Activity
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| Rare syndromic craniosynostosis or isolated multisuture synostosis v4.170 | ZCCHC11 |
Achchuthan Shanmugasundram gene: ZCCHC11 was added gene: ZCCHC11 was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature Mode of inheritance for gene: ZCCHC11 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: ZCCHC11 were set to 28808027; 36980886 Phenotypes for gene: ZCCHC11 were set to craniosynostosis, MONDO:0015469 Review for gene: ZCCHC11 was set to RED Added comment: An individual was described with metopic synostosis and a novel de novo frameshift variant in ZCCHC11 (p.Glu1275fs) (PMID:28808027). Sources: Literature |
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| Rare syndromic craniosynostosis or isolated multisuture synostosis v4.169 | ZBTB20 |
Achchuthan Shanmugasundram gene: ZBTB20 was added gene: ZBTB20 was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature Mode of inheritance for gene: ZBTB20 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: ZBTB20 were set to 34429528; 36980886 Phenotypes for gene: ZBTB20 were set to Primrose syndrome, OMIM:259050; craniosynostosis, MONDO:0015469 Review for gene: ZBTB20 was set to RED Added comment: A de novo missense variant (c.1948A>C; p.Asn650His) was identified in an individual from the 100k genomes project with craniosynostosis, congenital heart disease, intellectual disability, and spinal anomalies (PMID:34429528). Sources: Literature |
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| Rare syndromic craniosynostosis or isolated multisuture synostosis v4.165 | SRCAP |
Achchuthan Shanmugasundram gene: SRCAP was added gene: SRCAP was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature Mode of inheritance for gene: SRCAP was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: SRCAP were set to 33288889; 36980886 Review for gene: SRCAP was set to RED Added comment: One individual was described with a stop-gain variant in SRCAP (c.7303C>T; p.Arg2435Ter) in the Norwegian cohort (PMID:33288889). Sources: Literature |
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| Rare syndromic craniosynostosis or isolated multisuture synostosis v4.164 | SPRY4 |
Achchuthan Shanmugasundram gene: SPRY4 was added gene: SPRY4 was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature Mode of inheritance for gene: SPRY4 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: SPRY4 were set to 28808027; 36980886 Phenotypes for gene: SPRY4 were set to craniosynostosis, MONDO:0015469 Review for gene: SPRY4 was set to RED Added comment: An individual was described with a heterozygous de novo variant in SPRY4 (p.Glu160Ter) (PMID:28808027). This gene has a low pLI (0) suggesting tolerance to loss-of-function. Sources: Literature |
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| Rare syndromic craniosynostosis or isolated multisuture synostosis v4.162 | SMURF1 |
Achchuthan Shanmugasundram changed review comment from: An individual was described with metopic synostosis and a de novo variant in SMURF1 (p.Arg468Trp) (PMID:28808027) Sources: Literature; to: An individual was described with metopic synostosis and a de novo variant in SMURF1 (p.Arg468Trp) (PMID:28808027). Sources: Literature |
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| Rare syndromic craniosynostosis or isolated multisuture synostosis v4.162 | SMURF1 |
Achchuthan Shanmugasundram gene: SMURF1 was added gene: SMURF1 was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature Mode of inheritance for gene: SMURF1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: SMURF1 were set to 28808027; 36980886 Phenotypes for gene: SMURF1 were set to craniosynostosis, MONDO:0015469 Review for gene: SMURF1 was set to RED Added comment: An individual was described with metopic synostosis and a de novo variant in SMURF1 (p.Arg468Trp) (PMID:28808027) Sources: Literature |
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| Rare syndromic craniosynostosis or isolated multisuture synostosis v4.161 | SMC1A |
Achchuthan Shanmugasundram gene: SMC1A was added gene: SMC1A was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature Mode of inheritance for gene: SMC1A was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) Publications for gene: SMC1A were set to 29037998; 36980886 Phenotypes for gene: SMC1A were set to Cornelia de Lange syndrome 2, OMIM:300590; craniosynostosis, MONDO:0015469 Review for gene: SMC1A was set to RED Added comment: An X-linked dominant variant (c.3581A>G; p.Tyr1194Cys) was identified in an individual with Cornelia de Lange syndrome (characterised by dysmorphic facial features, growth, and developmental delay and syndromic craniosynostosis). Their mother was mosaic for the variant (PMID:29037998). Sources: Literature |
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| Rare syndromic craniosynostosis or isolated multisuture synostosis v4.160 | SMARCD2 |
Achchuthan Shanmugasundram gene: SMARCD2 was added gene: SMARCD2 was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature Mode of inheritance for gene: SMARCD2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: SMARCD2 were set to 28808027; 36980886 Phenotypes for gene: SMARCD2 were set to craniosynostosis, MONDO:0015469 Review for gene: SMARCD2 was set to RED Added comment: An individual was described with metopic synostosis and a de novo variant in SMARCD2 (p.Arg73Ter) (PMID:28808027). Sources: Literature |
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| Rare syndromic craniosynostosis or isolated multisuture synostosis v4.159 | SMAD2 |
Achchuthan Shanmugasundram gene: SMAD2 was added gene: SMAD2 was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature Mode of inheritance for gene: SMAD2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: SMAD2 were set to 34429528; 36980886 Phenotypes for gene: SMAD2 were set to Loeys-Dietz syndrome 6, OMIM:619656 Review for gene: SMAD2 was set to RED Added comment: A de novo variant in SMAD2 (c.1223T>C; p.Leu408Pro) was identified in an individual within the craniosynostosis cohort of the 100k genomes project. The variant was absent from gnomAD and was predicted to affect a residue within a functional domain (PMID:34429528). Sources: Literature |
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| Rare syndromic craniosynostosis or isolated multisuture synostosis v4.158 | SIX2 |
Achchuthan Shanmugasundram gene: SIX2 was added gene: SIX2 was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature Mode of inheritance for gene: SIX2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: SIX2 were set to 26581443; 36980886 Phenotypes for gene: SIX2 were set to six2-related frontonasal dysplasia, MONDO:0044628; craniosynostosis, MONDO:0015469 Review for gene: SIX2 was set to RED Added comment: A family with a dominantly inherited craniofacial phenotype (frontal bossing with high hairline, ptosis, hypertelorism, broad nasal tip, large anterior fontanelle, cranial base anomalies, and sagittal synostosis (only confirmed in one individual)) were identified on chromosomal microarray to harbour a heterozygous 108.3 kilobase deletion of chromosome 2p21 (disrupting SIX2 and the surround non-coding DNA) (PMID:26581443). Sources: Literature |
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| Rare syndromic craniosynostosis or isolated multisuture synostosis v4.156 | SCN8A |
Achchuthan Shanmugasundram changed review comment from: A heterozygous duplication involving SCN8A was identified in an individual with hearing impairment, hypermobility, intellectual disability, ventricular septal defect and craniosynostosis (c.3924dup; p.Arg1309Thrfs*3) (PMID:34429528) Sources: Literature; to: A heterozygous duplication involving SCN8A was identified in an individual with hearing impairment, hypermobility, intellectual disability, ventricular septal defect and craniosynostosis (c.3924dup; p.Arg1309Thrfs*3) (PMID:34429528). Sources: Literature |
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| Rare syndromic craniosynostosis or isolated multisuture synostosis v4.156 | SCN8A |
Achchuthan Shanmugasundram gene: SCN8A was added gene: SCN8A was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature Mode of inheritance for gene: SCN8A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: SCN8A were set to 34429528; 36980886 Phenotypes for gene: SCN8A were set to craniosynostosis, MONDO:0015469 Review for gene: SCN8A was set to RED Added comment: A heterozygous duplication involving SCN8A was identified in an individual with hearing impairment, hypermobility, intellectual disability, ventricular septal defect and craniosynostosis (c.3924dup; p.Arg1309Thrfs*3) (PMID:34429528) Sources: Literature |
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| Rare syndromic craniosynostosis or isolated multisuture synostosis v4.155 | RASAL2 |
Achchuthan Shanmugasundram gene: RASAL2 was added gene: RASAL2 was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature Mode of inheritance for gene: RASAL2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: RASAL2 were set to 28808027; 36980886 Phenotypes for gene: RASAL2 were set to craniosynostosis, MONDO:0015469 Review for gene: RASAL2 was set to RED Added comment: An individual was described with sagittal synostosis and a de novo variant in RASAL2 (p.Arg571Pro) (PMID:28808027) Sources: Literature |
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| Rare syndromic craniosynostosis or isolated multisuture synostosis v4.151 | PSMC5 |
Achchuthan Shanmugasundram gene: PSMC5 was added gene: PSMC5 was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature Mode of inheritance for gene: PSMC5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: PSMC5 were set to 28808027; 36980886 Phenotypes for gene: PSMC5 were set to craniosynostosis, MONDO:0015469 Review for gene: PSMC5 was set to RED Added comment: An individual was described with metopic synostosis and a de novo variant in PSMC5 (p.Arg317Trp) (PMID:28808027). Sources: Literature |
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| Rare syndromic craniosynostosis or isolated multisuture synostosis v4.150 | PSMC2 |
Achchuthan Shanmugasundram gene: PSMC2 was added gene: PSMC2 was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature Mode of inheritance for gene: PSMC2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: PSMC2 were set to 28808027; 36980886 Phenotypes for gene: PSMC2 were set to craniosynostosis, MONDO:0015469 Review for gene: PSMC2 was set to RED Added comment: An individual was described with metopic synostosis and a de novo variant in PSMC2 (p.Arg297Gly) (PMID:28808027). Sources: Literature |
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| Rare syndromic craniosynostosis or isolated multisuture synostosis v4.144 | OSTM1 | Achchuthan Shanmugasundram changed review comment from: An individual was reported with osteopetrosis, craniosynostosis, and Chiari malformation type 1 and two novel homozygous variants in OSTEM1. The first was a missense variant c.265T>A (p.Val122Asp), which was considered neutral. The second variant was a synonymous change (c.108C>T) but was predicted to create a new donor splice site and disrupt mRNA processing (PMID:23772242).; to: An individual was reported with osteopetrosis, craniosynostosis, and Chiari malformation type 1 and two novel homozygous variants in OSTEM1. The first was a missense variant c.265T>A (p.Val122Asp), which was considered neutral. The second variant was a synonymous change (c.108C>T) but was predicted to create a new donor splice site and disrupt mRNA processing (PMID:23772242). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Rare syndromic craniosynostosis or isolated multisuture synostosis v4.144 | NTRK2 |
Achchuthan Shanmugasundram gene: NTRK2 was added gene: NTRK2 was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature Mode of inheritance for gene: NTRK2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: NTRK2 were set to 27884935; 36980886 Phenotypes for gene: NTRK2 were set to Obesity, hyperphagia, and developmental delay, OMIM:613886; craniosynostosis, MONDO:0015469 Review for gene: NTRK2 was set to RED Added comment: A heterozygous stop-gain variant was identified in an individual with unicoronal synostosis, language delay, hyperphagic obesity, and aggression (c.1330G>T; p.Gly444*). It was suspected that the variant arose de novo but the father’s sample was not available for testing (PMID:27884935). Sources: Literature |
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| Rare syndromic craniosynostosis or isolated multisuture synostosis v4.143 | NAA25 |
Achchuthan Shanmugasundram gene: NAA25 was added gene: NAA25 was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature Mode of inheritance for gene: NAA25 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: NAA25 were set to 30152016; 36980886 Phenotypes for gene: NAA25 were set to craniosynostosis, MONDO:0015469 Review for gene: NAA25 was set to RED Added comment: One individual was described with sagittal synostosis to harbour a de novo frameshifting variant in NAA25 (p.Phe359fs*) (PMID:30152016). Sources: Literature |
