it is presumed the father of the second individual (DNA not available, mother does not have the duplication). Both carrier parents have hypodontia by report, but neither is known to have had synostosis suggesting incomplete penetrance for that phenotype. The grandfather of 1007 and 1019 is described as having an abnormal head shape with a narrow forehead and several missing teeth; DNA was not available from this individual. They state that this CNV was not found in 2,493 control individuals [Itsara et al., 2009]. They compared RUNX2 expression levels in osteoblasts from these two individuals to expression levels in osteoblasts from unaffected individuals (n = 6) and individuals with synostosis but without duplication of RUNX2 (n = 22). The average expression of RUNX2 in the samples from the two individuals was higher than all affected and unaffected cell lines but it was not a statistically significant difference so should be interpreted with caution. PMID: 23307468 - Varvagiannis et al 2013 - a girl with a de novo trisomy 6p12.3-p21.1 who showed craniosynostosis, manifested by the premature fusion of the right coronal and sagittal sutures, and also facial anomalies, psychomotor delay, and recurrent respiratory tract infections. MLPA analysis suggested a duplication of the entire RUNX2 gene. MLPA analysis indicated that the duplication was not present in parental blood samples. SNP array analysis identified the duplication was 6.9 Mb in size and mapped to 6p12.3–p21.1 (chr6: 40,797,975–47,701,961 NCBI Build 35; May 2004), thus encompassing 163 ENSEMBL genes. The finding of abnormal fontanelles and/or abnormal sutures, either manifested as craniosynostosis or not, has been documented in 5 cases in patients with pure partial trisomy 6p. No analysis of RUNX2 expression was performed. PMID: 23348268 - Greives et al 2013 - present a case study of a boy with an atypical skull deformity with pan-craniosynostosis whose microarray analysis revealed 4 copies of a 1.24-Mb region from 6p12.3 to 6p21.1 containing the RUNX2 gene. He presented as an infant with airway obstruction from choanal atresia. He was diagnosed with a closed anterior fontanelle, ventricular septal defect, restricted range of motion in his elbows, mild conductive hearing loss, and developmental delays. They note that his multisutural craniosynostosis is the most extensive associated with RUNX2. No segregation analysis given. PMID:25899668 - Molin et al 2015 - report on a family with an affected mother and three affected children. The four patients carried a 285 kb duplication identified by array comparative genomic hybridization. The duplication includes the entire sequence of RUNX2 and the 5' half of SUPT3H. We confirmed the duplication by real-time quantitative PCR in the four patients. Two children presented with the association of metopic craniosynostosis and oligo/hypodontia previously described, confirming the phenotype caused by RUNX2 duplication. The mother and one child had isolated hypodontia without craniosynostosis. The clinical presentation shown by syndromic patients IV‐1 and IV‐3 appears radically different from MDMHB, but shares a few similarities with previously duplication patients, including as hypodontia and craniosynostosis. Isolated hypodontia observed in Patients III‐2 and IV‐2 highlights a wider clinical spectrum associated with RUNX2 duplication, in addition to isolated and syndromic craniosynostosis and MDMHB. Decipher - there are 6 patients with RUNX2 duplications over 1 kb in size. None mention craniosynostosis as a feature, although abnormality of the face/triangular face is listed for the patient with the 3.59 Mb duplication. https://decipher.sanger.ac.uk/gene/RUNX2#variants/RUNX2/patient-overlap/cnvs Mouse models: PMIDs: 11581292 (Liu et al 2001) and 12167715 (Geoffroy et al 2002) - both surprisingly report transgenic mice overexpressing Cbfa1 (runx2) developed severe osteopenia. PMID: 21807129 - Maeno et al 2011 - report that in mice early onset of Runx2 expression in the cranial mesenchyme induced mineralization on E13.0, when no mineralization was observed in wild-type mice, and resulted in craniosynostosis. PMID: 23300083 McGee-Lawrence et al 2013 - Runx2-deficient mice die at birth because of a lack of skeletal ossification. Axin2-deficient mice develop craniosynostosis because of high β-catenin activity. Runx2 represses transcription of Axin2 mRNA. They state that their data are consistent with the idea that Runx2 plays a central role in the etiologies of several different forms of craniosynostosis. Control populations: A search for the smallest CNV in a patient with craniosynostosis from Molin et al 2015 in the Database of Genomic Variants using GRCh38 coordinates shows no invidiuals from control populations with CNVs that cover RUNX2 http://dgv.tcag.ca/gb2/gbrowse/dgv2_hg38/?name=chr6%3A45265488-45551053;search=Search. Summary: Loss of function variants, partial duplication of the the RUNX2 gene and full duplication of the RUNX2 gene appear to result in different phenotypes. With regards to full duplication, there are 4 cases reported in separate publications of duplications fully covering the RUNX2 gene and patients with a craniosynostosis phenotype. The smallest duplication is 285 kb and includes RUNX2 and the 5' half of SUPT3H. However, there appears to be incomplete penetrance with some carriers having a less severe phenotype. Mefford et al state the CNV they report was not found in 2,493 control individuals and CNVs covering RUNX2 were not found in the Database of Genomics Variants. Mouse models give conflicting evidence. Mouse models of runx2 over-expression surprisingly found they developed severe osteopenia. However, early onset of Runx2 expression resulted in craniosynostosis, and Runx2 was found to repress Axin2, low levels of which can result in craniosynostosis. ; to: Loss of functional mutations associated with CLEIDOCRANIAL DYSPLASIA in Gene2Phenotype (confirmed). In OMIM loss of function mutations are associated with several phenotypes including Cleidocranial dysplasia. A heterozygous duplication of some exons of RUNX2 is associated with Metaphyseal dysplasia with maxillary hypoplasia with or without brachydactyly . However, craniosynostosis is not listed as a feature of this disorder (PMID: 23290074, 25311905, 29891876) CNV EVIDENCE: PMID: 20683987 - Mefford et al 2010 - Evaluated 186 individuals with single-suture craniosynostosis for submicroscopic deletions and duplications using whole-genome array CGH. They identified a heterozygous inverted 1.1 Mb duplication including the entire sequence of RUNX2, MIR586, and some of CLIC5 and SUPT3H in two affected cousins (1007 and 1019) with metopic synostosis and hypodontia. The duplication was inherited from the mother of one individual and it is presumed the father of the second individual (DNA not available, mother does not have the duplication). Both carrier parents have hypodontia by report, but neither is known to have had synostosis suggesting incomplete penetrance for that phenotype. The grandfather of 1007 and 1019 is described as having an abnormal head shape with a narrow forehead and several missing teeth; DNA was not available from this individual. They state that this CNV was not found in 2,493 control individuals [Itsara et al., 2009]. They compared RUNX2 expression levels in osteoblasts from these two individuals to expression levels in osteoblasts from unaffected individuals (n = 6) and individuals with synostosis but without duplication of RUNX2 (n = 22). The average expression of RUNX2 in the samples from the two individuals was higher than all affected and unaffected cell lines but it was not a statistically significant difference so should be interpreted with caution. PMID: 23307468 - Varvagiannis et al 2013 - a girl with a de novo trisomy 6p12.3-p21.1 who showed craniosynostosis, manifested by the premature fusion of the right coronal and sagittal sutures, and also facial anomalies, psychomotor delay, and recurrent respiratory tract infections. MLPA analysis suggested a duplication of the entire RUNX2 gene. MLPA analysis indicated that the duplication was not present in parental blood samples. SNP array analysis identified the duplication was 6.9 Mb in size and mapped to 6p12.3–p21.1 (chr6: 40,797,975–47,701,961 NCBI Build 35; May 2004), thus encompassing 163 ENSEMBL genes. The finding of abnormal fontanelles and/or abnormal sutures, either manifested as craniosynostosis or not, has been documented in 5 cases in patients with pure partial trisomy 6p. No analysis of RUNX2 expression was performed. PMID: 23348268 - Greives et al 2013 - present a case study of a boy with an atypical skull deformity with pan-craniosynostosis whose microarray analysis revealed 4 copies of a 1.24-Mb region from 6p12.3 to 6p21.1 containing the RUNX2 gene. He presented as an infant with airway obstruction from choanal atresia. He was diagnosed with a closed anterior fontanelle, ventricular septal defect, restricted range of motion in his elbows, mild conductive hearing loss, and developmental delays. They note that his multisutural craniosynostosis is the most extensive associated with RUNX2. No segregation analysis given. PMID:25899668 - Molin et al 2015 - report on a family with an affected mother and three affected children. The four patients carried a 285 kb duplication identified by array comparative genomic hybridization. The duplication includes the entire sequence of RUNX2 and the 5' half of SUPT3H. We confirmed the duplication by real-time quantitative PCR in the four patients. Two children presented with the association of metopic craniosynostosis and oligo/hypodontia previously described, confirming the phenotype caused by RUNX2 duplication. The mother and one child had isolated hypodontia without craniosynostosis. The clinical presentation shown by syndromic patients IV‐1 and IV‐3 appears radically different from MDMHB, but shares a few similarities with previously duplication patients, including as hypodontia and craniosynostosis. Isolated hypodontia observed in Patients III‐2 and IV‐2 highlights a wider clinical spectrum associated with RUNX2 duplication, in addition to isolated and syndromic craniosynostosis and MDMHB. Decipher - there are 6 patients with RUNX2 duplications over 1 kb in size. None mention craniosynostosis as a feature, although abnormality of the face/triangular face is listed for the patient with the 3.59 Mb duplication. https://decipher.sanger.ac.uk/gene/RUNX2#variants/RUNX2/patient-overlap/cnvs Mouse models: PMIDs: 11581292 (Liu et al 2001) and 12167715 (Geoffroy et al 2002) - both surprisingly report transgenic mice overexpressing Cbfa1 (runx2) developed severe osteopenia. PMID: 21807129 - Maeno et al 2011 - report that in mice early onset of Runx2 expression in the cranial mesenchyme induced