Activity

Filter

Panel

Version

Gene or Genomic Entity Name

Date from

Date to

Date	Panel	Item	Activity
Filter activities 16 actions
07 Jan 2022	Rare syndromic craniosynostosis or isolated multisuture synostosis v2.60	CHD7	Helen Lord changed review comment from: Newborn with bicoronal synostosis in whom a de novo CHD7 variant was identified c.6157C>T p.(Arg2053) - NGS in proband, sanger sequencing used to exclude variant from the parents. Other features included choanal atresia, markedly asymmetric malformed ears, folded and clipped off helix and triangular concha, retrognathia, marked facial asymetry with left eye constantly closed and hypoplastic toenails. Heart ultrasound revealed a small ASD and ophthalmoplegic exam revealed left retinal coloboma and asymmetrically placed eyes. CHARGE syndrome was suspected in this patient. Of note, this variant has been reported previoulsy in the literature in indivdiuals with CHARGE syndrome and no craniosynostosis was noted. In this paper they mention two other cases reporteD in the literature in 2019/2020 where craniosynostosis was reported alongside a CHARGE phenotype and LOF variants were detected: Siakallis et al, 2019: 30498854 c.3106C>T p.(Arg1036) - CHARGE phenotype as well as synostosis of the coronal, left lambdoid and squamous sutures. Tonne et al 2020: 33288889 c.7593dup p.(Thr2532fs) - CHARGE phenotype as well as late-onset sagittal synostosis. Mouse studies indicate that CHD7 has a relevant dosage dependent role in the development of several craniofacial tissues - conditional knock out models showing among other bone and cartialage defects, frontal bone dysplasia. Zebrafish model of CHARGE - flattening of the head is observed. Sources: Expert Review; to: Newborn with bicoronal synostosis in whom a de novo CHD7 variant was identified c.6157C>T p.(Arg2053) - NGS in proband, sanger sequencing used to exclude variant from the parents. Other features included choanal atresia, markedly asymmetric malformed ears, folded and clipped off helix and triangular concha, retrognathia, marked facial asymetry with left eye constantly closed and hypoplastic toenails. Heart ultrasound revealed a small ASD and ophthalmoplegic exam revealed left retinal coloboma and asymmetrically placed eyes. CHARGE syndrome was suspected in this patient. Of note, this variant has been reported previoulsy in the literature in indivdiuals with CHARGE syndrome and no craniosynostosis was noted. In this paper they mention two other cases reporteD in the literature in 2019/2020 where craniosynostosis was reported alongside a CHARGE phenotype and LOF variants were detected: Siakallis et al, 2019: 30498854 c.3106C>T p.(Arg1036) - CHARGE phenotype as well as synostosis of the coronal, left lambdoid and squamous sutures. Tonne et al 2020: 33288889 c.7593dup p.(Thr2532fs) - CHARGE phenotype as well as late-onset sagittal synostosis. Mouse studies indicate that CHD7 has a relevant dosage dependent role in the development of several craniofacial tissues - conditional knock out models showing among other bone and cartialage defects, frontal bone dysplasia. Zebrafish model of CHARGE - flattening of the head is observed. Sources: Expert Review
07 Jan 2022	Rare syndromic craniosynostosis or isolated multisuture synostosis v2.60	CHD7	Helen Lord changed review comment from: Newborn with bicoronal synostosis in whom a de novo CHD7 variant was identified c.6157C>T p.(Arg2053) - NGS in proband, sanger sequencing used to exclude variant from the parents. Other features included choanal atresia, markedly asymmetric malformed ears, folded and clipped off helix and triangular concha, retrognathia, marked facial asymetry with left eye constantly closed and hypoplastic toenails. Heart ultrasound revealed a small ASD and ophthalmoplegic exam revealed left retinal coloboma and asymmetrically placed eyes. CHARGE syndrome was suspected in this patient. Of note, this variant has been reported previoulsy in the literature in indivdiuals with CHARGE syndrome and no craniosynostosis was noted. In this paper they mention two other cases reporteD in the literature in 2019/2020 where craniosynostosis was reported alongside a CHARGE phenotype and LOF variants were detected: Siakallis et al, 2019: 30498854 c.3106C>T p.(Arg1036) - CHARGE phenotype as well as synostosis of the coronal, left lambdoid and squamous sutures. Tonne et al 2020: 33288889 c.7593dup p.