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| Rare syndromic craniosynostosis or isolated multisuture synostosis v4.142 | MMP21 |
Achchuthan Shanmugasundram gene: MMP21 was added gene: MMP21 was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature Mode of inheritance for gene: MMP21 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MMP21 were set to 34429528; 36980886 Phenotypes for gene: MMP21 were set to craniosynostosis, MONDO:0015469 Review for gene: MMP21 was set to RED Added comment: Compound heterozygous variants (c.671_684del/ p.Val224Glyfs*29 and c.775C>G/ p.His259Asp) were identified in an individual within the 100kGP with heterotaxy and craniosynostosis (PMID:34429528) Sources: Literature |
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| Rare syndromic craniosynostosis or isolated multisuture synostosis v4.140 | MACF1 |
Achchuthan Shanmugasundram gene: MACF1 was added gene: MACF1 was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature Mode of inheritance for gene: MACF1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: MACF1 were set to 28808027; 36980886 Phenotypes for gene: MACF1 were set to craniosynostosis, MONDO:0015469 Review for gene: MACF1 was set to RED Added comment: An individual was described with sagittal synostosis and a novel splicing variant in MACF1 (IVS89+1G>A) (PMID:28808027). Sources: Literature |
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| Rare syndromic craniosynostosis or isolated multisuture synostosis v4.138 | KPTN |
Achchuthan Shanmugasundram gene: KPTN was added gene: KPTN was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature Mode of inheritance for gene: KPTN was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: KPTN were set to 24239382; 36980886 Phenotypes for gene: KPTN were set to Intellectual developmental disorder, autosomal recessive 41, OMIM:615637; craniosynostosis, MONDO:0015469 Review for gene: KPTN was set to AMBER Added comment: Four families were described with variants in KPTN and suspected craniosynostosis. Sagittal synostosis was confirmed in one individual from a family with three affected individuals. All families harboured a variant encoding p.Ser259*; this was homozygous in four individuals and in trans with another heterozygous variant (p.Met241_Gln246dup) in five individuals (PMID:24239382). Sources: Literature |
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| Rare syndromic craniosynostosis or isolated multisuture synostosis v4.133 | H3F3B |
Achchuthan Shanmugasundram gene: H3F3B was added gene: H3F3B was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature Mode of inheritance for gene: H3F3B was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: H3F3B were set to 33268356; 36980886 Phenotypes for gene: H3F3B were set to craniosynostosis, MONDO:0015469 Review for gene: H3F3B was set to RED Added comment: In a cohort of 33 patients with H3F3A variants and 13 patients with H3F3B variants, 5/13 (~40%) individuals with H3F3B variants were reported with “craniosynostosis or abnormal head shape”. Of these, it is not clear if these were radiologically confirmed and what proportion of this subset of patients had synostosis compared to dysmorphic features (PMID:33268356). Sources: Literature |
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| Rare syndromic craniosynostosis or isolated multisuture synostosis v4.132 | H3F3A |
Achchuthan Shanmugasundram gene: H3F3A was added gene: H3F3A was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature Mode of inheritance for gene: H3F3A was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: H3F3A were set to 33268356; 36980886 Phenotypes for gene: H3F3A were set to craniosynostosis, MONDO:0015469 Review for gene: H3F3A was set to RED Added comment: In a cohort of 33 patients with H3F3A variants and 13 patients with H3F3B variants, 9/33 (~30%) individuals with H3F3A variants were reported with “craniosynostosis or abnormal head shape”. Of these, it is not clear if these were radiologically confirmed and what proportion of this subset of patients had synostosis compared to dysmorphic features (PMID:33268356). Sources: Literature |
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| Rare syndromic craniosynostosis or isolated multisuture synostosis v4.130 | GPC4 |
Achchuthan Shanmugasundram gene: GPC4 was added gene: GPC4 was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature Mode of inheritance for gene: GPC4 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females Publications for gene: GPC4 were set to 31292255; 36980886 Phenotypes for gene: GPC4 were set to craniosynostosis, MONDO:0015469 Review for gene: GPC4 was set to RED Added comment: A variant in GPC4 was identified in an individual with syndromic craniosynostosis. The variant encoding p.Val152fs arose de novo in the mother (PMID:31292255) Sources: Literature |
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| Rare syndromic craniosynostosis or isolated multisuture synostosis v4.129 | GLI2 |
Achchuthan Shanmugasundram gene: GLI2 was added gene: GLI2 was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature Mode of inheritance for gene: GLI2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: GLI2 were set to 31292255; 36980886 Phenotypes for gene: GLI2 were set to craniosynostosis, MONDO:0015469 Review for gene: GLI2 was set to RED Added comment: A de novo GLI2 variant (p.Ala551Thr) was identified in an individual with syndromic craniosynostosis (PMID:31292255). Sources: Literature |
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| Rare syndromic craniosynostosis or isolated multisuture synostosis v4.127 | FTO |
Achchuthan Shanmugasundram gene: FTO was added gene: FTO was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature Mode of inheritance for gene: FTO was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: FTO were set to 26697951; 36980886 Phenotypes for gene: FTO were set to craniosynostosis, MONDO:0015469 Review for gene: FTO was set to RED Added comment: A homozygous variant in FTO (c.956G>A; p.Arg322Gln) was described in one individual with multiple malformation syndrome, which included craniosynostosis. Craniosynostosis is not a consistent feature of variants in FTO (PMID:26697951). Sources: Literature |
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| Rare syndromic craniosynostosis or isolated multisuture synostosis v4.125 | FOXP2 |
Achchuthan Shanmugasundram gene: FOXP2 was added gene: FOXP2 was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature Mode of inheritance for gene: FOXP2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: FOXP2 were set to 35080095; 36980886 Phenotypes for gene: FOXP2 were set to craniosynostosis, MONDO:0015469 Review for gene: FOXP2 was set to RED Added comment: A familial variant in FOXP2 (c.484del; p.Gln162fs) was identified in individuals with developmental delay, hypermetropia, orofacial dyspraxia and sagittal craniosynostosis. The variant is absent from gnomAD (PMID:35080095) Sources: Literature |
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| Rare syndromic craniosynostosis or isolated multisuture synostosis v4.119 | DVL3 |
Achchuthan Shanmugasundram gene: DVL3 was added gene: DVL3 was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature Mode of inheritance for gene: DVL3 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: DVL3 were set to 28808027; 36980886 Phenotypes for gene: DVL3 were set to craniosynostosis, MONDO:0015469 Review for gene: DVL3 was set to RED Added comment: An individual was described with sagittal synostosis and a de novo variant in DVL3 (p.Gly327fs*) (PMID:28808027). Sources: Literature |
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| Rare syndromic craniosynostosis or isolated multisuture synostosis v4.115 | CTNNA1 |
Achchuthan Shanmugasundram gene: CTNNA1 was added gene: CTNNA1 was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature Mode of inheritance for gene: CTNNA1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: CTNNA1 were set to 31292255; 36980886 Phenotypes for gene: CTNNA1 were set to craniosynostosis, MONDO:0015469 Review for gene: CTNNA1 was set to RED Added comment: A de novo insertion (p.Val374_375ins) was identified in an individual from a screen of patients with syndromic craniosynostosis. This patient had sagittal craniosynostosis (PMID:31292255). Sources: Literature |
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| Rare syndromic craniosynostosis or isolated multisuture synostosis v4.114 | COL11A1 |
Achchuthan Shanmugasundram gene: COL11A1 was added gene: COL11A1 was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature Mode of inheritance for gene: COL11A1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: COL11A1 were set to 34429528; 36980886 Phenotypes for gene: COL11A1 were set to craniosynostosis, MONDO:0015469 Review for gene: COL11A1 was set to RED Added comment: A de novo loss of function variant (c.2852+5G>A) was identified in an individual with craniosynostosis and a hearing impairment from the UK 100k genomes project (PMID:34429528) Sources: Literature |
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| Rare syndromic craniosynostosis or isolated multisuture synostosis v4.113 | CHD3 |
Achchuthan Shanmugasundram gene: CHD3 was added gene: CHD3 was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature Mode of inheritance for gene: CHD3 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: CHD3 were set to 30397230; 36980886 Phenotypes for gene: CHD3 were set to craniosynostosis, MONDO:0015469 Review for gene: CHD3 was set to RED Added comment: One of 35 individuals identified with Snijders Blok Campeau syndrome (neurodevelopmental disorder, macrocephaly and impaired speech and language) and with monoallelic variants in CHD3 gene (c.3482A>G; p.His1161Arg) presented with sagittal synostosis (PMID:30397230). In addition, one of 28 patients with sequence variants (c.52_53inv; p.Ser18Glu) in the DECIPHER database (https://www.deciphergenomics.org/) was reported with craniosynostosis as one of the phenotypes./ Sources: Literature |
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| Rare syndromic craniosynostosis or isolated multisuture synostosis v4.112 | CDK8 |
Achchuthan Shanmugasundram gene: CDK8 was added gene: CDK8 was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature Mode of inheritance for gene: CDK8 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: CDK8 were set to 30905399; 36980886 Phenotypes for gene: CDK8 were set to craniosynostosis, MONDO:0015469 Review for gene: CDK8 was set to RED Added comment: Metopic synostosis was described in one individual out of 12 reported with variants in CDK8 from PMID:30905399. This individual harboured a de novo c.88G>A (p.Gly30Ser) variant. Sources: Literature |
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| Rare syndromic craniosynostosis or isolated multisuture synostosis v4.110 | CACNA1E |
Achchuthan Shanmugasundram gene: CACNA1E was added gene: CACNA1E was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature Mode of inheritance for gene: CACNA1E was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: CACNA1E were set to 32530565; 36980886 Phenotypes for gene: CACNA1E were set to crannieynostosis, MONDO:0015469s Review for gene: CACNA1E was set to RED Added comment: A heterozygous splice variant (c.3674+5A>G) was identified in an individual from a cohort of patients with trigonocephaly (PMID:32530565). Sources: Literature |
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| Rare syndromic craniosynostosis or isolated multisuture synostosis v4.109 | BRWD3 |
Achchuthan Shanmugasundram changed review comment from: A de novo stop-gain variant (p.Gln1338*) was identified in an individual with craniosynostosis within the 100k genomes project cohort (PMID:34429528). In addition, one of 20 patients with sequence variants in BRWD3 gene from DECIPHER database (https://www.deciphergenomics.org/) was reported with craniosynostosis as one of the phenotypes. Sources: Literature; to: A de novo stop-gain variant (p.Gln1338*) was identified in an individual with craniosynostosis within the 100k genomes project cohort (PMID:34429528). In addition, one of 20 patients with sequence variants in BRWD3 gene (p.Gly707Val) from DECIPHER database (https://www.deciphergenomics.org/) was reported with craniosynostosis as one of the phenotypes. Sources: Literature |
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| Rare syndromic craniosynostosis or isolated multisuture synostosis v4.108 | BRWD3 |