mineralization on E13.0, when no mineralization was observed in wild-type mice, and resulted in craniosynostosis. PMID: 23300083 McGee-Lawrence et al 2013 - Runx2-deficient mice die at birth because of a lack of skeletal ossification. Axin2-deficient mice develop craniosynostosis because of high β-catenin activity. Runx2 represses transcription of Axin2 mRNA. They state that their data are consistent with the idea that Runx2 plays a central role in the etiologies of several different forms of craniosynostosis. Control populations: A search for the smallest CNV in a patient with craniosynostosis from Molin et al 2015 in the Database of Genomic Variants using GRCh38 coordinates shows no invidiuals from control populations with CNVs that cover RUNX2 http://dgv.tcag.ca/gb2/gbrowse/dgv2_hg38/?name=chr6%3A45265488-45551053;search=Search. Summary: Loss of function variants, partial duplication of the the RUNX2 gene and full duplication of the RUNX2 gene appear to result in different phenotypes. With regards to full duplication, there are 4 cases reported in separate publications of duplications fully covering the RUNX2 gene and patients with a craniosynostosis phenotype. The smallest duplication is 285 kb and includes RUNX2 and the 5' half of SUPT3H. However, there appears to be incomplete penetrance with some carriers having a less severe phenotype. Mefford et al state the CNV they report was not found in 2,493 control individuals and CNVs covering RUNX2 were not found in the Database of Genomics Variants. Mouse models give conflicting evidence. Mouse models of runx2 over-expression surprisingly found they developed severe osteopenia. However, early onset of Runx2 expression resulted in craniosynostosis, and Runx2 was found to repress Axin2, low levels of which can result in craniosynostosis. |
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| Rare syndromic craniosynostosis or isolated multisuture synostosis v1.123 | RUNX2 |
Eleanor Williams changed review comment from: Loss of functional mutations associated with CLEIDOCRANIAL DYSPLASIA in Gene2Phenotype (confirmed). In OMIM loss of function mutations are associated with several phenotypes including Cleidocranial dysplasia. A heterozygous duplication of some exons of RUNX2 is associated with Metaphyseal dysplasia with maxillary hypoplasia with or without brachydactyly . However, craniosynostosis is not listed as a feature of this disorder (PMID: 23290074, 25311905, 29891876 CNV EVIDENCE: PMID: 20683987 - Mefford et al 2010 - Evaluated 186 individuals with single-suture craniosynostosis for submicroscopic deletions and duplications using whole-genome array CGH. They identified a heterozygous inverted 1.1 Mb duplication including the entire sequence of RUNX2, MIR586, and some of CLIC5 and SUPT3H in two affected cousins (1007 and 1019) with metopic synostosis and hypodontia. The duplication was inherited from the mother of one individual and it is presumed the father of the second individual (DNA not available, mother does not have the duplication). Both carrier parents have hypodontia by report, but neither is known to have had synostosis suggesting incomplete penetrance for that phenotype. The grandfather of 1007 and 1019 is described as having an abnormal head shape with a narrow forehead and several missing teeth; DNA was not available from this individual. They state that this CNV was not found in 2,493 control individuals [Itsara et al., 2009]. They compared RUNX2 expression levels in osteoblasts from these two individuals to expression levels in osteoblasts from unaffected individuals (n = 6) and individuals with synostosis but without duplication of RUNX2 (n = 22). The average expression of RUNX2 in the samples from the two individuals was higher than all affected and unaffected cell lines but it was not a statistically significant difference so should be interpreted with caution. PMID: 23307468 - Varvagiannis et al 2013 - a girl with a de novo trisomy 6p12.3-p21.1 who showed craniosynostosis, manifested by the premature fusion of the right coronal and sagittal sutures, and also facial anomalies, psychomotor delay, and recurrent respiratory tract infections. MLPA analysis suggested a duplication of the entire RUNX2 gene. MLPA analysis indicated that the duplication was not present in parental blood samples. SNP array analysis identified the duplication was 6.9 Mb in size and mapped to 6p12.3–p21.1 (chr6: 40,797,975–47,701,961 NCBI Build 35; May 2004), thus encompassing 163 ENSEMBL genes. The finding of abnormal fontanelles and/or abnormal sutures, either manifested as craniosynostosis or not, has been documented in 5 cases in patients with pure partial trisomy 6p. No analysis of RUNX2 expression was performed. PMID: 23348268 - Greives et al 2013 - present a case study of a boy with an atypical skull deformity with pan-craniosynostosis whose microarray analysis revealed 4 copies of a 1.24-Mb region from 6p12.3 to 6p21.1 containing the RUNX2 gene. He presented as an infant with airway obstruction from choanal atresia. He was diagnosed with a closed anterior fontanelle, ventricular septal defect, restricted range of motion in his elbows, mild conductive hearing loss, and developmental delays. They note that his multisutural craniosynostosis is the most extensive associated with RUNX2. No segregation analysis given. PMID:25899668 - Molin et al 2015 - report on a family with an affected mother and three affected children. The four patients carried a 285 kb duplication identified by array comparative genomic hybridization. The duplication includes the entire sequence of RUNX2 and the 5' half of SUPT3H. We confirmed the duplication by real-time quantitative PCR in the four patients. Two children presented with the association of metopic craniosynostosis and oligo/hypodontia previously described, confirming the phenotype caused by RUNX2 duplication. The mother and one child had isolated hypodontia without craniosynostosis. The clinical presentation shown by syndromic patients IV‐1 and IV‐3 appears radically different from MDMHB, but shares a few similarities with previously duplication patients, including as hypodontia and craniosynostosis. Isolated hypodontia observed in Patients III‐2 and IV‐2 highlights a wider clinical spectrum associated with RUNX2 duplication, in addition to isolated and syndromic craniosynostosis and MDMHB. Decipher - there are 6 patients with RUNX2 duplications over 1 kb in size. None mention craniosynostosis as a feature, although abnormality of the face/triangular face is listed for the patient with the 3.59 Mb duplication. https://decipher.sanger.ac.uk/gene/RUNX2#variants/RUNX2/patient-overlap/cnvs Mouse models: PMIDs: 11581292 (Liu et al 2001) and 12167715 (Geoffroy et al 2002) - both surprisingly report transgenic mice overexpressing Cbfa1 (runx2) developed severe osteopenia. PMID: 21807129 - Maeno et al 2011 - report that in mice early onset of Runx2 expression in the cranial mesenchyme induced mineralization on E13.0, when no mineralization was observed in wild-type mice, and resulted in craniosynostosis. PMID: 23300083 McGee-Lawrence et al 2013 - Runx2-deficient mice die at birth because of a lack of skeletal ossification. Axin2-deficient mice develop craniosynostosis because of high β-catenin activity. Runx2 represses transcription of Axin2 mRNA. They state that their data are consistent with the idea that Runx2 plays a central role in the etiologies of several different forms of craniosynostosis. Control populations: A search for the smallest CNV in a patient with craniosynostosis from Molin et al 2015 in the Database of Genomics Variants using GRCh38 coordinates shows no invidiuals from control populations with CNVs that cover RUNX2 http://dgv.tcag.ca/gb2/gbrowse/dgv2_hg38/?name=chr6%3A45265488-45551053;search=Search. Summary: Loss of function variants, partial duplication of the the RUNX2 gene and full duplication of the RUNX2 gene appear to result in different phenotypes. With regards to full duplication, there are 4 cases reported in separate publications of duplications fully covering the RUNX2 gene and patients with a craniosynostosis phenotype. The smallest duplication is 285 kb and includes RUNX2 and the 5' half of SUPT3H. However, there appears to be incomplete penetrance with some carriers having a less severe phenotype. Mefford et al state the CNV they report was not found in 2,493 control individuals and CNVs covering RUNX2 were not found in the Database of Genomics Variants. Mouse models give conflicting evidence. Mouse models of runx2 over-expression surprisingly found they developed severe osteopenia. However, early onset of Runx2 expression resulted in craniosynostosis, and Runx2 was found to repress Axin2, low levels of which can result in craniosynostosis. ; to: Loss of functional mutations associated with CLEIDOCRANIAL DYSPLASIA in Gene2Phenotype (confirmed). In OMIM loss of function mutations are associated with several phenotypes including Cleidocranial dysplasia. A heterozygous duplication of some exons of RUNX2 is associated with Metaphyseal dysplasia with maxillary hypoplasia with or without brachydactyly . However, craniosynostosis is not listed as a feature of this disorder (PMID: 23290074, 25311905, 29891876 CNV EVIDENCE: PMID: 20683987 - Mefford et al 2010 - Evaluated 186 individuals with single-suture craniosynostosis for submicroscopic deletions and duplications using whole-genome array CGH. They identified a heterozygous inverted 1.1 Mb duplication including the entire sequence of RUNX2, MIR586, and some of CLIC5 and SUPT3H in two affected cousins (1007 and 1019) with metopic synostosis and hypodontia. The duplication was inherited from the mother of one individual and it is presumed the father of the second individual (DNA not available, mother does not have the duplication). Both carrier parents have hypodontia by report, but neither is known to have had synostosis suggesting incomplete penetrance for that phenotype. The grandfather of 1007 and 1019 is described as having an abnormal head shape with a narrow forehead and several missing teeth; DNA was not available from this individual. They state that this CNV was not found in 2,493 control individuals [Itsara et al., 2009]. They compared RUNX2 expression levels in osteoblasts from these two individuals to expression levels in osteoblasts from unaffected individuals (n = 6) and individuals with synostosis but without duplication of RUNX2 (n = 22). The average expression of RUNX2 in the samples from the two individuals was higher than all affected and unaffected cell lines but it was not a statistically significant difference so should be interpreted with caution. PMID: 23307468 - Varvagiannis et al 2013 - a girl with a de novo trisomy 6p12.3-p21.1 who showed craniosynostosis, manifested by the premature fusion of