(Thr2532fs) - CHARGE phenotype as well as late-onset sagittal synostosis. Mouse studies indicate that CHD7 has a relevant dosage dependent role in the development of several craniofacial tissues - conditional knock out models showing among other bone and cartialage defects, frontal bone dysplasia. Zebrafish model of CHARGE - flattening of the head is observed. Sources: Expert Review; to: Newborn with bicoronal synostosis in whom a de novo CHD7 variant was identified c.6157C>T p.(Arg2053) - NGS in proband, sanger sequencing used to exclude variant from the parents. Other features included choanal atresia, markedly asymmetric malformed ears, folded and clipped off helix and triangular concha, retrognathia, marked facial asymetry with left eye constantly closed and hypoplastic toenails. Heart ultrasound revealed a small ASD and ophthalmoplegic exam revealed left retinal coloboma and asymmetrically placed eyes. CHARGE syndrome was suspected in this patient. Of note, this variant has been reported previoulsy in the literature in indivdiuals with CHARGE syndrome and no craniosynostosis was noted. In this paper they mention two other cases reporteD in the literature in 2019/2020 where craniosynostosis was reported alongside a CHARGE phenotype and LOF variants were detected: Siakallis et al, 2019: 30498854 c.3106C>T p.(Arg1036) - CHARGE phenotype as well as synostosis of the coronal, left lambdoid and squamous sutures. Tonne et al 2020: 33288889 c.7593dup p.(Thr2532fs) - CHARGE phenotype as well as late-onset sagittal synostosis. Mouse studies indicate that CHD7 has a relevant dosage dependent role in the development of several craniofacial tissues - conditional knock out models showing among other bone and cartialage defects, frontal bone dysplasia. Zebrafish model of CHARGE - flattening of the head is observed. Sources: Expert Review
06 May 2021	Rare syndromic craniosynostosis or isolated multisuture synostosis v2.23	CHD7	Helen Lord gene: CHD7 was added gene: CHD7 was added to Craniosynostosis. Sources: Expert Review Mode of inheritance for gene: CHD7 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: CHD7 were set to 33844462; 30498854; 33288889 Phenotypes for gene: CHD7 were set to craniosynostosis Review for gene: CHD7 was set to AMBER Added comment: Newborn with bicoronal synostosis in whom a de novo CHD7 variant was identified c.6157C>T p.(Arg2053) - NGS in proband, sanger sequencing used to exclude variant from the parents. Other features included choanal atresia, markedly asymmetric malformed ears, folded and clipped off helix and triangular concha, retrognathia, marked facial asymetry with left eye constantly closed and hypoplastic toenails. Heart ultrasound revealed a small ASD and ophthalmoplegic exam revealed left retinal coloboma and asymmetrically placed eyes. CHARGE syndrome was suspected in this patient. Of note, this variant has been reported previoulsy in the literature in indivdiuals with CHARGE syndrome and no craniosynostosis was noted. In this paper they mention two other cases reporteD in the literature in 2019/2020 where craniosynostosis was reported alongside a CHARGE phenotype and LOF variants were detected: Siakallis et al, 2019: 30498854 c.3106C>T p.(Arg1036) - CHARGE phenotype as well as synostosis of the coronal, left lambdoid and squamous sutures. Tonne et al 2020: 33288889 c.7593dup p.(Thr2532fs) - CHARGE phenotype as well as late-onset sagittal synostosis. Mouse studies indicate that CHD7 has a relevant dosage dependent role in the development of several craniofacial tissues - conditional knock out models showing among other bone and cartialage defects, frontal bone dysplasia. Zebrafish model of CHARGE - flattening of the head is observed. Sources: Expert Review