Achchuthan Shanmugasundram gene: BRWD3 was added gene: BRWD3 was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature Mode of inheritance for gene: BRWD3 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females Publications for gene: BRWD3 were set to 34429528; 36980886 Review for gene: BRWD3 was set to RED Added comment: A de novo stop-gain variant (p.Gln1338*) was identified in an individual with craniosynostosis within the 100k genomes project cohort (PMID:34429528). In addition, one of 20 patients with sequence variants in BRWD3 gene from DECIPHER database (https://www.deciphergenomics.org/) was reported with craniosynostosis as one of the phenotypes. Sources: Literature |
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| Rare syndromic craniosynostosis or isolated multisuture synostosis v4.107 | AXIN1 |
Achchuthan Shanmugasundram gene: AXIN1 was added gene: AXIN1 was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature Mode of inheritance for gene: AXIN1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: AXIN1 were set to 28808027; 36980886 Phenotypes for gene: AXIN1 were set to craniosynostosis, MONDO:0015469 Review for gene: AXIN1 was set to RED Added comment: PMID:28808027 reported an individual with sagittal synostosis and a de novo heterozygous variant in AXIN1 gene. Sources: Literature |
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| Rare syndromic craniosynostosis or isolated multisuture synostosis v4.106 | ARAP3 |
Achchuthan Shanmugasundram gene: ARAP3 was added gene: ARAP3 was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature Mode of inheritance for gene: ARAP3 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: ARAP3 were set to 28808027; 36980886 Phenotypes for gene: ARAP3 were set to craniosynostosis, MONDO:0015469 Review for gene: ARAP3 was set to RED Added comment: PMID:28808027 reported an individual identified with a de novo variant in ARAP3 (IVS6+1delGT) and presenting with metopic synostosis. As there is only one case reported so far, this gene should be rated red. Sources: Literature |
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| Rare syndromic craniosynostosis or isolated multisuture synostosis v4.96 | SMAD3 |
Achchuthan Shanmugasundram changed review comment from: PMID:29392890 - It has been reviewed in this publication that craniosynostosis has only been reported once in a SMAD3 patient. But, no reference was given. PMID:31569402 - Dolichocephaly has been reported in patients. However, it is not clear whether craniosynostosis has been present in these cases. PMID:32935439 - One case of LDS with biallelic variants presented with craniosynostosis. PMID:36980886 - one craniosynostosi case with splicing variant in SMAD3 from the cohort of 617 individuals. This gene has been associated with LDS in OMIM (MIM #613795) and Gene2Phenotype (with 'definitive' rating in DD panel). However, craniosynostosis was not reported as part of phenotypes in OMIM.; to: PMID:29392890 - It has been reviewed in this publication that craniosynostosis has only been reported once in a SMAD3 patient. But, no reference was given. PMID:31569402 - Dolichocephaly has been reported in patients. However, it is not clear whether craniosynostosis has been present in these cases. PMID:32935439 - One case of LDS with biallelic variants presented with craniosynostosis. PMID:36980886 - one craniosynostosi case with splicing variant in SMAD3 from the cohort of 617 individuals. This gene has been associated with LDS in OMIM (MIM #613795) and Gene2Phenotype (with 'definitive' rating in DD panel). However, craniosynostosis was not reported as part of this phenotype in OMIM. |
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| Rare syndromic craniosynostosis or isolated multisuture synostosis v4.87 | RSPRY1 |
Achchuthan Shanmugasundram changed review comment from: As reviewed by Rebecca Tooze, craniosynostosis was reported in a family of four affected individuals identified with homozygous variants in RSPRY1 from PMID:26365341, and in three out of four affected individuals from a family and another unrelated individual with RSPRY1 variants from PMID:30063090. Although the phenotype is not fully penetrant from the family of four cases from PMID:30063090, this gene can be rated GREEN on the basis of the presence of phenotype in three unrelated cases and the phenotype being fully penetrant from the family reported in PMID:26365341. This gene has been associated with relevant phenotypes in both OMIM (MIM #616723) and Gene2Phenotype (with 'strong' rating in the DD panel).; to: As reviewed by Rebecca Tooze, craniosynostosis was reported in a family of four affected individuals identified with homozygous variants in RSPRY1 from PMID:26365341, and in three out of four affected individuals from a family and another unrelated individual with RSPRY1 variants from PMID:30063090. This gene has been associated with relevant phenotypes in both OMIM (MIM #616723) and Gene2Phenotype (with 'strong' rating in the DD panel). |
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| Rare syndromic craniosynostosis or isolated multisuture synostosis v4.86 | RSPRY1 |
Achchuthan Shanmugasundram changed review comment from: As reviewed by Rebecca Tooze, craniosynostosis was reported in a family of four affected individuals identified with homozygous variants in RSPRY1 from PMID:26365341, and in three out of four affected individuals from a family and another unrelated individual with RSPRY1 variants from PMID:30063090. Although the phenotype is not fully penetrant from the family of four cases from PMID:30063090, this gene can be rated GREEN on the basis of the presence of phenotype in three unrelated cases and the phenotype being fully penetrant from the family reported in PMID:26365341.; to: As reviewed by Rebecca Tooze, craniosynostosis was reported in a family of four affected individuals identified with homozygous variants in RSPRY1 from PMID:26365341, and in three out of four affected individuals from a family and another unrelated individual with RSPRY1 variants from PMID:30063090. Although the phenotype is not fully penetrant from the family of four cases from PMID:30063090, this gene can be rated GREEN on the basis of the presence of phenotype in three unrelated cases and the phenotype being fully penetrant from the family reported in PMID:26365341. This gene has been associated with relevant phenotypes in both OMIM (MIM #616723) and Gene2Phenotype (with 'strong' rating in the DD panel). |
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| Rare syndromic craniosynostosis or isolated multisuture synostosis v4.82 | RSPRY1 | Achchuthan Shanmugasundram changed review comment from: As reviewed by Rebecca Tooze, craniosynostosis was reported in a family of four affected individuals identified with homozygous variants in RSPRY1 from PMID:26365341, and in three out of four affected individuals from a family and another unrelated individual with RSPRY1 variants from PMID:30063090. Although the phenotype is not fully penetrant from the family of four cases from PMID:30063090, this gene can be rated GREEN on the basis of the presence of phenotype in three unrelated cases.; to: As reviewed by Rebecca Tooze, craniosynostosis was reported in a family of four affected individuals identified with homozygous variants in RSPRY1 from PMID:26365341, and in three out of four affected individuals from a family and another unrelated individual with RSPRY1 variants from PMID:30063090. Although the phenotype is not fully penetrant from the family of four cases from PMID:30063090, this gene can be rated GREEN on the basis of the presence of phenotype in three unrelated cases and the phenotype being fully penetrant from the family reported in PMID:26365341. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Rare syndromic craniosynostosis or isolated multisuture synostosis v4.56 | DPF2 |
Achchuthan Shanmugasundram changed review comment from: Comment on list classification: As reviewed by Rebecca Tooze (University of Oxford), there are two cases of confirmed craniosynostosis with the same variant (p.Asp346Gly). Although there is a third case with trigonocephaly harbouring a different variant (p.Asp340Glufs*12), craniosynostosis was not radiologically confirmed in this individual. Hence, this gene should be rated AMBER.; to: Comment on list classification: As reviewed by Rebecca Tooze (University of Oxford), there are two cases of confirmed craniosynostosis with the same variant (p.Asp346Gly). Although there is a third case with trigonocephaly harbouring a different variant (p.Asp340Glufs*12), craniosynostosis was not radiologically confirmed in this individual. Hence, this gene should be rated AMBER. This gene has been associated with Coffin-Siris syndrome in both OMIM (MIM #618027) and Gene2Phenotype (with a 'strong' rating in the DD panel). |
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| Rare syndromic craniosynostosis or isolated multisuture synostosis v4.55 | DPF2 | Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Rebecca Tooze (University of Oxford), there are two cases of confirmed craniosynostosis with the same variant (p.Asp346Gly). Although there is a third case with trigonocephaly harbouring a different variant (p.Asp340Glufs*12), craniosynostosis was not radiologically confirmed in this individual. Hence, this gene should be rated AMBER. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Rare syndromic craniosynostosis or isolated multisuture synostosis v4.1 | ADAMTSL4 |
Achchuthan Shanmugasundram changed review comment from: PMID:20702823 reported 10 affected individuals from five unrelated Norwegian families with homozygous variants (c.767_786del/ p.Gln256Profs∗38) and they presented with ectopia lentis et pupillae. All these patients were surgically corrected for craniosynostosis. PMID:22871183 reported a patient with right coronal synostosis and bilateral ectopia lentis, who harboured the same homozygous deletion variant. The proband's mother, father and one sibling are heterozygous carriers of the variant. PMID:28642162 reported a Dutch family with monozygotic twins harbouring compound heterozygous variants (c.767_786del/ p.Gln256Profs∗38 & c.2254C > T/ p.Gln752∗) and both presented with craniosynostosis and ectopia lentis. PMID:35378950 reported two unrelated families with craniosynostosis and ectopia lentis. Family 1’s proband is compound heterozygous (c.767_786del & c.2177 + 3_2177 + ) and family 2 has two homozygous affected siblings with c.767_786del, however the older sister did not have craniosynostosis (ectopia lentis only).; to: PMID:20702823 reported 10 affected individuals from five unrelated Norwegian families with homozygous variants (c.767_786del/ p.Gln256Profs∗38) and they presented with ectopia lentis et pupillae. All these patients were surgically corrected for craniosynostosis. PMID:22871183 reported a patient with right coronal synostosis and bilateral ectopia lentis, who harboured the same homozygous deletion variant. The proband's mother, father and one sibling are heterozygous carriers of the variant. PMID:28642162 reported a Dutch family with monozygotic twins harbouring compound heterozygous variants (c.767_786del/ p.Gln256Profs∗38 & c.2254C > T/ p.Gln752∗) and both presented with craniosynostosis and ectopia lentis. PMID:35378950 reported two unrelated families with craniosynostosis and ectopia lentis. Family 1’s proband is compound heterozygous (c.767_786del & c.2177 + 3_2177 + ) and family 2 has two homozygous affected siblings with c.767_786del, however the older sister did not have craniosynostosis (ectopia lentis only). |
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| Rare syndromic craniosynostosis or isolated multisuture synostosis v3.4 | SPRY1 |
Rebecca Tooze gene: SPRY1 was added gene: SPRY1 was added to Craniosynostosis. Sources: Literature Mode of inheritance for gene: SPRY1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SPRY1 were set to PMID: 36543535 Review for gene: SPRY1 was set to AMBER Added comment: • Single report of a homozygous loss of function variant (c.80T>A; p.(Leu27*)) in a patient with sagittal craniosynostosis, alongside hearing and kidney anomalies. Functional studies show complete absence of the protein and support variant pathogenicity (Tooze et al., 2022a). This is the first human description but there are available animal models showing the role of SPRY1 in craniofacial development. • An individual was described with a heterozygous variant in SPRY1: p.(Gln6fs) (Timberlake et al., 2017), but evidence suggests that heterozygous loss-of-function variants are not pathogenic (see above reference). Sources: Literature |
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| Rare syndromic craniosynostosis or isolated multisuture synostosis v3.4 | FBXO11 |
Rebecca Tooze gene: FBXO11 was added gene: FBXO11 was added to Craniosynostosis. Sources: Literature Mode of inheritance for gene: FBXO11 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Review for gene: FBXO11 was set to GREEN Added comment: • A de novo insertion was identified within the 100kGP cohort of patients with craniosynostosis: c.2731_2732insGACA; p.(Thr911Argfs*5) (Hyder et al., 2021). • Two patients were described with craniosynostosis and variants in FBXO11: c.2518T>C, p.(Ser840Pro) in an individual with sagittal synostosis, and hg19: chr2: g.48060020C>G, c.1042- 1G>C; p.(?) (Gregor et al., 2018). Sources: Literature |