the right coronal and sagittal sutures, and also facial anomalies, psychomotor delay, and recurrent respiratory tract infections. MLPA analysis suggested a duplication of the entire RUNX2 gene. MLPA analysis indicated that the duplication was not present in parental blood samples. SNP array analysis identified the duplication was 6.9 Mb in size and mapped to 6p12.3–p21.1 (chr6: 40,797,975–47,701,961 NCBI Build 35; May 2004), thus encompassing 163 ENSEMBL genes. The finding of abnormal fontanelles and/or abnormal sutures, either manifested as craniosynostosis or not, has been documented in 5 cases in patients with pure partial trisomy 6p. No analysis of RUNX2 expression was performed. PMID: 23348268 - Greives et al 2013 - present a case study of a boy with an atypical skull deformity with pan-craniosynostosis whose microarray analysis revealed 4 copies of a 1.24-Mb region from 6p12.3 to 6p21.1 containing the RUNX2 gene. He presented as an infant with airway obstruction from choanal atresia. He was diagnosed with a closed anterior fontanelle, ventricular septal defect, restricted range of motion in his elbows, mild conductive hearing loss, and developmental delays. They note that his multisutural craniosynostosis is the most extensive associated with RUNX2. No segregation analysis given. PMID:25899668 - Molin et al 2015 - report on a family with an affected mother and three affected children. The four patients carried a 285 kb duplication identified by array comparative genomic hybridization. The duplication includes the entire sequence of RUNX2 and the 5' half of SUPT3H. We confirmed the duplication by real-time quantitative PCR in the four patients. Two children presented with the association of metopic craniosynostosis and oligo/hypodontia previously described, confirming the phenotype caused by RUNX2 duplication. The mother and one child had isolated hypodontia without craniosynostosis. The clinical presentation shown by syndromic patients IV‐1 and IV‐3 appears radically different from MDMHB, but shares a few similarities with previously duplication patients, including as hypodontia and craniosynostosis. Isolated hypodontia observed in Patients III‐2 and IV‐2 highlights a wider clinical spectrum associated with RUNX2 duplication, in addition to isolated and syndromic craniosynostosis and MDMHB. Decipher - there are 6 patients with RUNX2 duplications over 1 kb in size. None mention craniosynostosis as a feature, although abnormality of the face/triangular face is listed for the patient with the 3.59 Mb duplication. https://decipher.sanger.ac.uk/gene/RUNX2#variants/RUNX2/patient-overlap/cnvs Mouse models: PMIDs: 11581292 (Liu et al 2001) and 12167715 (Geoffroy et al 2002) - both surprisingly report transgenic mice overexpressing Cbfa1 (runx2) developed severe osteopenia. PMID: 21807129 - Maeno et al 2011 - report that in mice early onset of Runx2 expression in the cranial mesenchyme induced mineralization on E13.0, when no mineralization was observed in wild-type mice, and resulted in craniosynostosis. PMID: 23300083 McGee-Lawrence et al 2013 - Runx2-deficient mice die at birth because of a lack of skeletal ossification. Axin2-deficient mice develop craniosynostosis because of high β-catenin activity. Runx2 represses transcription of Axin2 mRNA. They state that their data are consistent with the idea that Runx2 plays a central role in the etiologies of several different forms of craniosynostosis. Control populations: A search for the smallest CNV in a patient with craniosynostosis from Molin et al 2015 in the Database of Genomic Variants using GRCh38 coordinates shows no invidiuals from control populations with CNVs that cover RUNX2 http://dgv.tcag.ca/gb2/gbrowse/dgv2_hg38/?name=chr6%3A45265488-45551053;search=Search. Summary: Loss of function variants, partial duplication of the the RUNX2 gene and full duplication of the RUNX2 gene appear to result in different phenotypes. With regards to full duplication, there are 4 cases reported in separate publications of duplications fully covering the RUNX2 gene and patients with a craniosynostosis phenotype. The smallest duplication is 285 kb and includes RUNX2 and the 5' half of SUPT3H. However, there appears to be incomplete penetrance with some carriers having a less severe phenotype. Mefford et al state the CNV they report was not found in 2,493 control individuals and CNVs covering RUNX2 were not found in the Database of Genomics Variants. Mouse models give conflicting evidence. Mouse models of runx2 over-expression surprisingly found they developed severe osteopenia. However, early onset of Runx2 expression resulted in craniosynostosis, and Runx2 was found to repress Axin2, low levels of which can result in craniosynostosis. |
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| Rare syndromic craniosynostosis or isolated multisuture synostosis v1.123 | RUNX2 |
Eleanor Williams changed review comment from: Loss of functional mutations associated with CLEIDOCRANIAL DYSPLASIA in Gene2Phenotype (confirmed). In OMIM loss of function mutations are associated with several phenotypes including Cleidocranial dysplasia. A heterozygous duplication of some exons of RUNX2 is associated with Metaphyseal dysplasia with maxillary hypoplasia with or without brachydactyly . However, craniosynostosis is not listed as a feature of this disorder (PMID: 23290074, 25311905, 29891876 CNV EVIDENCE: PMID: 20683987 - Mefford et al 2010 - Evaluated 186 individuals with single-suture craniosynostosis for submicroscopic deletions and duplications using whole-genome array CGH. They identified a heterozygous inverted 1.1 Mb duplication including the entire sequence of RUNX2, MIR586, and some of CLIC5 and SUPT3H in two affected cousins (1007 and 1019) with metopic synostosis and hypodontia. The duplication was inherited from the mother of one individual and it is presumed the father of the second individual (DNA not available, mother does not have the duplication). Both carrier parents have hypodontia by report, but neither is known to have had synostosis suggesting incomplete penetrance for that phenotype. The grandfather of 1007 and 1019 is described as having an abnormal head shape with a narrow forehead and several missing teeth; DNA was not available from this individual. They state that this CNV was not found in 2,493 control individuals [Itsara et al., 2009]. They compared RUNX2 expression levels in osteoblasts from these two individuals to expression levels in osteoblasts from unaffected individuals (n = 6) and individuals with synostosis but without duplication of RUNX2 (n = 22). The average expression of RUNX2 in the samples from the two individuals was higher than all affected and unaffected cell lines but it was not a statistically significant difference so should be interpreted with caution. PMID: 23307468 - Varvagiannis et al 2013 - a girl with a de novo trisomy 6p12.3-p21.1 who showed craniosynostosis, manifested by the premature fusion of the right coronal and sagittal sutures, and also facial anomalies, psychomotor delay, and recurrent respiratory tract infections. MLPA analysis suggested a duplication of the entire RUNX2 gene. MLPA analysis indicated that the duplication was not present in parental blood samples. SNP array analysis identified the duplication was 6.9 Mb in size and mapped to 6p12.3–p21.1 (chr6: 40,797,975–47,701,961 NCBI Build 35; May 2004), thus encompassing 163 ENSEMBL genes. The finding of abnormal fontanelles and/or abnormal sutures, either manifested as craniosynostosis or not, has been documented in 5 cases in patients with pure partial trisomy 6p. No analysis of RUNX2 expression was performed. PMID: 23348268 - Greives et al 2013 - present a case study of a boy with an atypical skull deformity with pan-craniosynostosis whose microarray analysis revealed 4 copies of a 1.24-Mb region from 6p12.3 to 6p21.1 containing the RUNX2 gene. He presented as an infant with airway obstruction from choanal atresia. He was diagnosed with a closed anterior fontanelle, ventricular septal defect, restricted range of motion in his elbows, mild conductive hearing loss, and developmental delays. They note that his multisutural craniosynostosis is the most extensive associated with RUNX2. No segregation analysis given. PMID:25899668 - Molin et al 2015 - report on a family with an affected mother and three affected children. The four patients carried a 285 kb duplication identified by array comparative genomic hybridization. The duplication includes the entire sequence of RUNX2 and the 5' half of SUPT3H. We confirmed the duplication by real-time quantitative PCR in the four patients. Two children presented with the association of metopic craniosynostosis and oligo/hypodontia previously described, confirming the phenotype caused by RUNX2 duplication. The mother and one child had isolated hypodontia without craniosynostosis. The clinical presentation shown by syndromic patients IV‐1 and IV‐3 appears radically different from MDMHB, but shares a few similarities with previously duplication patients, including as hypodontia and craniosynostosis. Isolated hypodontia observed in Patients III‐2 and IV‐2 highlights a wider clinical spectrum associated with RUNX2 duplication, in addition to isolated and syndromic craniosynostosis and MDMHB. Decipher - there are 6 patients with RUNX2 duplications over 1 kb in size. None mention craniosynostosis as a feature, although abnormality of the face/triangular face is listed for the patient with the 3.59 Mb duplication. https://decipher.sanger.ac.uk/gene/RUNX2#variants/RUNX2/patient-overlap/cnvs Mouse models: PMIDs: 11581292 (Liu et al 2001) and 12167715 (Geoffroy et al 2002) - both surprisingly report transgenic mice overexpressing Cbfa1 (runx2) developed severe osteopenia. PMID: 21807129 - Maeno et al 2011 - report that in mice early onset of Runx2 expression in the cranial mesenchyme induced mineralization on E13.0, when no mineralization was observed in wild-type mice, and resulted in craniosynostosis. PMID: 23300083 McGee-Lawrence et al 2013 - Runx2-deficient mice die at birth because of a lack of skeletal ossification. Axin2-deficient mice develop craniosynostosis because of high β-catenin activity. Runx2 represses transcription of Axin2 mRNA. They state that their data are consistent with the idea that Runx2 plays a central role in the etiologies of several different forms of craniosynostosis. Summary: Loss of function variants, partial duplication of the the RUNX2 gene and full duplication of the RUNX2 gene appear to result in different phenotypes. With regards to full duplication, there are 4 cases reported in separate publications of duplications fully covering the RUNX2 gene and patients with a craniosynostosis phenotype. The smallest duplication is 285 kb and includes RUNX2 and the 5' half of SUPT3H. However, there