14 Aug 2019	Rare syndromic craniosynostosis or isolated multisuture synostosis v1.126	TMCO1	Eleanor Williams changed review comment from: Associated with Craniofacial dysmorphism, skeletal anomalies, and mental retardation syndrome (#213980) in OMIM and Gene2Phenotype (confirmed) PMID: 20018682 - Xin et al 2010 - identified an autosomal recessive condition in 11 individuals in the Old Order Amish of northeastern Ohio. The syndrome was characterized by distinctive craniofacial dysmorphism, skeletal anomalies, and mental retardation. They identified a homozygous frameshift mutation, c.139_140delAG, in TMCO1 in all affected members of the extended pedigree. 2 of the 11 individuals showed craniosynostosis. PMID: 24424126 - Pehlivan et al 2014 - report a patient with cerebro-facio-thoracic dysplasia with a homozygous splice-site mutation TMC01 identified using WES. Cranial MRI revealed frontotemporal atrophy, dilated lateral ventricles and a short, dysgenetic corpus callosum. PMID: 24194475 - Alanay et al 2013 - identified a homozygous nonsense founder mutation, p.Arg87Ter (c.259 C>T), in TMCO1 in 4 families of Turkish origin with Cerebrofaciothoracic dysplasia. Patient 4 from family 2 had a Prominent metopic suture (craniosynostosis). 3 cases with craniosynostosis reported.; to: Associated with Craniofacial dysmorphism, skeletal anomalies, and mental retardation syndrome (#213980) in OMIM and Gene2Phenotype (confirmed) PMID: 20018682 - Xin et al 2010 - identified an autosomal recessive condition in 11 individuals in the Old Order Amish of northeastern Ohio. The syndrome was characterized by distinctive craniofacial dysmorphism, skeletal anomalies, and mental retardation. They identified a homozygous frameshift mutation, c.139_140delAG, in TMCO1 in all affected members of the extended pedigree. 2 of the 11 individuals showed craniosynostosis. PMID: 24424126 - Pehlivan et al 2014 - report a patient with cerebro-facio-thoracic dysplasia with a homozygous splice-site mutation TMC01 identified using WES. Cranial MRI revealed frontotemporal atrophy, dilated lateral ventricles and a short, dysgenetic corpus callosum. PMID: 24194475 - Alanay et al 2013 - identified a homozygous nonsense founder mutation, p.Arg87Ter (c.259 C>T), in TMCO1 in 4 families of Turkish origin with Cerebrofaciothoracic dysplasia. Patient 4 from family 2 had a Prominent metopic suture (craniosynostosis). 3 cases with craniosynostosis reported. Other cases have been reported, but without craniosysnosotis e.g. PMID: 23320496, PMID: 31102500, PMID: 30556256
14 Aug 2019	Rare syndromic craniosynostosis or isolated multisuture synostosis v1.124	TMCO1	Eleanor Williams commented on gene: TMCO1: Associated with Craniofacial dysmorphism, skeletal anomalies, and mental retardation syndrome (#213980) in OMIM and Gene2Phenotype (confirmed) PMID: 20018682 - Xin et al 2010 - identified an autosomal recessive condition in 11 individuals in the Old Order Amish of northeastern Ohio. The syndrome was characterized by distinctive craniofacial dysmorphism, skeletal anomalies, and mental retardation. They identified a homozygous frameshift mutation, c.139_140delAG, in TMCO1 in all affected members of the extended pedigree. 2 of the 11 individuals showed craniosynostosis. PMID: 24424126 - Pehlivan et al 2014 - report a patient with cerebro-facio-thoracic dysplasia with a homozygous splice-site mutation TMC01 identified using WES. Cranial MRI revealed frontotemporal atrophy, dilated lateral ventricles and a short, dysgenetic corpus callosum. PMID: 24194475 - Alanay et al 2013 - identified a homozygous nonsense founder mutation, p.Arg87Ter (c.259 C>T), in TMCO1 in 4 families of Turkish origin with Cerebrofaciothoracic dysplasia. Patient 4 from family 2 had a Prominent metopic suture (craniosynostosis). 3 cases with craniosynostosis reported.
01 Jul 2019	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.
26 Jun 2019	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.
26 Jun 2019	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.
26 Jun 2019	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.
26 Jun 2019	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.
26 Jun 2019	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.
26 Jun 2019	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.
11 May 2019	Rare syndromic craniosynostosis or isolated multisuture synostosis v1.72	ATR	Eleanor Williams Added phenotypes Seckel syndrome 1 210600 for gene: ATR
05 Mar 2019	Rare syndromic craniosynostosis or isolated multisuture synostosis v1.47	ATR	Tracy Lester reviewed gene: ATR: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: Seckel syndrome 1 - 210600; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
05 Mar 2019	Rare syndromic craniosynostosis or isolated multisuture synostosis v1.46	ATR	Eleanor Williams reviewed gene: ATR: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
05 Mar 2019	Rare syndromic craniosynostosis or isolated multisuture synostosis v1.45	ATR	Eleanor Williams Source NHS GMS was added to ATR.