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| Rare syndromic craniosynostosis or isolated multisuture synostosis v3.4 | CDK13 |
Rebecca Tooze gene: CDK13 was added gene: CDK13 was added to Craniosynostosis. Sources: Literature Mode of inheritance for gene: CDK13 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Review for gene: CDK13 was set to GREEN Added comment: • A de novo missense variant was identified within the UK 100kGP cohort of patients with craniosynostosis: c.2563G>C; p.(Asp855His) (Hyder et al., 2021). • A further de novo variant was identified in an individual within the Norwegian cohort: c.2524A>G; p.(Asn842Asp) (Tønne et al., 2021). • Two patients were described with craniosynostosis in a cohort of patients with congenital heart defects, dysmorphic facial features, and intellectual disability (Bostwick et al., 2017) Four independent cases identified. Sources: Literature |
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| Rare syndromic craniosynostosis or isolated multisuture synostosis v3.4 | ASXL3 |
Rebecca Tooze gene: ASXL3 was added gene: ASXL3 was added to Craniosynostosis. Sources: Literature Mode of inheritance for gene: ASXL3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Review for gene: ASXL3 was set to AMBER Added comment: • A de novo c.3033dup; p.(Leu1012Serfs*23) was identified in a patient with metopic synostosis within the Norwegian cohort (Tønne et al., 2021). • A six-year-old with microcephaly, autism, global developmental delay, and metopic craniosynostosis was found on exome sequencing to harbour a heterozygous two base pair de novo deletion, c.1897_1898delCA; p.(Gln633Valfs*13) in ASXL3 (Dinwiddie et al., 2013). • A heterozygous de novo single nucleotide variant (c.3039+1G>A; p.(?)) in the invariant “GT” splice donor site of exon 11 was identified in an individual with a prominent forehead, thick eyebrows, long lashes, exotropia, depressed nasal ridge, thin upper lip vermillion, hirsutism, microcephaly, bilateral camptodactyly of third, fourth and fifth fingers, deep palmar creases, and small hands and feet. Craniosynostosis is not confirmed (Hori et al., 2016). Two cases of loss-of-function variants in ASXL3; only one has radiologically confirmed craniosynostosis. Sources: Literature |
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| Rare syndromic craniosynostosis or isolated multisuture synostosis v3.4 | ARID1B |
Rebecca Tooze gene: ARID1B was added gene: ARID1B was added to Craniosynostosis. Sources: Literature,Research Mode of inheritance for gene: ARID1B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Review for gene: ARID1B was set to GREEN Added comment: • Analysis of the UK 100kGP identified a frameshift variant in ARID1B in a patient with intellectual disability and sagittal synostosis: c.3594delinsCCCCCA; p.(Gly1199Profs*14) (Hyder et al., 2021). • A further frameshifting variant was described in an individual within the Chinese cohort with sagittal craniosynostosis c.2346_2352del; p.(Ser784Cysfs*59) (Chen et al., 2022). • An additional patient was described with trigonocephaly and motor developmental delay with a variant in ARID1B: c.2277delC; p.(Pro760fs) (Suzuki et al., 2020). • A de novo variant affecting ARID1B (c.1468_1472delTGGGC; p.(Trp490Glyfs*43)) was identified in an individual with craniosynostosis out of a cohort of neurodevelopmental disorder patients (Mignot et al., 2016). Sources: Literature, Research |
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| Rare syndromic craniosynostosis or isolated multisuture synostosis v2.48 | LTBP1 | Eleanor Williams Added comment: Comment on list classification: Promoting from grey to amber but with a recommendation for green rating following GMS review. 4 cases reported with craniosynostosis in 6/8 individuals | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Rare syndromic craniosynostosis or isolated multisuture synostosis v2.40 | SMAD3 |
Eleanor Williams changed review comment from: Associated with Loeys-Dietz syndrome 3 #613795 (AD) in OMIM but craniosynostosis not listed as a clinical feature. PMID: 20301312 - Loeys and Dietz (2008 updated 2018) - Gene Reviews - states that in severe presentation, craniofacial anomalies in individuals with LDS are characterized by widely spaced eyes and craniosynostosis. PMID: 29392890 - Schepers et al 2018 - review of genes/variants associated with Loeys-Dietz syndrome. Table 5 indicates that only SMAD3 variants are associated with craniosynostosis and text says that "craniosynostosis has only been reported once in a SMAD3 patient" but no reference is given. Looking at reported phenotypes for LDS patients with a SMAD3 variant: PMID: 31569402 - Camerota et al 2019 - report 4 families with LDS and SMAD3 variants. 3/9 individuals from 3 different Italian families presented with dolichocephaly among other phenotypes. 4 families reported with SMAD3 variants in total, each with a different likely causative variant. PMID: 32935439 - Baskin et al 2020 - first report of a LDS patient with biallelic SMAD3 variants (affecting splice site). Proband had classic Loeys-Dietz features, including dysmorphic facial features, significant scoliosis, and pectus excavatum, arachnodactyly, severe aortic root dilation, and diffuse arterial tortuosity. His parents are each heterozygous for the likely pathogenic variant and are more mildly affected. Dolichocephaly in the proband is mentioned.; to: Associated with Loeys-Dietz syndrome 3 #613795 (AD) in OMIM but craniosynostosis not listed as a clinical feature. PMID: 20301312 - Loeys and Dietz (2008 updated 2018) - Gene Reviews - states that in severe presentation, craniofacial anomalies in individuals with LDS are characterized by widely spaced eyes and craniosynostosis. PMID: 29392890 - Schepers et al 2018 - review of genes/variants associated with Loeys-Dietz syndrome. Table 5 indicates that only SMAD3 variants are associated with craniosynostosis and text says that "craniosynostosis has only been reported once in a SMAD3 patient" but no reference is given. Looking at reported phenotypes for LDS patients with a SMAD3 variant and craniosynostosis phenotype: PMID: 31569402 - Camerota et al 2019 - report 4 families with LDS and SMAD3 variants. 3/9 individuals from 3 different Italian families presented with dolichocephaly among other phenotypes. 4 families reported with SMAD3 variants in total, each with a different likely causative variant. PMID: 32935439 - Baskin et al 2020 - first report of a LDS patient with biallelic SMAD3 variants (affecting splice site). Proband had classic Loeys-Dietz features, including dysmorphic facial features, significant scoliosis, and pectus excavatum, arachnodactyly, severe aortic root dilation, and diffuse arterial tortuosity. His parents are each heterozygous for the likely pathogenic variant and are more mildly affected. Dolichocephaly in the proband is mentioned. |
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| Rare syndromic craniosynostosis or isolated multisuture synostosis v2.36 | MASP1 |
Eleanor Williams edited their review of gene: MASP1: Added comment: Checking for further reported cases: PMID: 30601195 - Basdemirci et al 2019 - 3 siblings with 3MC syndrome in which a novel homozygous missense mutation, p.V704G, in MASP1 was identified in 2 of the siblings (not clear if the 3rd sibling was analysed). Craniosynostosis/skull asymmetry is reported in 2 siblings but no details given. PMID: 29407414 - Graul-Neumann et al 2018 - 1adult female with a homozygous 2kb deletion, partially affecting exon 12 of MASP1 found by trio exome sequencing. She has the characteristic facial gestalt and typical multiple congenital anomalies but lacking the key feature cleft lip and palate. At birth craniofacial dysmorphism with skull asymmetry, open sutura metopica and facial asymmetry were noted among other features. PMID: 26419238 - Atik et al 2015 - report on 6 unrelated children with 3MC1 syndrome. Sanger sequencing of MASP1 found 2 different splice site variants, and 3 different missense variants in the 6 probands. Two are reported to have craniosynostosis/skull asymmetry but no details given. No mention of craniosynostosis or skull asymmetry: PMID: 21035106 - Sirmaci et al 2010 - 3 individuals from 2 consanguineous Turkish families with 3MC. A missense and nonsense mutation in MASP1 were found by WES and Sanger sequencing in the two families respectively. Craniosynostosis is NOT mentioned as part of the phenotype.; Changed publications to: 30601195, 29407414, 26419238, 21035106, 21258343, 26789649 |
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| Rare syndromic craniosynostosis or isolated multisuture synostosis v2.31 | FGF10 | Eleanor Williams changed review comment from: As expert reviewer reports PMID: 29215649 (Lee et al 2018) conducted a study in which 233 individuals with craniosynostosis where screened with a 20-gene panel which was designed based on the genes' association with craniosynostosis. Heterozygous variants (1 frameshift, 1 nonsense) were identified in 2 patients.; to: As expert reviewer reports PMID: 29215649 (Lee et al 2018) conducted a study in which 233 individuals with craniosynostosis where screened with a 20-gene panel which was designed based on the genes' association with craniosynostosis. Heterozygous variants (1 frameshift, 1 nonsense) in FGF10 were identified in 2 patients. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Rare syndromic craniosynostosis or isolated multisuture synostosis v2.25 | CHD5 |
Ivone Leong changed review comment from: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in Gene2Phenotype (possible) but not in OMIM. PMID: 33944996. Age ranged from 3 years - 22 years. 9/14 individuals had ID (only 6 of 9 patients were assessed for severity with 2 moderate ID and 4 severe cases). 10/16 individuals had epilepsy. 7/14 had hypotonia and 3/7 had craniosynostosis. 16 different variants were identified (11 missense, 1 frameshift, 2 nonsense and 2 splice site variants). There are >3 unrelated cases, therefore there is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.; to: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in Gene2Phenotype (possible) but not in OMIM. PMID: 33944996. Age ranged from 3 years - 22 years. 9/14 individuals had ID (only 6 of 9 patients were assessed for severity with 2 moderate ID and 4 severe cases). 10/16 individuals had epilepsy. 7/14 had hypotonia and 3/7 had craniosynostosis. 16 different variants were identified (11 missense, 1 frameshift, 2 nonsense and 2 splice site variants). As less than half the cases had craniosynostosis, this gene has been given an Amber rating awaiting more cases. |
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| Rare syndromic craniosynostosis or isolated multisuture synostosis v2.23 | LTBP1 |
Zornitza Stark gene: LTBP1 was added gene: LTBP1 was added to Craniosynostosis. Sources: Literature Mode of inheritance for gene: LTBP1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: LTBP1 were set to 33991472 Phenotypes for gene: LTBP1 were set to Craniosynostosis; cutis laxa; intelectual disability Review for gene: LTBP1 was set to GREEN Added comment: PMID:33991472 - Premature truncating variants in multiple affected individuals from 4 unrelated consanguineous families. - Affected individuals present with connective tissue features (cutis laxa and inguinal hernia), craniofacial dysmorphology, variable heart defects, and prominent skeletal features (craniosynostosis, short stature, brachydactyly, and syndactyly). - Functional studies done on patient fibroblasts and zebrafish models. Sources: Literature |
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| Rare syndromic craniosynostosis or isolated multisuture synostosis v2.16 | TRAF7 |
Andrew Wilkie gene: TRAF7 was added gene: TRAF7 was added to Craniosynostosis. Sources: Expert Review Mode of inheritance for gene: TRAF7 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: TRAF7 were set to 32376980 Phenotypes for gene: TRAF7 were set to craniosynostosis Penetrance for gene: TRAF7 were set to Incomplete Review for gene: TRAF7 was set to GREEN Added comment: Castilla-Vallmanya et al (2020) reported the phenotypes associated with 45 heterozygous variants in TRAF7, missense mutations of which cause a recently recognised neurodevelopmental disorder. 3 of these individuals were reported to have craniosynostosis. The submitter is aware of two additional unpublished cases with TRAF7 missense variants and craniosynostosis; one of these was missed in 100kGP by the GEL/GMC pipeline because TRAF7 was not included in PanelApp, the other is an unpublished case from Rotterdam. In summary there appears to be sufficient evidence that craniosynostosis is a significant albeit low-frequency complication of pathogenic TRAF7 variants, which cause a complex neurodevelopmental disorder. Sources: Expert Review |