appears to be incomplete penetrance with some carriers having a less severe phenotype. Mefford et al state the CNV they report was not found in 2,493 control individuals. Mouse models give conflicting evidence. Mouse models of runx2 over-expression surprisingly found they developed severe osteopenia. However, early onset of Runx2 expression resulted in craniosynostosis, and Runx2 was found to repress Axin2, low levels of which can result in craniosynostosis. ; to: Loss of functional mutations associated with CLEIDOCRANIAL DYSPLASIA in Gene2Phenotype (confirmed). In OMIM loss of function mutations are associated with several phenotypes including Cleidocranial dysplasia. A heterozygous duplication of some exons of RUNX2 is associated with Metaphyseal dysplasia with maxillary hypoplasia with or without brachydactyly . However, craniosynostosis is not listed as a feature of this disorder (PMID: 23290074, 25311905, 29891876 CNV EVIDENCE: PMID: 20683987 - Mefford et al 2010 - Evaluated 186 individuals with single-suture craniosynostosis for submicroscopic deletions and duplications using whole-genome array CGH. They identified a heterozygous inverted 1.1 Mb duplication including the entire sequence of RUNX2, MIR586, and some of CLIC5 and SUPT3H in two affected cousins (1007 and 1019) with metopic synostosis and hypodontia. The duplication was inherited from the mother of one individual and it is presumed the father of the second individual (DNA not available, mother does not have the duplication). Both carrier parents have hypodontia by report, but neither is known to have had synostosis suggesting incomplete penetrance for that phenotype. The grandfather of 1007 and 1019 is described as having an abnormal head shape with a narrow forehead and several missing teeth; DNA was not available from this individual. They state that this CNV was not found in 2,493 control individuals [Itsara et al., 2009]. They compared RUNX2 expression levels in osteoblasts from these two individuals to expression levels in osteoblasts from unaffected individuals (n = 6) and individuals with synostosis but without duplication of RUNX2 (n = 22). The average expression of RUNX2 in the samples from the two individuals was higher than all affected and unaffected cell lines but it was not a statistically significant difference so should be interpreted with caution. PMID: 23307468 - Varvagiannis et al 2013 - a girl with a de novo trisomy 6p12.3-p21.1 who showed craniosynostosis, manifested by the premature fusion of the right coronal and sagittal sutures, and also facial anomalies, psychomotor delay, and recurrent respiratory tract infections. MLPA analysis suggested a duplication of the entire RUNX2 gene. MLPA analysis indicated that the duplication was not present in parental blood samples. SNP array analysis identified the duplication was 6.9 Mb in size and mapped to 6p12.3–p21.1 (chr6: 40,797,975–47,701,961 NCBI Build 35; May 2004), thus encompassing 163 ENSEMBL genes. The finding of abnormal fontanelles and/or abnormal sutures, either manifested as craniosynostosis or not, has been documented in 5 cases in patients with pure partial trisomy 6p. No analysis of RUNX2 expression was performed. PMID: 23348268 - Greives et al 2013 - present a case study of a boy with an atypical skull deformity with pan-craniosynostosis whose microarray analysis revealed 4 copies of a 1.24-Mb region from 6p12.3 to 6p21.1 containing the RUNX2 gene. He presented as an infant with airway obstruction from choanal atresia. He was diagnosed with a closed anterior fontanelle, ventricular septal defect, restricted range of motion in his elbows, mild conductive hearing loss, and developmental delays. They note that his multisutural craniosynostosis is the most extensive associated with RUNX2. No segregation analysis given. PMID:25899668 - Molin et al 2015 - report on a family with an affected mother and three affected children. The four patients carried a 285 kb duplication identified by array comparative genomic hybridization. The duplication includes the entire sequence of RUNX2 and the 5' half of SUPT3H. We confirmed the duplication by real-time quantitative PCR in the four patients. Two children presented with the association of metopic craniosynostosis and oligo/hypodontia previously described, confirming the phenotype caused by RUNX2 duplication. The mother and one child had isolated hypodontia without craniosynostosis. The clinical presentation shown by syndromic patients IV‐1 and IV‐3 appears radically different from MDMHB, but shares a few similarities with previously duplication patients, including as hypodontia and craniosynostosis. Isolated hypodontia observed in Patients III‐2 and IV‐2 highlights a wider clinical spectrum associated with RUNX2 duplication, in addition to isolated and syndromic craniosynostosis and MDMHB. Decipher - there are 6 patients with RUNX2 duplications over 1 kb in size. None mention craniosynostosis as a feature, although abnormality of the face/triangular face is listed for the patient with the 3.59 Mb duplication. https://decipher.sanger.ac.uk/gene/RUNX2#variants/RUNX2/patient-overlap/cnvs Mouse models: PMIDs: 11581292 (Liu et al 2001) and 12167715 (Geoffroy et al 2002) - both surprisingly report transgenic mice overexpressing Cbfa1 (runx2) developed severe osteopenia. PMID: 21807129 - Maeno et al 2011 - report that in mice early onset of Runx2 expression in the cranial mesenchyme induced mineralization on E13.0, when no mineralization was observed in wild-type mice, and resulted in craniosynostosis. PMID: 23300083 McGee-Lawrence et al 2013 - Runx2-deficient mice die at birth because of a lack of skeletal ossification. Axin2-deficient mice develop craniosynostosis because of high β-catenin activity. Runx2 represses transcription of Axin2 mRNA. They state that their data are consistent with the idea that Runx2 plays a central role in the etiologies of several different forms of craniosynostosis. Control populations: A search for the smallest CNV in a patient with craniosynostosis from Molin et al 2015 in the Database of Genomics Variants using GRCh38 coordinates shows no invidiuals from control populations with CNVs that cover RUNX2 http://dgv.tcag.ca/gb2/gbrowse/dgv2_hg38/?name=chr6%3A45265488-45551053;search=Search. Summary: Loss of function variants, partial duplication of the the RUNX2 gene and full duplication of the RUNX2 gene appear to result in different phenotypes. With regards to full duplication, there are 4 cases reported in separate publications of duplications fully covering the RUNX2 gene and patients with a craniosynostosis phenotype. The smallest duplication is 285 kb and includes RUNX2 and the 5' half of SUPT3H. However, there appears to be incomplete penetrance with some carriers having a less severe phenotype. Mefford et al state the CNV they report was not found in 2,493 control individuals and CNVs covering RUNX2 were not found in the Database of Genomics Variants. Mouse models give conflicting evidence. Mouse models of runx2 over-expression surprisingly found they developed severe osteopenia. However, early onset of Runx2 expression resulted in craniosynostosis, and Runx2 was found to repress Axin2, low levels of which can result in craniosynostosis. |
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| Rare syndromic craniosynostosis or isolated multisuture synostosis v1.123 | RUNX2 |
Eleanor Williams changed review comment from: Loss of functional mutations associated with CLEIDOCRANIAL DYSPLASIA in Gene2Phenotype (confirmed). In OMIM loss of function mutations are associated with several phenotypes including Cleidocranial dysplasia. A heterozygous duplication of some exons of RUNX2 is associated with Metaphyseal dysplasia with maxillary hypoplasia with or without brachydactyly . However, craniosynostosis is not listed as a feature of this disorder (PMID: 23290074, 25311905, 29891876 CNV EVIDENCE: PMID: 20683987 - Mefford et al 2010 - Evaluated 186 individuals with single-suture craniosynostosis for submicroscopic deletions and duplications using whole-genome array CGH. They identified a heterozygous inverted 1.1 Mb duplication including the entire sequence of RUNX2, MIR586, and some of CLIC5 and SUPT3H in two affected cousins (1007 and 1019) with metopic synostosis and hypodontia. The duplication was inherited from the mother of one individual and it is presumed the father of the second individual (DNA not available, mother does not have the duplication). Both carrier parents have hypodontia by report, but neither is known to have had synostosis suggesting incomplete penetrance for that phenotype. The grandfather of 1007 and 1019 is described as having an abnormal head shape with a narrow forehead and several missing teeth; DNA was not available from this individual. They state that this CNV was not found in 2,493 control individuals [Itsara et al., 2009]. They compared RUNX2 expression levels in osteoblasts from these two individuals to expression levels in osteoblasts from unaffected individuals (n = 6) and individuals with synostosis but without duplication of RUNX2 (n = 22). The average expression of RUNX2 in the samples from the two individuals was higher than all affected and unaffected cell lines but it was not a statistically significant difference in RUNX2 expression levels so should be interpreted with caution. PMID: 23307468 - Varvagiannis et al 2013 - a girl with a de novo trisomy 6p12.3-p21.1 who showed craniosynostosis, manifested by the premature fusion of the right coronal and sagittal sutures, and also facial anomalies, psychomotor delay, and recurrent respiratory tract infections. MLPA analysis suggested a duplication of the entire RUNX2 gene. MLPA analysis indicated that the duplication was not present in parental blood samples. SNP array analysis identified the duplication was 6.9 Mb in size and mapped to 6p12.3–p21.1 (chr6: 40,797,975–47,701,961 NCBI Build 35; May 2004), thus encompassing 163 ENSEMBL genes. The finding of abnormal fontanelles and/or abnormal sutures, either manifested as craniosynostosis or not, has been documented in 5 cases in patients with pure partial trisomy 6p. No analysis of RUNX2 expression was performed. PMID: 23348268 - Greives et al 2013 - present a case study of a boy with an atypical skull deformity with pan-craniosynostosis whose microarray analysis revealed 4 copies of a 1.24-Mb region from 6p12.3 to 6p21.1 containing the RUNX2 gene. He presented as an infant with airway obstruction from choanal atresia. He was diagnosed with a closed anterior fontanelle, ventricular septal defect, restricted range of motion in his elbows, mild conductive hearing loss, and developmental delays. They note that his multisutural craniosynostosis is the most extensive associated with RUNX2. No segregation analysis given. PMID:25899668 - Molin et al 2015 - report on a family with an affected mother and three affected children. The four patients carried a 285 kb duplication identified by array comparative genomic hybridization. The duplication includes the entire sequence of RUNX2 and the 5' half of SUPT3H. We confirmed the duplication by real-time quantitative PCR in the four patients. Two children presented with the association of metopic craniosynostosis and oligo/hypodontia previously described, confirming the phenotype caused by RUNX2 duplication. The mother and one child had isolated hypodontia without craniosynostosis. The clinical presentation shown by syndromic patients IV‐1 and IV‐3 appears radically different from MDMHB, but shares a few similarities with previously duplication patients, including as hypodontia and craniosynostosis. Isolated hypodontia observed in Patients III‐2 and IV‐2 highlights a wider clinical spectrum associated with RUNX2 duplication, in addition to isolated and syndromic craniosynostosis and MDMHB. Decipher - there are 6 patients with RUNX2 duplications over 1 kb in size. None mention craniosynostosis as a feature, although abnormality of the face/triangular face is listed for the patient with the 3.59 Mb duplication. https://decipher.sanger.ac.uk/gene/RUNX2#variants/RUNX2/patient-overlap/cnvs Mouse models: PMIDs: 11581292 (Liu et al 2001) and 12167715 (Geoffroy et al 2002) - both surprisingly report transgenic mice overexpressing Cbfa1 (runx2) developed severe osteopenia. PMID: 21807129 - Maeno et al 2011 - report that in mice early onset of Runx2 expression in the cranial mesenchyme induced mineralization on E13.0, when no mineralization was observed in wild-type mice, and resulted in craniosynostosis. PMID: 23300083 McGee-Lawrence et al 2013 - Runx2-deficient mice die at birth because of a lack of skeletal ossification. Axin2-deficient mice develop craniosynostosis because of high β-catenin activity. Runx2 represses transcription of Axin2 mRNA. They state that their data are consistent with the idea that Runx2 plays a central role in the etiologies of several different forms of craniosynostosis. Summary: Loss of function variants, partial duplication of the the RUNX2 gene and full duplication of the RUNX2 gene appear to result in different phenotypes. With regards to full duplication, there are 4 cases reported in separate publications of duplications fully covering the RUNX2 gene and patients with a craniosynostosis phenotype. The smallest duplication is 285 kb and includes RUNX2 and the 5' half of SUPT3H. However, there appears to be incomplete penetrance with some carriers having a less severe phenotype. Mefford et al state the CNV they report was not found in 2,493 control individuals. Mouse models give conflicting evidence. Mouse models of runx2 over-expression surprisingly found they developed severe osteopenia. However, early onset of Runx2 expression resulted in craniosynostosis, and Runx2 was found to repress Axin2, low levels of which can result in craniosynostosis. ; to: Loss of functional mutations associated with CLEIDOCRANIAL DYSPLASIA in Gene2Phenotype (confirmed). In OMIM loss of function mutations are associated with several phenotypes including Cleidocranial dysplasia. A heterozygous duplication of some exons of RUNX2 is associated with Metaphyseal dysplasia with maxillary hypoplasia with or without brachydactyly . However, craniosynostosis is not listed as a feature of this disorder (PMID: 23290074, 25311905, 29891876 CNV EVIDENCE: PMID: 20683987 - Mefford et al 2010 - Evaluated 186 individuals with single-suture craniosynostosis for submicroscopic deletions and duplications using whole-genome array CGH. They identified a heterozygous inverted 1.1 Mb duplication including the entire sequence of RUNX2, MIR586, and some of CLIC5 and SUPT3H in two affected cousins (1007 and 1019) with metopic synostosis and hypodontia. The duplication was inherited from the mother of one individual and it is presumed the father of the second individual (DNA not available, mother does not have the duplication). Both carrier parents have hypodontia by report, but neither is known to have had synostosis suggesting incomplete penetrance for that phenotype. The grandfather of 1007 and 1019 is described as having an abnormal head shape with a narrow forehead and several missing teeth; DNA was not available from this individual. They state that this CNV was not found in 2,493 control individuals [Itsara et al., 2009]. They compared RUNX2 expression levels in osteoblasts from these two individuals to expression levels in osteoblasts from unaffected individuals (n = 6) and individuals with synostosis but without duplication of RUNX2 (n = 22). The average expression of RUNX2 in the samples from the two individuals was higher than all affected and unaffected cell lines but it was not a statistically significant difference so should be interpreted with caution. PMID: 23307468 - Varvagiannis et al 2013 - a girl with a de novo trisomy 6p12.3-p21.1 who showed craniosynostosis, manifested by the premature fusion of the right coronal and sagittal sutures, and also facial anomalies, psychomotor delay, and recurrent respiratory tract infections. MLPA analysis suggested a duplication of the entire RUNX2 gene. MLPA analysis indicated that the duplication was not present in parental blood samples. SNP array analysis identified the duplication was 6.9 Mb in size and mapped to 6p12.3–p21.1 (chr6: 40,797,975–47,701,961 NCBI Build 35; May 2004), thus encompassing 163 ENSEMBL genes. The finding of abnormal fontanelles and/or abnormal sutures, either manifested as craniosynostosis or not, has been documented in 5 cases in patients with pure partial trisomy 6p. No analysis of RUNX2 expression was performed. PMID: 23348268 - Greives et al 2013 - present a case study of a boy with an atypical skull deformity with pan-craniosynostosis whose microarray analysis revealed 4 copies of a 1.24-Mb region from 6p12.3 to 6p21.1 containing the RUNX2 gene. He presented as an infant with airway obstruction from choanal atresia. He was diagnosed with a closed anterior fontanelle, ventricular septal defect, restricted range of motion in his elbows, mild conductive hearing loss, and developmental delays. They note that his multisutural craniosynostosis is the most extensive associated with RUNX2. No segregation analysis given. PMID:25899668 - Molin et al 2015 - report on a family with an affected mother and three affected children. The four patients carried a 285 kb duplication identified by array comparative genomic hybridization. The duplication includes the entire sequence of RUNX2 and the 5' half of SUPT3H. We confirmed the duplication by real-time quantitative PCR in the four patients. Two children presented with the association of metopic craniosynostosis and oligo/hypodontia previously described, confirming the phenotype caused by RUNX2 duplication. The mother and one child had isolated hypodontia without craniosynostosis. The clinical presentation shown by syndromic patients IV‐1 and IV‐3 appears radically different from MDMHB, but shares a few similarities with previously duplication patients, including as hypodontia and craniosynostosis. Isolated hypodontia observed in Patients III‐2 and IV‐2 highlights a wider clinical spectrum associated with RUNX2 duplication, in addition to isolated and syndromic craniosynostosis and MDMHB. Decipher - there are 6 patients with RUNX2 duplications over 1 kb in size. None mention craniosynostosis as a feature, although abnormality of the face/triangular face is listed for the patient with the 3.59 Mb duplication. https://decipher.sanger.ac.uk/gene/RUNX2#variants/RUNX2/patient-overlap/cnvs Mouse models: PMIDs: 11581292 (Liu et al 2001) and 12167715 (Geoffroy et al 2002) - both surprisingly report transgenic mice overexpressing Cbfa1 (runx2) developed severe osteopenia. PMID: 21807129 - Maeno et al 2011 - report that in mice early onset of Runx2 expression in the cranial mesenchyme induced mineralization on E13.0, when no mineralization was observed in wild-type mice, and resulted in craniosynostosis. PMID: 23300083 McGee-Lawrence et al 2013 - Runx2-deficient mice die at birth because of a lack of skeletal ossification. Axin2-deficient mice develop craniosynostosis because of high β-catenin activity. Runx2 represses transcription of Axin2 mRNA. They state that their data are consistent with the idea that Runx2 plays a central role in the etiologies of several different forms of craniosynostosis. Summary: Loss of function variants, partial duplication of the the RUNX2 gene and full duplication of the RUNX2 gene appear to result in different phenotypes. With regards to full duplication, there are 4 cases reported in separate publications of duplications fully covering the RUNX2 gene and patients with a craniosynostosis phenotype. The smallest duplication is 285 kb and includes RUNX2 and the 5' half of SUPT3H. However, there appears to be incomplete penetrance with some carriers having a less severe phenotype. Mefford et al state the CNV they report was not found in 2,493 control individuals. Mouse models give conflicting evidence. Mouse models of runx2 over-expression surprisingly found they developed severe osteopenia. However, early onset of Runx2 expression resulted in craniosynostosis, and Runx2 was found to repress Axin2, low levels of which can result in craniosynostosis. |
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| Rare syndromic craniosynostosis or isolated multisuture synostosis v1.123 | RUNX2 |
Eleanor Williams changed review comment from: Loss of functional mutations associated with CLEIDOCRANIAL DYSPLASIA in Gene2Phenotype (confirmed). In OMIM loss of function mutations are associated with several phenotypes including Cleidocranial dysplasia. A heterozygous duplication of some exons of RUNX2 is associated with Metaphyseal dysplasia with maxillary hypoplasia with or without brachydactyly . However, craniosynostosis is not listed as a feature of this disorder (PMID: 23290074, 25311905, 29891876 CNV EVIDENCE: PMID: 20683987 - Mefford et al 2010 - Evaluated 186 individuals with single-suture craniosynostosis for submicroscopic deletions and duplications using whole-genome array CGH. They identified a heterozygous inverted 1.1 Mb duplication including the entire sequence of RUNX2, MIR586, and some of CLIC5 and SUPT3H in two affected cousins (1007 and 1019) with metopic synostosis and hypodontia. The duplication was inherited from the mother of one individual and it is presumed the father of the second individual (DNA not available, mother does not have the duplication). Both carrier parents have hypodontia by report, but neither is known to have had synostosis suggesting incomplete penetrance for that phenotype. The grandfather of 1007 and 1019 is described as having an abnormal head shape with a narrow forehead and several missing teeth; DNA was not available from this individual. They state that this CNV was not found in 2,493 control individuals [Itsara et al., 2009]. They compared RUNX2 expression levels in osteoblasts from these two individuals to expression levels in osteoblasts from unaffected individuals (n = 6) and individuals with synostosis but without duplication of RUNX2 (n = 22). The average expression of RUNX2 in the samples from the two individuals was higher than all affected and unaffected cell lines but it was not a statistically significant difference in RUNX2 expression levels so should be interpreted with caution. PMID: 23307468 - Varvagiannis et al 2013 - a girl with a de novo trisomy 6p12.3-p21.1 who showed craniosynostosis, manifested by the premature fusion of the right coronal and sagittal sutures, and also facial anomalies, psychomotor delay, and recurrent respiratory tract infections. MLPA analysis suggested a duplication of the entire RUNX2 gene. MLPA analysis indicated that the duplication was not present in parental blood samples. SNP array analysis identified the duplication was 6.9 Mb in size and mapped to 6p12.3–p21.1 (chr6: 40,797,975–47,701,961 NCBI Build 35; May 2004), thus encompassing 163 ENSEMBL genes. The finding of abnormal fontanelles and/or abnormal sutures, either manifested as craniosynostosis or not, has been documented in 5 cases in patients with pure partial trisomy 6p. No analysis of RUNX2 expression was performed. PMID: 23348268 - Greives et al 2013 - present a case study of a boy with an atypical skull deformity with pan-craniosynostosis whose microarray analysis revealed 4 copies of a 1.24-Mb region from 6p12.3 to 6p21.1 containing the RUNX2 gene. He presented as an infant with airway obstruction from choanal atresia. He was diagnosed with a closed anterior fontanelle, ventricular septal defect, restricted range of motion in his elbows, mild conductive hearing loss, and developmental delays. They note that his multisutural craniosynostosis is the most extensive associated with RUNX2. No segregation analysis given. PMID:25899668 - Molin et al 2015 - report on a family with an affected mother and three affected children. The four patients carried a 285 kb duplication identified by array comparative genomic hybridization. The duplication includes the entire sequence of RUNX2 and the 5' half of SUPT3H. We confirmed the duplication by real-time quantitative PCR in the four patients. Two children presented with the association of metopic craniosynostosis and oligo/hypodontia previously described, confirming the phenotype caused by RUNX2 duplication. The mother and one child had isolated hypodontia without craniosynostosis. The clinical presentation shown by syndromic patients IV‐1 and IV‐3 appears radically different from MDMHB, but shares a few similarities with previously duplication patients, including as hypodontia and craniosynostosis. Isolated hypodontia observed in Patients III‐2 and IV‐2 highlights a wider clinical spectrum associated with RUNX2 duplication, in addition to isolated and syndromic craniosynostosis and MDMHB. Decipher - there are 6 patients with RUNX2 duplications over 1 kb in size. None mention craniosynostosis as a feature, although abnormality of the face/triangular face is listed for the patient with the 3.59 Mb duplication. https://decipher.sanger.ac.uk/gene/RUNX2#variants/RUNX2/patient-overlap/cnvs Mouse models: PMIDs: 11581292 (Liu et al 2001) and 12167715 (Geoffroy et al 2002) - both surprisingly report transgenic mice overexpressing Cbfa1 (runx2) developed severe osteopenia. PMID: 21807129 - Maeno et al 2011 - report that in mice early onset of Runx2 expression in the cranial mesenchyme induced mineralization on E13.0, when no mineralization was observed in wild-type mice, and resulted in craniosynostosis. PMID: 23300083 McGee-Lawrence et al 2013 - Runx2-deficient mice die at birth because of a lack of skeletal ossification. Axin2-deficient mice develop craniosynostosis because of high β-catenin activity. Runx2 represses transcription of Axin2 mRNA. They state that their data are consistent with the idea that Runx2 plays a central role in the etiologies of several different forms of craniosynostosis. Summary: Loss of function variants, partial duplication of the the RUNX2 gene and full duplication of the RUNX2 gene appear to result in different phenotypes. With regards to full duplication, there are 4 cases reported in separate publications of duplications fully covering the RUNX2 gene and patients with a craniosynostosis phenotype. The smallest duplication is 285 kb and includes RUNX2 and the 5' half of SUPT3H. However, there appears to be incomplete penetrance with some carriers having a less severe phenotype. Mefford et al state the CNV they report was not found in 2,493 control individuals. Mouse models give conflicting evidence. Mouse models of runx2 over-expression surprisingly found they developed severe osteopenia. However, early onset of Runx2 expression resulted in craniosynostosis, and Runx2 was found to repress Axin2, low levels of which can result in craniosynostosis. ; to: Loss of functional mutations associated with CLEIDOCRANIAL DYSPLASIA in Gene2Phenotype (confirmed). In OMIM loss of function mutations are associated with several phenotypes including Cleidocranial dysplasia. A heterozygous duplication of some exons of RUNX2 is associated with Metaphyseal dysplasia with maxillary hypoplasia with or without brachydactyly . However, craniosynostosis is not listed as a feature of this disorder (PMID: 23290074, 25311905, 29891876 CNV EVIDENCE: PMID: 20683987 - Mefford et al 2010 - Evaluated 186 individuals with single-suture craniosynostosis for submicroscopic deletions and duplications using whole-genome array CGH. They identified a heterozygous inverted 1.1 Mb duplication including the entire sequence of RUNX2, MIR586, and some of CLIC5 and SUPT3H in two affected cousins (1007 and 1019) with metopic synostosis and hypodontia. The duplication was inherited from the mother of one individual and it is presumed the father of the second individual (DNA not available, mother does not have the duplication). Both carrier parents have hypodontia by report, but neither is known to have had synostosis suggesting incomplete penetrance for that phenotype. The grandfather of 1007 and 1019 is described as having an abnormal head shape with a narrow forehead and several missing teeth; DNA was not available from this individual. They state that this CNV was not found in 2,493 control individuals [Itsara et al., 2009]. They compared RUNX2 expression levels in osteoblasts from these two individuals to expression levels in osteoblasts from unaffected individuals (n = 6) and individuals with synostosis but without duplication of RUNX2 (n = 22). The average expression of RUNX2 in the samples from the two individuals was higher than all affected and unaffected cell lines but it was not a statistically significant difference in RUNX2 expression levels so should be interpreted with caution. PMID: 23307468 - Varvagiannis et al 2013 - a girl with a de novo trisomy 6p12.3-p21.1 who showed craniosynostosis, manifested by the premature fusion of the right coronal and sagittal sutures, and also facial anomalies, psychomotor delay, and recurrent respiratory tract infections. MLPA analysis suggested a duplication of the entire RUNX2 gene. MLPA analysis indicated that the duplication was not present in parental blood samples. SNP array analysis identified the duplication was 6.9 Mb in size and mapped to 6p12.3–p21.1 (chr6: 40,797,975–47,701,961 NCBI Build 35; May 2004), thus encompassing 163 ENSEMBL genes. The finding of abnormal fontanelles and/or abnormal sutures, either manifested as craniosynostosis or not, has been documented in 5 cases in patients with pure partial trisomy 6p. No analysis of RUNX2 expression was performed. PMID: 23348268 - Greives et al 2013 - present a case study of a boy with an atypical skull deformity with pan-craniosynostosis whose microarray analysis revealed 4 copies of a 1.24-Mb region from 6p12.3 to 6p21.1 containing the RUNX2 gene. He presented as an infant with airway obstruction from choanal atresia. He was diagnosed with a closed anterior fontanelle, ventricular septal defect, restricted range of motion in his elbows, mild conductive hearing loss, and developmental delays. They note that his multisutural craniosynostosis is the most extensive associated with RUNX2. No segregation analysis given. PMID:25899668 - Molin et al 2015 - report on a family with an affected mother and three affected children. The four patients carried a 285 kb duplication identified by array comparative genomic hybridization. The duplication includes the entire sequence of RUNX2 and the 5' half of SUPT3H. We confirmed the duplication by real-time quantitative PCR in the four patients. Two children presented with the association of metopic craniosynostosis and oligo/hypodontia previously described, confirming the phenotype caused by RUNX2 duplication. The mother and one child had isolated hypodontia without craniosynostosis. The clinical presentation shown by syndromic patients IV‐1 and IV‐3 appears radically different from MDMHB, but shares a few similarities with previously duplication patients, including as hypodontia and craniosynostosis. Isolated hypodontia observed in Patients III‐2 and IV‐2 highlights a wider clinical spectrum associated with RUNX2 duplication, in addition to isolated and syndromic craniosynostosis and MDMHB. Decipher - there are 6 patients with RUNX2 duplications over 1 kb in size. None mention craniosynostosis as a feature, although abnormality of the face/triangular face is listed for the patient with the 3.59 Mb duplication. https://decipher.sanger.ac.uk/gene/RUNX2#variants/RUNX2/patient-overlap/cnvs Mouse models: PMIDs: 11581292 (Liu et al 2001) and 12167715 (Geoffroy et al 2002) - both surprisingly report transgenic mice overexpressing Cbfa1 (runx2) developed severe osteopenia. PMID: 21807129 - Maeno et al 2011 - report that in mice early onset of Runx2 expression in the cranial mesenchyme induced mineralization on E13.0, when no mineralization was observed in wild-type mice, and resulted in craniosynostosis. PMID: 23300083 McGee-Lawrence et al 2013 - Runx2-deficient mice die at birth because of a lack of skeletal ossification. Axin2-deficient mice develop craniosynostosis because of high β-catenin activity. Runx2 represses transcription of Axin2 mRNA. They state that their data are consistent with the idea that Runx2 plays a central role in the etiologies of several different forms of craniosynostosis. Summary: Loss of function variants, partial duplication of the the RUNX2 gene and full duplication of the RUNX2 gene appear to result in different phenotypes. With regards to full duplication, there are 4 cases reported in separate publications of duplications fully covering the RUNX2 gene and patients with a craniosynostosis phenotype. The smallest duplication is 285 kb and includes RUNX2 and the 5' half of SUPT3H. However, there appears to be incomplete penetrance with some carriers having a less severe phenotype. Mefford et al state the CNV they report was not found in 2,493 control individuals. Mouse models give conflicting evidence. Mouse models of runx2 over-expression surprisingly found they developed severe osteopenia. However, early onset of Runx2 expression resulted in craniosynostosis, and Runx2 was found to repress Axin2, low levels of which can result in craniosynostosis. |