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| Rare syndromic craniosynostosis or isolated multisuture synostosis v2.16 | SIX1 |
Andrew Wilkie edited their review of gene: SIX1: Added comment: Calpena et al (2021) identified 7 families in which the proband had craniosynostosis (affecting at least the sagittal suture in all cases) and a heterozygous SIX1 variant (4 nonsense + 3 missense in highly conserved residues of SIX domain or homeodomain). SIX1 mutations (mostly missense) were previously described in branchio-otic syndrome (BOS). Patients and carriers in the extended family variably had features of BOS (including branchial cysts, ear tags or pits, and hearing loss), but there were also several non-penetrant heterozygous individuals, indicating substantial variation in expressivity. The absolute proportion of all craniosynostosis cases found to have SIX1 variants was low (7/1629, 0.4%), but much higher [4/23 (17%)] in those with the rare "Mercedez-Benz" pattern (sagittal + bilambdoid synostosis). SIX1 analysis is therefore particularly indicated in individuals with either (1) additional BOS features or (2) sagittal+bilambdoid synostosis.; Changed rating: GREEN; Changed publications: 33436522 |
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| Rare syndromic craniosynostosis or isolated multisuture synostosis v2.13 | PJA1 |
Arina Puzriakova gene: PJA1 was added gene: PJA1 was added to Craniosynostosis. Sources: Expert list founder-effect tags were added to gene: PJA1. Mode of inheritance for gene: PJA1 was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) Publications for gene: PJA1 were set to 32530565 Phenotypes for gene: PJA1 were set to Trigonocephaly; Intellectual disability Added comment: Recurrent variant, p.Arg376Cys, reported in 7 Japanese individuals from 5 independent families, of which 5 patients were diagnosed with mild trigonocephaly. Some supportive data in a mouse model. Individuals shared a common haplotype, suggestive of founder effect. Sources: Expert list |
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| Rare syndromic craniosynostosis or isolated multisuture synostosis v2.9 | ZNF462 |
Zornitza Stark gene: ZNF462 was added gene: ZNF462 was added to Craniosynostosis. Sources: Expert list Mode of inheritance for gene: ZNF462 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: ZNF462 were set to 28513610 Phenotypes for gene: ZNF462 were set to Weiss-Kruszka syndrome, MIM# 618619 Review for gene: ZNF462 was set to GREEN gene: ZNF462 was marked as current diagnostic Added comment: Craniosynostosis observed in 38% of affected individuals. Sources: Expert list |
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| Rare syndromic craniosynostosis or isolated multisuture synostosis v2.9 | HNRNPK |
Zornitza Stark gene: HNRNPK was added gene: HNRNPK was added to Craniosynostosis. Sources: Expert list Mode of inheritance for gene: HNRNPK was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: HNRNPK were set to 26173930; 26954065; 29904177 Phenotypes for gene: HNRNPK were set to Au-Kline syndrome, MIM# 616580 Review for gene: HNRNPK was set to GREEN gene: HNRNPK was marked as current diagnostic Added comment: Multiple unrelated individuals with Au-Kline syndrome (approx 1/3) have craniosynostosis - sagittal, metopic, lambdoid. Sources: Expert list |
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| Rare syndromic craniosynostosis or isolated multisuture synostosis v2.9 | FGF10 |
Zornitza Stark gene: FGF10 was added gene: FGF10 was added to Craniosynostosis. Sources: Expert list Mode of inheritance for gene: FGF10 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: FGF10 were set to 29215649 Phenotypes for gene: FGF10 were set to Craniosynostosis Review for gene: FGF10 was set to AMBER Added comment: Two individuals reported with variants in this gene as part of a large craniosynostosis cohort. Sources: Expert list |
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| 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 |
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| 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. |
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| Rare syndromic craniosynostosis or isolated multisuture synostosis v1.123 | RUNX2 |
Eleanor Williams changed review comment from: Loss of functional mutations associated with CLEIDOCRANIAL DYSPLASIA in Gene2Phenotype (confirmed). In OMIM loss of function mutations are associated with several phenotypes including Cleidocranial dysplasia. A heterozygous duplication of some exons of RUNX2 is associated with Metaphyseal dysplasia with maxillary hypoplasia with or without brachydactyly . However, craniosynostosis is not listed as a feature of this disorder (PMID: 23290074, 25311905, 29891876 CNV EVIDENCE: PMID: 20683987 - Mefford et al 2010 - Evaluated 186 individuals with single-suture craniosynostosis for submicroscopic deletions and duplications using whole-genome array CGH. They identified a heterozygous inverted 1.1 Mb duplication including the entire sequence of RUNX2, MIR586, and some of CLIC5 and SUPT3H in two affected cousins (1007 and 1019) with metopic synostosis and hypodontia. The duplication was inherited from the mother of one individual and it is presumed the father of the second individual (DNA not available, mother does not have the duplication). Both carrier parents have hypodontia by report, but neither is known to have had synostosis suggesting incomplete penetrance for that phenotype. The grandfather of 1007 and 1019 is described as having an abnormal head shape with a narrow forehead and several missing teeth; DNA was not available from this individual. They state that this CNV was not found in 2,493 control individuals [Itsara et al., 2009]. They compared RUNX2 expression levels in osteoblasts from these two individuals to expression levels in osteoblasts from unaffected individuals (n = 6) and individuals with synostosis but without duplication of RUNX2 (n = 22). The average expression of RUNX2 in the samples from the two individuals was higher than all affected and unaffected cell lines but it was not a statistically significant difference so should be interpreted with caution. PMID: 23307468 - Varvagiannis et al 2013 - a girl with a de novo trisomy 6p12.3-p21.1 who showed craniosynostosis, manifested by the premature fusion of the right coronal and sagittal sutures, and also facial anomalies, psychomotor delay, and recurrent respiratory tract infections. MLPA analysis suggested a duplication of the entire RUNX2 gene. MLPA analysis indicated that the duplication was not present in parental blood samples. SNP array analysis identified the duplication was 6.9 Mb in size and mapped to 6p12.3–p21.1 (chr6: 40,797,975–47,701,961 NCBI Build 35; May 2004), thus encompassing 163 ENSEMBL genes. The finding of abnormal fontanelles and/or abnormal sutures, either manifested as craniosynostosis or not, has been documented in 5 cases in patients with pure partial trisomy 6p. No analysis of RUNX2 expression was performed. PMID: 23348268 - Greives et al 2013 - present a case study of a boy with an atypical skull deformity with pan-craniosynostosis whose microarray analysis revealed 4 copies of a 1.24-Mb region from 6p12.3 to 6p21.1 containing the RUNX2 gene. He presented as an infant with airway obstruction from choanal atresia. He was diagnosed with a closed anterior fontanelle, ventricular septal defect, restricted range of motion in his elbows, mild conductive hearing loss, and developmental delays. They note that his multisutural craniosynostosis is the most extensive associated with RUNX2. No segregation analysis given. PMID:25899668 - Molin et al 2015 - report on a family with an affected mother and three affected children. The four patients carried a 285 kb duplication identified by array comparative genomic hybridization. The duplication includes the entire sequence of RUNX2 and the 5' half of SUPT3H. We confirmed the duplication by real-time quantitative PCR in the four patients. Two children presented with the association of metopic craniosynostosis and oligo/hypodontia previously described, confirming the phenotype caused by RUNX2 duplication. The mother and one child had isolated hypodontia without craniosynostosis. The clinical presentation shown by syndromic patients IV‐1 and IV‐3 appears radically different from MDMHB, but shares a few similarities with previously duplication patients, including as hypodontia and craniosynostosis. Isolated hypodontia observed in Patients III‐2 and IV‐2 highlights a wider clinical spectrum associated with RUNX2 duplication, in addition to isolated and syndromic craniosynostosis and MDMHB. Decipher - there are 6 patients with RUNX2 duplications over 1 kb in size. None mention craniosynostosis as a feature, although abnormality of the face/triangular face is listed for the patient with the 3.59 Mb duplication. https://decipher.sanger.ac.uk/gene/RUNX2#variants/RUNX2/patient-overlap/cnvs Mouse models: PMIDs: 11581292 (Liu et al 2001) and 12167715 (Geoffroy et al 2002) - both surprisingly report transgenic mice overexpressing Cbfa1 (runx2) developed severe osteopenia. PMID: 21807129 - Maeno et al 2011 - report that in mice early onset of Runx2 expression in the cranial mesenchyme induced mineralization on E13.0, when no mineralization was observed in wild-type mice, and resulted in craniosynostosis. PMID: 23300083 McGee-Lawrence et al 2013 - Runx2-deficient mice die at birth because of a lack of skeletal ossification. Axin2-deficient mice develop craniosynostosis because of high β-catenin activity. Runx2 represses transcription of Axin2 mRNA. They state that their data are consistent with the idea that Runx2 plays a central role in the etiologies of several different forms of craniosynostosis. Control populations: A search for the smallest CNV in a patient with craniosynostosis from Molin et al 2015 in the Database of Genomic Variants using GRCh38 coordinates shows no invidiuals from control populations with CNVs that cover RUNX2 http://dgv.tcag.ca/gb2/gbrowse/dgv2_hg38/?name=chr6%3A45265488-45551053;search=Search. Summary: Loss of function variants, partial duplication of the the RUNX2 gene and full duplication of the RUNX2 gene appear to result in different phenotypes. With regards to full duplication, there are 4 cases reported in separate publications of duplications fully covering the RUNX2 gene and patients with a craniosynostosis phenotype. The smallest duplication is 285 kb and includes RUNX2 and the 5' half of SUPT3H. However, there appears to be incomplete penetrance with some carriers having a less severe phenotype. Mefford et al state the CNV they report was not found in 2,493 control individuals and CNVs covering RUNX2 were not found in the Database of Genomics Variants. Mouse models give conflicting evidence. Mouse models of runx2 over-expression surprisingly found they developed severe osteopenia. However, early onset of Runx2 expression resulted in craniosynostosis, and Runx2 was found to repress Axin2, low levels of which can result in craniosynostosis. ; to: Loss of functional mutations associated with CLEIDOCRANIAL DYSPLASIA in Gene2Phenotype (confirmed). In OMIM loss of function mutations are associated with several phenotypes including Cleidocranial dysplasia. A heterozygous duplication of some exons of RUNX2 is associated with Metaphyseal dysplasia with maxillary hypoplasia with or without brachydactyly . However, craniosynostosis is not listed as a feature of this disorder (PMID: 23290074, 25311905, 29891876) CNV EVIDENCE: PMID: 20683987 - Mefford et al 2010 - Evaluated 186 individuals with single-suture craniosynostosis for submicroscopic deletions and duplications using whole-genome array CGH. They identified a heterozygous inverted 1.1 Mb duplication including the entire sequence of RUNX2, MIR586, and some of CLIC5 and SUPT3H in two affected cousins (1007 and 1019) with metopic synostosis and hypodontia. The duplication was inherited from the mother of one individual and it is presumed the father of the second individual (DNA not available, mother does not have the duplication). Both carrier parents have hypodontia by report, but neither is known to have had synostosis suggesting incomplete penetrance for that phenotype. The grandfather of 1007 and 1019 is described as having an abnormal head shape with a narrow forehead and several missing teeth; DNA was not available from this individual. They state that this CNV was not found in 2,493 control individuals [Itsara et al., 2009]. They compared RUNX2 expression levels in osteoblasts from these two individuals to expression levels in osteoblasts from unaffected individuals (n = 6) and individuals with synostosis but without duplication of RUNX2 (n = 22). The average expression of RUNX2 in the samples from the two individuals was higher than all affected and unaffected cell lines but it was not a statistically significant difference so should be interpreted with caution. PMID: 