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| Rare syndromic craniosynostosis or isolated multisuture synostosis v1.123 | RUNX2 |
Eleanor Williams changed review comment from: Loss of functional mutations associated with CLEIDOCRANIAL DYSPLASIA in Gene2Phenotype (confirmed). In OMIM loss of function mutations are associated with several phenotypes including Cleidocranial dysplasia. A heterozygous duplication of some exons of RUNX2 is associated with Metaphyseal dysplasia with maxillary hypoplasia with or without brachydactyly . However, craniosynostosis is not listed as a feature of this disorder (PMID: 23290074, 25311905, 29891876 CNV EVIDENCE: PMID: 20683987 - Mefford et al 2010 - Evaluated 186 individuals with single-suture craniosynostosis for submicroscopic deletions and duplications using whole-genome array CGH. They identified a heterozygous inverted 1.1 Mb duplication including the entire sequence of RUNX2, MIR586, and some of CLIC5 and SUPT3H in two affected cousins (1007 and 1019) with metopic synostosis and hypodontia. The duplication was inherited from the mother of one individual and it is presumed the father of the second individual (DNA not available, mother does not have the duplication). Both carrier parents have hypodontia by report, but neither is known to have had synostosis suggesting incomplete penetrance for that phenotype. The grandfather of 1007 and 1019 is described as having an abnormal head shape with a narrow forehead and several missing teeth; DNA was not available from this individual. They compared RUNX2 expression levels in osteoblasts from these two individuals to expression levels in osteoblasts from unaffected individuals (n = 6) and individuals with synostosis but without duplication of RUNX2 (n = 22). The average expression of RUNX2 in the samples from the two individuals was higher than all affected and unaffected cell lines but it was not a statistically significant difference in RUNX2 expression levels so should be interpreted with caution. PMID: 23307468 - Varvagiannis et al 2013 - a girl with a de novo trisomy 6p12.3-p21.1 who showed craniosynostosis, manifested by the premature fusion of the right coronal and sagittal sutures, and also facial anomalies, psychomotor delay, and recurrent respiratory tract infections. MLPA analysis suggested a duplication of the entire RUNX2 gene. MLPA analysis indicated that the duplication was not present in parental blood samples. SNP array analysis identified the duplication was 6.9 Mb in size and mapped to 6p12.3–p21.1 (chr6: 40,797,975–47,701,961 NCBI Build 35; May 2004), thus encompassing 163 ENSEMBL genes. The finding of abnormal fontanelles and/or abnormal sutures, either manifested as craniosynostosis or not, has been documented in 5 cases in patients with pure partial trisomy 6p. No analysis of RUNX2 expression was performed. PMID: 23348268 - Greives et al 2013 - present a case study of a boy with an atypical skull deformity with pan-craniosynostosis whose microarray analysis revealed 4 copies of a 1.24-Mb region from 6p12.3 to 6p21.1 containing the RUNX2 gene. He presented as an infant with airway obstruction from choanal atresia. He was diagnosed with a closed anterior fontanelle, ventricular septal defect, restricted range of motion in his elbows, mild conductive hearing loss, and developmental delays. No segregation analysis given. PMID: McGee-Lawrence et al 2013 - Axin2-deficient mice develop craniosynostosis because of high β-catenin activity. Runx2 represses transcription of Axin2 mRNA. To determine whether Runx2 contributes to the etiology of Axin2 deficiency-induced craniosynostosis, they generated Axin2(-/-):Runx2(+/-) mice. These double mutant mice had longer skulls than Axin2(-/-) mice, indicating that Runx2 haploinsufficiency rescued the craniosynostosis phenotype of Axin2(-/-) mice PMID:25899668 - Molin et al 2015 - report on a family with an affected mother and three affected children. The four patients carried a 285 kb duplication identified by array comparative genomic hybridization. The duplication includes the entire sequence of RUNX2 and the 5' half of SUPT3H. We confirmed the duplication by real-time quantitative PCR in the four patients. Two children presented with the association of metopic craniosynostosis and oligo/hypodontia previously described, confirming the phenotype caused by RUNX2 duplication. The mother and one child had isolated hypodontia without craniosynostosis. The clinical presentation shown by syndromic Patients IV‐1 and IV‐3 appears radically different from MDMHB, but shares a few similarities with previously duplication patients, including as hypodontia and craniosynostosis. Isolated hypodontia observed in Patients III‐2 and IV‐2 highlights a wider clinical spectrum associated with RUNX2 duplication, in addition to isolated and syndromic craniosynostosis and MDMHB. Decipher - there are 6 patients with RUNX2 duplications over 1 kb in size. None mention craniosynostosis as a feature, although abnormality of the face/triangular face is listed for the patient with the 3.59 Mb duplication. https://decipher.sanger.ac.uk/gene/RUNX2#variants/RUNX2/patient-overlap/cnvs Summary: Loss of function variants, partial duplication of the the RUNX2 gene and full duplication of the RUNX2 gene appear to result in different phenotypes. With regards to full duplication, there are 4 cases reported in separate publications of duplications fully covering the RUNX2 gene and patients with a craniosynostosis phenotype. The smallest duplication is 285 kb and includes RUNX2 and the 5' half of SUPT3H. However, there appears to be incomplete penetrance with some carriers having a less severe phenotype. Frequency of CNVs covering this region in the general population have not been reported.; to: Loss of functional mutations associated with CLEIDOCRANIAL DYSPLASIA in Gene2Phenotype (confirmed). In OMIM loss of function mutations are associated with several phenotypes including Cleidocranial dysplasia. A heterozygous duplication of some exons of RUNX2 is associated with Metaphyseal dysplasia with maxillary hypoplasia with or without brachydactyly . However, craniosynostosis is not listed as a feature of this disorder (PMID: 23290074, 25311905, 29891876 CNV EVIDENCE: PMID: 20683987 - Mefford et al 2010 - Evaluated 186 individuals with single-suture craniosynostosis for submicroscopic deletions and duplications using whole-genome array CGH. They identified a heterozygous inverted 1.1 Mb duplication including the entire sequence of RUNX2, MIR586, and some of CLIC5 and SUPT3H in two affected cousins (1007 and 1019) with metopic synostosis and hypodontia. The duplication was inherited from the mother of one individual and it is presumed the father of the second individual (DNA not available, mother does not have the duplication). Both carrier parents have hypodontia by report, but neither is known to have had synostosis suggesting incomplete penetrance for that phenotype. The grandfather of 1007 and 1019 is described as having an abnormal head shape with a narrow forehead and several missing teeth; DNA was not available from this individual. They state that this CNV was not found in 2,493 control individuals [Itsara et al., 2009]. They compared RUNX2 expression levels in osteoblasts from these two individuals to expression levels in osteoblasts from unaffected individuals (n = 6) and individuals with synostosis but without duplication of RUNX2 (n = 22). The average expression of RUNX2 in the samples from the two individuals was higher than all affected and unaffected cell lines but it was not a statistically significant difference in RUNX2 expression levels so should be interpreted with caution. PMID: 23307468 - Varvagiannis et al 2013 - a girl with a de novo trisomy 6p12.3-p21.1 who showed craniosynostosis, manifested by the premature fusion of the right coronal and sagittal sutures, and also facial anomalies, psychomotor delay, and recurrent respiratory tract infections. MLPA analysis suggested a duplication of the entire RUNX2 gene. MLPA analysis indicated that the duplication was not present in parental blood samples. SNP array analysis identified the duplication was 6.9 Mb in size and mapped to 6p12.3–p21.1 (chr6: 40,797,975–47,701,961 NCBI Build 35; May 2004), thus encompassing 163 ENSEMBL genes. The finding of abnormal fontanelles and/or abnormal sutures, either manifested as craniosynostosis or not, has been documented in 5 cases in patients with pure partial trisomy 6p. No analysis of RUNX2 expression was performed. PMID: 23348268 - Greives et al 2013 - present a case study of a boy with an atypical skull deformity with pan-craniosynostosis whose microarray analysis revealed 4 copies of a 1.24-Mb region from 6p12.3 to 6p21.1 containing the RUNX2 gene. He presented as an infant with airway obstruction from choanal atresia. He was diagnosed with a closed anterior fontanelle, ventricular septal defect, restricted range of motion in his elbows, mild conductive hearing loss, and developmental delays. They note that his multisutural craniosynostosis is the most extensive associated with RUNX2. No segregation analysis given. PMID:25899668 - Molin et al 2015 - report on a family with an affected mother and three affected children. The four patients carried a 285 kb duplication identified by array comparative genomic hybridization. The duplication includes the entire sequence of RUNX2 and the 5' half of SUPT3H. We confirmed the duplication by real-time quantitative PCR in the four patients. Two children presented with the association of metopic craniosynostosis and oligo/hypodontia previously described, confirming the phenotype caused by RUNX2 duplication. The mother and one child had isolated hypodontia without craniosynostosis. The clinical presentation shown by syndromic patients IV‐1 and IV‐3 appears radically different from MDMHB, but shares a few similarities with previously duplication patients, including as hypodontia and craniosynostosis. Isolated hypodontia observed in Patients III‐2 and IV‐2 highlights a wider clinical spectrum