23307468 - Varvagiannis et al 2013 - a girl with a de novo trisomy 6p12.3-p21.1 who showed craniosynostosis, manifested by the premature fusion of the right coronal and sagittal sutures, and also facial anomalies, psychomotor delay, and recurrent respiratory tract infections. MLPA analysis suggested a duplication of the entire RUNX2 gene. MLPA analysis indicated that the duplication was not present in parental blood samples. SNP array analysis identified the duplication was 6.9 Mb in size and mapped to 6p12.3–p21.1 (chr6: 40,797,975–47,701,961 NCBI Build 35; May 2004), thus encompassing 163 ENSEMBL genes. The finding of abnormal fontanelles and/or abnormal sutures, either manifested as craniosynostosis or not, has been documented in 5 cases in patients with pure partial trisomy 6p. No analysis of RUNX2 expression was performed. PMID: 23348268 - Greives et al 2013 - present a case study of a boy with an atypical skull deformity with pan-craniosynostosis whose microarray analysis revealed 4 copies of a 1.24-Mb region from 6p12.3 to 6p21.1 containing the RUNX2 gene. He presented as an infant with airway obstruction from choanal atresia. He was diagnosed with a closed anterior fontanelle, ventricular septal defect, restricted range of motion in his elbows, mild conductive hearing loss, and developmental delays. They note that his multisutural craniosynostosis is the most extensive associated with RUNX2. No segregation analysis given. PMID:25899668 - Molin et al 2015 - report on a family with an affected mother and three affected children. The four patients carried a 285 kb duplication identified by array comparative genomic hybridization. The duplication includes the entire sequence of RUNX2 and the 5' half of SUPT3H. We confirmed the duplication by real-time quantitative PCR in the four patients. Two children presented with the association of metopic craniosynostosis and oligo/hypodontia previously described, confirming the phenotype caused by RUNX2 duplication. The mother and one child had isolated hypodontia without craniosynostosis. The clinical presentation shown by syndromic patients IV‐1 and IV‐3 appears radically different from MDMHB, but shares a few similarities with previously duplication patients, including as hypodontia and craniosynostosis. Isolated hypodontia observed in Patients III‐2 and IV‐2 highlights a wider clinical spectrum associated with RUNX2 duplication, in addition to isolated and syndromic craniosynostosis and MDMHB. Decipher - there are 6 patients with RUNX2 duplications over 1 kb in size. None mention craniosynostosis as a feature, although abnormality of the face/triangular face is listed for the patient with the 3.59 Mb duplication. https://decipher.sanger.ac.uk/gene/RUNX2#variants/RUNX2/patient-overlap/cnvs Mouse models: PMIDs: 11581292 (Liu et al 2001) and 12167715 (Geoffroy et al 2002) - both surprisingly report transgenic mice overexpressing Cbfa1 (runx2) developed severe osteopenia. PMID: 21807129 - Maeno et al 2011 - report that in mice early onset of Runx2 expression in the cranial mesenchyme induced mineralization on E13.0, when no mineralization was observed in wild-type mice, and resulted in craniosynostosis. PMID: 23300083 McGee-Lawrence et al 2013 - Runx2-deficient mice die at birth because of a lack of skeletal ossification. Axin2-deficient mice develop craniosynostosis because of high β-catenin activity. Runx2 represses transcription of Axin2 mRNA. They state that their data are consistent with the idea that Runx2 plays a central role in the etiologies of several different forms of craniosynostosis. Control populations: A search for the smallest CNV in a patient with craniosynostosis from Molin et al 2015 in the Database of Genomic Variants using GRCh38 coordinates shows no invidiuals from control populations with CNVs that cover RUNX2 http://dgv.tcag.ca/gb2/gbrowse/dgv2_hg38/?name=chr6%3A45265488-45551053;search=Search. Summary: Loss of function variants, partial duplication of the the RUNX2 gene and full duplication of the RUNX2 gene appear to result in different phenotypes. With regards to full duplication, there are 4 cases reported in separate publications of duplications fully covering the RUNX2 gene and patients with a craniosynostosis phenotype. The smallest duplication is 285 kb and includes RUNX2 and the 5' half of SUPT3H. However, there appears to be incomplete penetrance with some carriers having a less severe phenotype. Mefford et al state the CNV they report was not found in 2,493 control individuals and CNVs covering RUNX2 were not found in the Database of Genomics Variants. Mouse models give conflicting evidence. Mouse models of runx2 over-expression surprisingly found they developed severe osteopenia. However, early onset of Runx2 expression resulted in craniosynostosis, and Runx2 was found to repress Axin2, low levels of which can result in craniosynostosis. |
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| Rare syndromic craniosynostosis or isolated multisuture synostosis v1.123 | RUNX2 |
Eleanor Williams changed review comment from: Loss of functional mutations associated with CLEIDOCRANIAL DYSPLASIA in Gene2Phenotype (confirmed). In OMIM loss of function mutations are associated with several phenotypes including Cleidocranial dysplasia. A heterozygous duplication of some exons of RUNX2 is associated with Metaphyseal dysplasia with maxillary hypoplasia with or without brachydactyly . However, craniosynostosis is not listed as a feature of this disorder (PMID: 23290074, 25311905, 29891876 CNV EVIDENCE: PMID: 20683987 - Mefford et al 2010 - Evaluated 186 individuals with single-suture craniosynostosis for submicroscopic deletions and duplications using whole-genome array CGH. They identified a heterozygous inverted 1.1 Mb duplication including the entire sequence of RUNX2, MIR586, and some of CLIC5 and SUPT3H in two affected cousins (1007 and 1019) with metopic synostosis and hypodontia. The duplication was inherited from the mother of one individual and it is presumed the father of the second individual (DNA not available, mother does not have the duplication). Both carrier parents have hypodontia by report, but neither is known to have had synostosis suggesting incomplete penetrance for that phenotype. The grandfather of 1007 and 1019 is described as having an abnormal head shape with a narrow forehead and several missing teeth; DNA was not available from this individual. They state that this CNV was not found in 2,493 control individuals [Itsara et al., 2009]. They compared RUNX2 expression levels in osteoblasts from these two individuals to expression levels in osteoblasts from unaffected individuals (n = 6) and individuals with synostosis but without duplication of RUNX2 (n = 22). The average expression of RUNX2 in the samples from the two individuals was higher than all affected and unaffected cell lines but it was not a statistically significant difference so should be interpreted with caution. PMID: 23307468 - Varvagiannis et al 2013 - a girl with a de novo trisomy 6p12.3-p21.1 who showed craniosynostosis, manifested by the premature fusion of the right coronal and sagittal sutures, and also facial anomalies, psychomotor delay, and recurrent respiratory tract infections. MLPA analysis suggested a duplication of the entire RUNX2 gene. MLPA analysis indicated that the duplication was not present in parental blood samples. SNP array analysis identified the duplication was 6.9 Mb in size and mapped to 6p12.3–p21.1 (chr6: 40,797,975–47,701,961 NCBI Build 35; May 2004), thus encompassing 163 ENSEMBL genes. The finding of abnormal fontanelles and/or abnormal sutures, either manifested as craniosynostosis or not, has been documented in 5 cases in patients with pure partial trisomy 6p. No analysis of RUNX2 expression was performed. PMID: 23348268 - Greives et al 2013 - present a case study of a boy with an atypical skull deformity with pan-craniosynostosis whose microarray analysis revealed 4 copies of a 1.24-Mb region from 6p12.3 to 6p21.1 containing the RUNX2 gene. He presented as an infant with airway obstruction from choanal atresia. He was diagnosed with a closed anterior fontanelle, ventricular septal defect, restricted range of motion in his elbows, mild conductive hearing loss, and developmental delays. They note that his multisutural craniosynostosis is the most extensive associated with RUNX2. No segregation analysis given. PMID:25899668 - Molin et al 2015 - report on a family with an affected mother and three affected children. The four patients carried a 285 kb duplication identified by array comparative genomic hybridization. The duplication includes the entire sequence of RUNX2 and the 5' half of SUPT3H. We confirmed the duplication by real-time quantitative PCR in the four patients. Two children presented with the association of metopic craniosynostosis and oligo/hypodontia previously described, confirming the phenotype caused by RUNX2 duplication. The mother and one child had isolated hypodontia without craniosynostosis. The clinical presentation shown by syndromic patients IV‐1 and IV‐3 appears radically different from MDMHB, but shares a few similarities with previously duplication patients, including as hypodontia and craniosynostosis. Isolated hypodontia observed in Patients III‐2 and IV‐2 highlights a wider clinical spectrum associated with RUNX2 duplication, in addition to isolated and syndromic craniosynostosis and MDMHB. Decipher - there are 6 patients with RUNX2 duplications over 1 kb in size. None mention craniosynostosis as a feature, although abnormality of the face/triangular face is listed for the patient with the 3.59 Mb duplication. https://decipher.sanger.ac.uk/gene/RUNX2#variants/RUNX2/patient-overlap/cnvs Mouse models: PMIDs: 11581292 (Liu et al 2001) and 12167715 (Geoffroy et al 2002) - both surprisingly report transgenic mice overexpressing Cbfa1 (runx2) developed severe osteopenia. PMID: 21807129 - Maeno et al 2011 - report that in mice early onset of Runx2 expression in the cranial mesenchyme induced mineralization on E13.0, when no mineralization was observed in wild-type mice, and resulted in craniosynostosis. PMID: 23300083 McGee-Lawrence et al 2013 - Runx2-deficient mice die at birth because of a lack of skeletal ossification. Axin2-deficient mice develop craniosynostosis because of high β-catenin activity. Runx2 represses transcription of Axin2 mRNA. They state that their data are consistent with the idea that Runx2 plays a central role in the etiologies of several different forms of craniosynostosis. Control populations: A search for the smallest CNV in a patient with craniosynostosis from Molin et al 2015 in the Database of Genomics Variants using GRCh38 coordinates shows no invidiuals from control populations with CNVs that cover RUNX2 http://dgv.tcag.ca/gb2/gbrowse/dgv2_hg38/?name=chr6%3A45265488-45551053;search=Search. Summary: Loss of function variants, partial duplication of the the RUNX2 gene and full duplication of the RUNX2 gene appear to result in different phenotypes. With regards to full duplication, there are 4 cases reported in separate publications of duplications fully covering the RUNX2 gene and patients with a craniosynostosis phenotype. The smallest duplication is 285 kb and includes RUNX2 and the 5' half of SUPT3H. However, there appears to be incomplete penetrance with some carriers having a less severe phenotype. Mefford et al state the CNV they report was not found in 2,493 control individuals and CNVs covering RUNX2 were not found in the Database of Genomics Variants. Mouse models give conflicting evidence. Mouse models of runx2 over-expression surprisingly found they developed severe osteopenia. However, early onset of Runx2 expression resulted in craniosynostosis, and Runx2 was found to repress Axin2, low levels of which can result in craniosynostosis. ; to: Loss of functional mutations associated with CLEIDOCRANIAL DYSPLASIA in Gene2Phenotype (confirmed). In OMIM loss of function mutations are associated with several phenotypes including Cleidocranial dysplasia. A heterozygous duplication of some exons of RUNX2 is associated with Metaphyseal dysplasia with maxillary hypoplasia with or without brachydactyly . However, craniosynostosis is not listed as a feature of this disorder (PMID: 23290074, 25311905, 29891876 CNV EVIDENCE: PMID: 20683987 - Mefford et al 2010 - Evaluated 186 individuals with single-suture craniosynostosis for submicroscopic deletions and duplications using whole-genome array CGH. They identified a heterozygous inverted 1.1 Mb duplication including the entire sequence of RUNX2, MIR586, and some of CLIC5 and SUPT3H in two affected cousins (1007 and 1019) with metopic synostosis and hypodontia. The duplication was inherited from the mother of one individual and it is presumed the father of the second individual (DNA not available, mother does not have the duplication). Both carrier parents have hypodontia by report, but neither is known to have had synostosis suggesting incomplete penetrance