associated with RUNX2 duplication, in addition to isolated and syndromic craniosynostosis and MDMHB. Decipher - there are 6 patients with RUNX2 duplications over 1 kb in size. None mention craniosynostosis as a feature, although abnormality of the face/triangular face is listed for the patient with the 3.59 Mb duplication. https://decipher.sanger.ac.uk/gene/RUNX2#variants/RUNX2/patient-overlap/cnvs Mouse models: PMIDs: 11581292 (Liu et al 2001) and 12167715 (Geoffroy et al 2002) - both surprisingly report transgenic mice overexpressing Cbfa1 (runx2) developed severe osteopenia. PMID: 21807129 - Maeno et al 2011 - report that in mice early onset of Runx2 expression in the cranial mesenchyme induced mineralization on E13.0, when no mineralization was observed in wild-type mice, and resulted in craniosynostosis. PMID: 23300083 McGee-Lawrence et al 2013 - Runx2-deficient mice die at birth because of a lack of skeletal ossification. Axin2-deficient mice develop craniosynostosis because of high β-catenin activity. Runx2 represses transcription of Axin2 mRNA. They state that their data are consistent with the idea that Runx2 plays a central role in the etiologies of several different forms of craniosynostosis. Summary: Loss of function variants, partial duplication of the the RUNX2 gene and full duplication of the RUNX2 gene appear to result in different phenotypes. With regards to full duplication, there are 4 cases reported in separate publications of duplications fully covering the RUNX2 gene and patients with a craniosynostosis phenotype. The smallest duplication is 285 kb and includes RUNX2 and the 5' half of SUPT3H. However, there appears to be incomplete penetrance with some carriers having a less severe phenotype. Mefford et al state the CNV they report was not found in 2,493 control individuals. Mouse models give conflicting evidence. Mouse models of runx2 over-expression surprisingly found they developed severe osteopenia. However, early onset of Runx2 expression resulted in craniosynostosis, and Runx2 was found to repress Axin2, low levels of which can result in craniosynostosis. |
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| Rare syndromic craniosynostosis or isolated multisuture synostosis v1.123 | RUNX2 |
Eleanor Williams commented on gene: RUNX2: Loss of functional mutations associated with CLEIDOCRANIAL DYSPLASIA in Gene2Phenotype (confirmed). In OMIM loss of function mutations are associated with several phenotypes including Cleidocranial dysplasia. A heterozygous duplication of some exons of RUNX2 is associated with Metaphyseal dysplasia with maxillary hypoplasia with or without brachydactyly . However, craniosynostosis is not listed as a feature of this disorder (PMID: 23290074, 25311905, 29891876 CNV EVIDENCE: PMID: 20683987 - Mefford et al 2010 - Evaluated 186 individuals with single-suture craniosynostosis for submicroscopic deletions and duplications using whole-genome array CGH. They identified a heterozygous inverted 1.1 Mb duplication including the entire sequence of RUNX2, MIR586, and some of CLIC5 and SUPT3H in two affected cousins (1007 and 1019) with metopic synostosis and hypodontia. The duplication was inherited from the mother of one individual and it is presumed the father of the second individual (DNA not available, mother does not have the duplication). Both carrier parents have hypodontia by report, but neither is known to have had synostosis suggesting incomplete penetrance for that phenotype. The grandfather of 1007 and 1019 is described as having an abnormal head shape with a narrow forehead and several missing teeth; DNA was not available from this individual. They compared RUNX2 expression levels in osteoblasts from these two individuals to expression levels in osteoblasts from unaffected individuals (n = 6) and individuals with synostosis but without duplication of RUNX2 (n = 22). The average expression of RUNX2 in the samples from the two individuals was higher than all affected and unaffected cell lines but it was not a statistically significant difference in RUNX2 expression levels so should be interpreted with caution. PMID: 23307468 - Varvagiannis et al 2013 - a girl with a de novo trisomy 6p12.3-p21.1 who showed craniosynostosis, manifested by the premature fusion of the right coronal and sagittal sutures, and also facial anomalies, psychomotor delay, and recurrent respiratory tract infections. MLPA analysis suggested a duplication of the entire RUNX2 gene. MLPA analysis indicated that the duplication was not present in parental blood samples. SNP array analysis identified the duplication was 6.9 Mb in size and mapped to 6p12.3–p21.1 (chr6: 40,797,975–47,701,961 NCBI Build 35; May 2004), thus encompassing 163 ENSEMBL genes. The finding of abnormal fontanelles and/or abnormal sutures, either manifested as craniosynostosis or not, has been documented in 5 cases in patients with pure partial trisomy 6p. No analysis of RUNX2 expression was performed. PMID: 23348268 - Greives et al 2013 - present a case study of a boy with an atypical skull deformity with pan-craniosynostosis whose microarray analysis revealed 4 copies of a 1.24-Mb region from 6p12.3 to 6p21.1 containing the RUNX2 gene. He presented as an infant with airway obstruction from choanal atresia. He was diagnosed with a closed anterior fontanelle, ventricular septal defect, restricted range of motion in his elbows, mild conductive hearing loss, and developmental delays. No segregation analysis given. PMID: McGee-Lawrence et al 2013 - Axin2-deficient mice develop craniosynostosis because of high β-catenin activity. Runx2 represses transcription of Axin2 mRNA. To determine whether Runx2 contributes to the etiology of Axin2 deficiency-induced craniosynostosis, they generated Axin2(-/-):Runx2(+/-) mice. These double mutant mice had longer skulls than Axin2(-/-) mice, indicating that Runx2 haploinsufficiency rescued the craniosynostosis phenotype of Axin2(-/-) mice PMID:25899668 - Molin et al 2015 - report on a family with an affected mother and three affected children. The four patients carried a 285 kb duplication identified by array comparative genomic hybridization. The duplication includes the entire sequence of RUNX2 and the 5' half of SUPT3H. We confirmed the duplication by real-time quantitative PCR in the four patients. Two children presented with the association of metopic craniosynostosis and oligo/hypodontia previously described, confirming the phenotype caused by RUNX2 duplication. The mother and one child had isolated hypodontia without craniosynostosis. The clinical presentation shown by syndromic Patients IV‐1 and IV‐3 appears radically different from MDMHB, but shares a few similarities with previously duplication patients, including as hypodontia and craniosynostosis. Isolated hypodontia observed in Patients III‐2 and IV‐2 highlights a wider clinical spectrum associated with RUNX2 duplication, in addition to isolated and syndromic craniosynostosis and MDMHB. Decipher - there are 6 patients with RUNX2 duplications over 1 kb in size. None mention craniosynostosis as a feature, although abnormality of the face/triangular face is listed for the patient with the 3.59 Mb duplication. https://decipher.sanger.ac.uk/gene/RUNX2#variants/RUNX2/patient-overlap/cnvs Summary: Loss of function variants, partial duplication of the the RUNX2 gene and full duplication of the RUNX2 gene appear to result in different phenotypes. With regards to full duplication, there are 4 cases reported in separate publications of duplications fully covering the RUNX2 gene and patients with a craniosynostosis phenotype. The smallest duplication is 285 kb and includes RUNX2 and the 5' half of SUPT3H. However, there appears to be incomplete penetrance with some carriers having a less severe phenotype. Frequency of CNVs covering this region in the general population have not been reported. |
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| Rare syndromic craniosynostosis or isolated multisuture synostosis v1.80 | SEC24D |
Eleanor Williams commented on gene: SEC24D: Associated with Cole-Carpenter syndrome 2 #616294 in OMIM and probable association with SYNDROMIC OSTEOGENESIS IMPERFECTA in Gene2Phenotype. PMID: 25683121 - Garbes et al 2015 - 7 year old boy with a syndromic form of OI that clinically classified as Cole-Carpenter syndrome, based on the history of multiple pre- and postnatal fractures and the presence of distinct craniofacial malformations. Compound heterozygosity for a SEC24D nonsense mutation (c.613C>T [p.Gln205*]) and for a missense mutation (c.3044C>T [p.Ser1015Phe]). The medaka mutant vbi, caused by a sec24d nonsense mutation, is characterized by short body length, OI, and craniofacial malformations—including an impaired ossification of the neurocranium (note, Sec24d-null mice are embryonic lethal prior to skeletal development). Fetuses with suspected to be affected by a severe type of OI from second family are likely compound heterozygous for SEC24D mutations c.3044C>T (p.Ser1015Phe) and c.2933A>C (p.Gln978Pro). PMID: 30462379 - Takeyari et al 2018 - Japanese boy with syndromic OI. His features include a short trunk, and craniofacial abnormalities including ocular proptosis, marked frontal bossing, midface hypoplasia, and micrognathia. He was compound heterogzyous for 2 variants in the SEC24D gene (NM_014822:c.1450C>T:p.Arg484* and c.938G>A:p.Arg313His) . PMID: 27942778 - Zhang et al 2017 - 2 unrelated families with individuals with osteogenesis imperfecta. Compound heterozygous variants in SEC24D were found in both. Family 1 - c.2723G>A (p. Cys908Tyr) and c.2842T>C (p. Ser948Pro). Family 2 - c.938G>A (p. Arg313His) and c.875C>T (p. Pro292Leu). Proband from family 1 showed skull deformities associated with a broad frontoapical ossification defect, a widened sagittal suture, and Wormian bones. In the proband from family 2 the anterior fontanel was not closed, and he did not have obvious facial dysmorphism. Consulting with the Genomics England Team with respect to the relevance to craniosynostosis of these phenotypes. |
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| Rare syndromic craniosynostosis or isolated multisuture synostosis v1.47 | ERF | Tracy Lester reviewed gene: ERF: Rating: GREEN; Mode of pathogenicity: ; Publications: 26097063, 23354439; Phenotypes: Craniosynostosis 4, 600775; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Rare syndromic craniosynostosis or isolated multisuture synostosis v1.46 | ERF | Eleanor Williams reviewed gene: ERF: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Rare syndromic craniosynostosis or isolated multisuture synostosis v1.45 | ERF |
Eleanor Williams Source NHS GMS was added to ERF. Rating Changed from Green List (high evidence) to Green List (high evidence) |
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