for that phenotype. The grandfather of 1007 and 1019 is described as having an abnormal head shape with a narrow forehead and several missing teeth; DNA was not available from this individual. They state that this CNV was not found in 2,493 control individuals [Itsara et al., 2009]. They compared RUNX2 expression levels in osteoblasts from these two individuals to expression levels in osteoblasts from unaffected individuals (n = 6) and individuals with synostosis but without duplication of RUNX2 (n = 22). The average expression of RUNX2 in the samples from the two individuals was higher than all affected and unaffected cell lines but it was not a statistically significant difference so should be interpreted with caution. PMID: 23307468 - Varvagiannis et al 2013 - a girl with a de novo trisomy 6p12.3-p21.1 who showed craniosynostosis, manifested by the premature fusion of the right coronal and sagittal sutures, and also facial anomalies, psychomotor delay, and recurrent respiratory tract infections. MLPA analysis suggested a duplication of the entire RUNX2 gene. MLPA analysis indicated that the duplication was not present in parental blood samples. SNP array analysis identified the duplication was 6.9 Mb in size and mapped to 6p12.3–p21.1 (chr6: 40,797,975–47,701,961 NCBI Build 35; May 2004), thus encompassing 163 ENSEMBL genes. The finding of abnormal fontanelles and/or abnormal sutures, either manifested as craniosynostosis or not, has been documented in 5 cases in patients with pure partial trisomy 6p. No analysis of RUNX2 expression was performed. PMID: 23348268 - Greives et al 2013 - present a case study of a boy with an atypical skull deformity with pan-craniosynostosis whose microarray analysis revealed 4 copies of a 1.24-Mb region from 6p12.3 to 6p21.1 containing the RUNX2 gene. He presented as an infant with airway obstruction from choanal atresia. He was diagnosed with a closed anterior fontanelle, ventricular septal defect, restricted range of motion in his elbows, mild conductive hearing loss, and developmental delays. They note that his multisutural craniosynostosis is the most extensive associated with RUNX2. No segregation analysis given. PMID:25899668 - Molin et al 2015 - report on a family with an affected mother and three affected children. The four patients carried a 285 kb duplication identified by array comparative genomic hybridization. The duplication includes the entire sequence of RUNX2 and the 5' half of SUPT3H. We confirmed the duplication by real-time quantitative PCR in the four patients. Two children presented with the association of metopic craniosynostosis and oligo/hypodontia previously described, confirming the phenotype caused by RUNX2 duplication. The mother and one child had isolated hypodontia without craniosynostosis. The clinical presentation shown by syndromic patients IV‐1 and IV‐3 appears radically different from MDMHB, but shares a few similarities with previously duplication patients, including as hypodontia and craniosynostosis. Isolated hypodontia observed in Patients III‐2 and IV‐2 highlights a wider clinical spectrum associated with RUNX2 duplication, in addition to isolated and syndromic craniosynostosis and MDMHB. Decipher - there are 6 patients with RUNX2 duplications over 1 kb in size. None mention craniosynostosis as a feature, although abnormality of the face/triangular face is listed for the patient with the 3.59 Mb duplication. https://decipher.sanger.ac.uk/gene/RUNX2#variants/RUNX2/patient-overlap/cnvs Mouse models: PMIDs: 11581292 (Liu et al 2001) and 12167715 (Geoffroy et al 2002) - both surprisingly report transgenic mice overexpressing Cbfa1 (runx2) developed severe osteopenia. PMID: 21807129 - Maeno et al 2011 - report that in mice early onset of Runx2 expression in the cranial mesenchyme induced mineralization on E13.0, when no mineralization was observed in wild-type mice, and resulted in craniosynostosis. PMID: 23300083 McGee-Lawrence et al 2013 - Runx2-deficient mice die at birth because of a lack of skeletal ossification. Axin2-deficient mice develop craniosynostosis because of high β-catenin activity. Runx2 represses transcription of Axin2 mRNA. They state that their data are consistent with the idea that Runx2 plays a central role in the etiologies of several different forms of craniosynostosis. Control populations: A search for the smallest CNV in a patient with craniosynostosis from Molin et al 2015 in the Database of Genomic Variants using GRCh38 coordinates shows no invidiuals from control populations with CNVs that cover RUNX2 http://dgv.tcag.ca/gb2/gbrowse/dgv2_hg38/?name=chr6%3A45265488-45551053;search=Search. Summary: Loss of function variants, partial duplication of the the RUNX2 gene and full duplication of the RUNX2 gene appear to result in different phenotypes. With regards to full duplication, there are 4 cases reported in separate publications of duplications fully covering the RUNX2 gene and patients with a craniosynostosis phenotype. The smallest duplication is 285 kb and includes RUNX2 and the 5' half of SUPT3H. However, there appears to be incomplete penetrance with some carriers having a less severe phenotype. Mefford et al state the CNV they report was not found in 2,493 control individuals and CNVs covering RUNX2 were not found in the Database of Genomics Variants. Mouse models give conflicting evidence. Mouse models of runx2 over-expression surprisingly found they developed severe osteopenia. However, early onset of Runx2 expression resulted in craniosynostosis, and Runx2 was found to repress Axin2, low levels of which can result in craniosynostosis. |
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| Rare syndromic craniosynostosis or isolated multisuture synostosis v1.123 | RUNX2 |
Eleanor Williams changed review comment from: Loss of functional mutations associated with CLEIDOCRANIAL DYSPLASIA in Gene2Phenotype (confirmed). In OMIM loss of function mutations are associated with several phenotypes including Cleidocranial dysplasia. A heterozygous duplication of some exons of RUNX2 is associated with Metaphyseal dysplasia with maxillary hypoplasia with or without brachydactyly . However, craniosynostosis is not listed as a feature of this disorder (PMID: 23290074, 25311905, 29891876 CNV EVIDENCE: PMID: 20683987 - Mefford et al 2010 - Evaluated 186 individuals with single-suture craniosynostosis for submicroscopic deletions and duplications using whole-genome array CGH. They identified a heterozygous inverted 1.1 Mb duplication including the entire sequence of RUNX2, MIR586, and some of CLIC5 and SUPT3H in two affected cousins (1007 and 1019) with metopic synostosis and hypodontia. The duplication was inherited from the mother of one individual and it is presumed the father of the second individual (DNA not available, mother does not have the duplication). Both carrier parents have hypodontia by report, but neither is known to have had synostosis suggesting incomplete penetrance for that phenotype. The grandfather of 1007 and 1019 is described as having an abnormal head shape with a narrow forehead and several missing teeth; DNA was not available from this individual. They state that this CNV was not found in 2,493 control individuals [Itsara et al., 2009]. They compared RUNX2 expression levels in osteoblasts from these two individuals to expression levels in osteoblasts from unaffected individuals (n = 6) and individuals with synostosis but without duplication of RUNX2 (n = 22). The average expression of RUNX2 in the samples from the two individuals was higher than all affected and unaffected cell lines but it was not a statistically significant difference so should be interpreted with caution. PMID: 23307468 - Varvagiannis et al 2013 - a girl with a de novo trisomy 6p12.3-p21.1 who showed craniosynostosis, manifested by the premature fusion of the right coronal and sagittal sutures, and also facial anomalies, psychomotor delay, and recurrent respiratory tract infections. MLPA analysis suggested a duplication of the entire RUNX2 gene. MLPA analysis indicated that the duplication was not present in parental blood samples. SNP array analysis identified the duplication was 6.9 Mb in size and mapped to 6p12.3–p21.1 (chr6: 40,797,975–47,701,961 NCBI Build 35; May 2004), thus encompassing 163 ENSEMBL genes. The finding of abnormal fontanelles and/or abnormal sutures, either manifested as craniosynostosis or not, has been documented in 5 cases in patients with pure partial trisomy 6p. No analysis of RUNX2 expression was performed. PMID: 23348268 - Greives et al 2013 - present a case study of a boy with an atypical skull deformity with pan-craniosynostosis whose microarray analysis revealed 4 copies of a 1.24-Mb region from 6p12.3 to 6p21.1 containing the RUNX2 gene. He presented as an infant with airway obstruction from choanal atresia. He was diagnosed with a closed anterior fontanelle, ventricular septal defect, restricted range of motion in his elbows, mild conductive hearing loss, and developmental delays. They note that his multisutural craniosynostosis is the most extensive associated with RUNX2. No segregation analysis given. PMID:25899668 - Molin et al 2015 - report on a family with an affected mother and three affected children. The four patients carried a 285 kb duplication identified by array comparative genomic hybridization. The duplication includes the entire sequence of RUNX2 and the 5' half of SUPT3H. We confirmed the duplication by real-time quantitative PCR in the four patients. Two children presented with the association of metopic craniosynostosis and oligo/hypodontia previously described, confirming the phenotype caused by RUNX2 duplication. The mother and one child had isolated hypodontia without craniosynostosis. The clinical presentation shown by syndromic patients IV‐1 and IV‐3 appears radically different from MDMHB, but shares a few similarities with previously duplication patients, including as hypodontia and craniosynostosis. Isolated hypodontia observed in Patients III‐2 and IV‐2 highlights a wider clinical spectrum associated with RUNX2 duplication, in addition to isolated and syndromic craniosynostosis and MDMHB. Decipher - there are 6 patients with RUNX2 duplications over 1 kb in size. None mention craniosynostosis as a feature, although abnormality of the face/triangular face is listed for the patient with the 3.59 Mb duplication. https://decipher.sanger.ac.uk/gene/RUNX2#variants/RUNX2/patient-overlap/cnvs Mouse models: PMIDs: 11581292 (Liu et al 2001) and 12167715 (Geoffroy et al 2002) - both surprisingly report transgenic mice overexpressing Cbfa1 (runx2) developed severe osteopenia. PMID: 21807129 - Maeno et al 2011 - report that in mice early onset of Runx2 expression in the cranial mesenchyme induced mineralization on E13.0, when no mineralization was observed in wild-type mice, and resulted in craniosynostosis. PMID: 23300083 McGee-Lawrence et al 2013 - Runx2-deficient mice die at birth because of a lack of skeletal ossification. Axin2-deficient mice develop craniosynostosis because of high β-catenin activity. Runx2 represses transcription of Axin2 mRNA. They state that their data are consistent with the idea that Runx2 plays a central role in the etiologies of several different forms of craniosynostosis. Summary: Loss of function variants, partial duplication of the the RUNX2 gene and full duplication of the RUNX2 gene appear to result in different phenotypes. With regards to full duplication, there are 4 cases reported in separate publications of duplications fully covering the RUNX2 gene and patients with a craniosynostosis phenotype. The smallest duplication is 285 kb and includes RUNX2 and the 5' half of SUPT3H. However, there appears to be incomplete penetrance with some carriers having a less severe phenotype. Mefford et al state the CNV they report was not found in 2,493 control individuals. Mouse models give conflicting evidence. Mouse models of runx2 over-expression surprisingly found they developed severe osteopenia. However, early onset of Runx2 expression resulted in craniosynostosis, and Runx2 was found to repress Axin2, low levels of which can result in craniosynostosis. ; to: Loss of functional mutations associated with CLEIDOCRANIAL DYSPLASIA in Gene2Phenotype (confirmed). In OMIM loss of function mutations are associated with several phenotypes including Cleidocranial dysplasia. A heterozygous duplication of some exons of RUNX2 is associated with Metaphyseal dysplasia with maxillary hypoplasia with or without brachydactyly . However, craniosynostosis is not listed as a feature of this disorder (PMID: 23290074, 25311905, 29891876 CNV EVIDENCE: PMID: 20683987 - Mefford et al 2010 - Evaluated 186 individuals with single-suture craniosynostosis for submicroscopic deletions and duplications using whole-genome array CGH. They identified a heterozygous inverted 1.1 Mb duplication including the entire sequence of RUNX2, MIR586, and some of CLIC5 and SUPT3H in two affected cousins (1007 and 1019) with metopic synostosis and hypodontia. The duplication was inherited from the mother of one individual and it is presumed the father of the second individual (DNA not available, mother does not have the duplication). Both carrier parents have hypodontia by report, but neither is known to have had synostosis suggesting incomplete penetrance for that phenotype. The grandfather of 1007 and 1019 is described as having an abnormal head shape with a narrow forehead and several missing teeth; DNA was not available from this individual. They state that this CNV was not found in 2,493 control individuals [Itsara et al., 2009]. They compared RUNX2 expression levels in osteoblasts from these two individuals to expression levels in osteoblasts from unaffected individuals (n = 6) and individuals with synostosis but without duplication of RUNX2 (n = 22). The average expression of RUNX2 in the samples from the two individuals was higher than all affected and unaffected cell lines but it was not a statistically significant difference so should be interpreted with caution. PMID: 23307468 - Varvagiannis et al 2013 - a girl with a de novo trisomy 6p12.3-p21.1 who showed craniosynostosis, manifested by the premature fusion of the right coronal and sagittal sutures, and also facial anomalies, psychomotor delay, and recurrent respiratory tract infections. MLPA analysis suggested a duplication of the entire RUNX2 gene. MLPA analysis indicated that the duplication was not present in parental blood samples. SNP array analysis identified the duplication was 6.9 Mb in size and mapped to 6p12.3–p21.1 (chr6: 40,797,975–47,701,961 NCBI Build 35; May 2004), thus encompassing 163 ENSEMBL genes. The finding of abnormal fontanelles and/or abnormal sutures, either manifested as craniosynostosis or not, has been documented in 5 cases in patients with pure partial trisomy 6p. No analysis of RUNX2 expression was performed. PMID: 23348268 - Greives et al 2013 - present a case study of a boy with an atypical skull deformity with pan-craniosynostosis whose microarray analysis revealed 4 copies of a 1.24-Mb region from 6p12.3 to 6p21.1 containing the RUNX2 gene. He presented as an infant with airway obstruction from choanal atresia. He was diagnosed with a closed anterior fontanelle, ventricular septal defect, restricted range of motion in his elbows, mild conductive hearing loss, and developmental delays. They note that his multisutural craniosynostosis is the most extensive associated with RUNX2. No segregation analysis given. PMID:25899668 - Molin et al 2015 - report on a family with an affected mother and three affected children. The four patients carried a 285 kb duplication identified by array comparative genomic hybridization. The duplication includes the entire sequence of RUNX2 and the 5' half of SUPT3H. We confirmed the duplication by real-time quantitative PCR in the four patients. Two children presented with the association of metopic craniosynostosis and oligo/hypodontia previously described, confirming the phenotype caused by RUNX2 duplication. The mother and one child had isolated hypodontia without craniosynostosis. The clinical presentation shown by syndromic patients IV‐1 and IV‐3 appears radically different from MDMHB, but shares a few similarities with previously duplication patients, including as hypodontia and craniosynostosis. Isolated hypodontia observed in Patients III‐2 and IV‐2 highlights a wider clinical spectrum associated with RUNX2 duplication, in addition to isolated and syndromic craniosynostosis and MDMHB. Decipher - there are 6 patients with RUNX2 duplications over 1 kb in size. None mention craniosynostosis as a feature, although abnormality of the face/triangular face is listed for the patient with the 3.59 Mb duplication. https://decipher.sanger.ac.uk/gene/RUNX2#variants/RUNX2/patient-overlap/cnvs Mouse models: PMIDs: 11581292 (Liu et al 2001) and 12167715 (Geoffroy et al 2002) - both surprisingly report transgenic mice overexpressing Cbfa1 (runx2) developed severe osteopenia. PMID: 21807129 - Maeno et al 2011 - report that in mice early onset of Runx2 expression in the cranial mesenchyme induced mineralization on E13.0, when no mineralization was observed in wild-type mice, and resulted in craniosynostosis. PMID: 23300083 McGee-Lawrence et al 2013 - Runx2-deficient mice die at birth because of a lack of skeletal ossification. Axin2-deficient mice develop craniosynostosis because of high β-catenin activity. Runx2 represses transcription of Axin2 mRNA. They state that their data are consistent with the idea that Runx2 plays a central role in the etiologies of several different forms of craniosynostosis. Control populations: A search for the smallest CNV in a patient with craniosynostosis from Molin et al 2015 in the Database of Genomics Variants using GRCh38 coordinates shows no invidiuals from control populations with CNVs that cover RUNX2 http://dgv.tcag.ca/gb2/gbrowse/dgv2_hg38/?name=chr6%3A45265488-45551053;search=Search. Summary: Loss of function variants, partial duplication of the the RUNX2 gene and full duplication of the RUNX2 gene appear to result in different phenotypes. With regards to full duplication, there are 4 cases reported in separate publications of duplications fully covering the RUNX2 gene and patients with a craniosynostosis phenotype. The smallest duplication is 285 kb and includes RUNX2 and the 5' half of SUPT3H. However, there appears to be incomplete penetrance with some carriers having a less severe phenotype. Mefford et al state the CNV they report was not found in 2,493 control individuals and CNVs covering RUNX2 were not found in the Database of Genomics Variants. Mouse models give conflicting evidence. Mouse models of runx2 over-expression surprisingly found they developed severe osteopenia. However, early onset of Runx2 expression resulted in craniosynostosis, and Runx2 was found to repress Axin2, low levels of which can result in craniosynostosis. |
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| Rare syndromic craniosynostosis or isolated multisuture synostosis v1.123 | RUNX2 |
Eleanor Williams changed review comment from: Loss of functional mutations associated with CLEIDOCRANIAL DYSPLASIA in Gene2Phenotype (confirmed). In OMIM loss of function mutations are associated with several phenotypes including Cleidocranial dysplasia. A heterozygous duplication of some exons of RUNX2 is associated with Metaphyseal dysplasia with maxillary hypoplasia with or without brachydactyly . However, craniosynostosis is not listed as a feature of this disorder (PMID: 23290074, 25311905, 29891876 CNV EVIDENCE: PMID: 20683987 - Mefford et al 2010 - Evaluated 186 individuals with single-suture craniosynostosis for submicroscopic deletions and duplications using whole-genome array CGH. They identified a heterozygous inverted 1.1 Mb duplication including the entire sequence of RUNX2, MIR586, and some of CLIC5 and SUPT3H in two affected cousins (1007 and 1019) with metopic synostosis and hypodontia. The duplication was inherited from the mother of one individual and it is presumed the father of the second individual (DNA not available, mother does not have the duplication). Both carrier parents have hypodontia by report, but neither is known to have had synostosis suggesting incomplete penetrance for that phenotype. The grandfather of 1007 and 1019 is described as having an abnormal head shape with a narrow forehead and several missing teeth; DNA was not available from this individual. They state that this CNV was not found in 2,493 control individuals [Itsara et al., 2009]. They compared RUNX2 expression levels in osteoblasts from these two individuals to expression levels in osteoblasts from unaffected individuals (n = 6) and individuals with synostosis but without duplication of RUNX2 (n = 22). The average expression of RUNX2 in the samples from the two individuals was higher than all affected and unaffected cell lines but it was not a statistically significant difference in RUNX2 expression levels so should be interpreted with caution. PMID: 23307468 - Varvagiannis et al 2013 - a girl with a de novo trisomy 6p12.3-p21.1 who showed craniosynostosis, manifested by the premature fusion of the right coronal and sagittal sutures, and also facial anomalies, psychomotor delay, and recurrent respiratory tract infections. MLPA analysis suggested a duplication of the entire RUNX2 gene. MLPA analysis indicated that the duplication was not present in parental blood samples. SNP array analysis identified the duplication was 6.9 Mb in size and mapped to 6p12.3–p21.1 (chr6: 40,797,975–47,701,961 NCBI Build 35; May 2004), thus encompassing 163 ENSEMBL genes. The finding of abnormal fontanelles and/or abnormal sutures, either manifested as craniosynostosis or not, has been documented in 5 cases in patients with pure partial trisomy 6p. No analysis of RUNX2 expression was performed. PMID: 23348268 - Greives et al 2013 - present a case study of a boy with an atypical skull deformity with pan-craniosynostosis whose microarray analysis revealed 4 copies of a 1.24-Mb region from 6p12.3 to 6p21.1 containing the RUNX2 gene. He presented as an infant with airway obstruction from choanal atresia. He was diagnosed with a closed anterior fontanelle, ventricular septal defect, restricted range of motion in his elbows, mild conductive hearing loss, and developmental delays. They note that his multisutural craniosynostosis is the most extensive associated with RUNX2. No segregation analysis given. PMID:25899668 - Molin et al 2015 - report on a family with an affected mother and three affected children. The four patients carried a 285 kb duplication identified by array comparative genomic hybridization. The duplication includes the entire sequence of RUNX2 and the 5' half of SUPT3H. We confirmed the duplication by real-time quantitative PCR in the four patients. Two children presented with the association of metopic craniosynostosis and oligo/hypodontia previously described, confirming the phenotype caused by RUNX2 duplication. The mother and one child had isolated hypodontia without craniosynostosis. The clinical presentation shown by syndromic patients IV‐1 and IV‐3 appears radically different from MDMHB, but shares a few similarities with previously duplication patients, including as hypodontia and craniosynostosis. Isolated hypodontia observed in Patients III‐2 and IV‐2 highlights a wider clinical spectrum associated with RUNX2 duplication, in addition to isolated and syndromic craniosynostosis and MDMHB. Decipher - there are 6 patients with RUNX2 duplications over 1 kb in size. None mention craniosynostosis as a feature, although abnormality of the face/triangular face is listed for the patient with the 3.59 Mb duplication. https://decipher.sanger.ac.uk/gene/RUNX2#variants/RUNX2/patient-overlap/cnvs Mouse models: PMIDs: 11581292 (Liu et al 2001) and 12167715 (Geoffroy et al 2002) - both surprisingly report transgenic mice overexpressing Cbfa1 (runx2) developed severe osteopenia. PMID: 21807129 - Maeno et al 2011 - report that in mice early onset of Runx2 expression in the cranial mesenchyme induced mineralization on E13.0, when no mineralization was observed in wild-type mice, and resulted in craniosynostosis. PMID: 23300083 McGee-Lawrence et al 2013 - Runx2-deficient mice die at birth because of a lack of skeletal ossification. Axin2-deficient mice develop craniosynostosis because of high β-catenin activity. Runx2 represses transcription of Axin2 mRNA. They state that their data are consistent with the idea that Runx2 plays a central role in the etiologies of several different forms of craniosynostosis. Summary: Loss of function variants, partial duplication of the the RUNX2 gene and full duplication of the RUNX2 gene appear to result in different phenotypes. With regards to full duplication, there are 4 cases reported in separate publications of duplications fully covering the RUNX2 gene and patients with a craniosynostosis phenotype. The smallest duplication is 285 kb and includes RUNX2 and the 5' half of SUPT3H. However, there appears to be incomplete penetrance with some carriers having a less severe phenotype. Mefford et al state the CNV they report was not found in 2,493 control individuals. Mouse models give conflicting evidence. Mouse models of runx2 over-expression surprisingly found they developed severe osteopenia. However, early onset of Runx2 expression resulted in craniosynostosis, and Runx2 was found to repress Axin2, low levels of which can result in craniosynostosis. ; to: Loss of functional mutations associated with CLEIDOCRANIAL DYSPLASIA in Gene2Phenotype (confirmed). In OMIM loss of function mutations are associated with several phenotypes including Cleidocranial dysplasia. A heterozygous duplication of some exons of RUNX2 is associated with Metaphyseal dysplasia with maxillary hypoplasia with or without brachydactyly . However, craniosynostosis is not listed as a feature of this disorder (PMID: 23290074, 25311905, 29891876 CNV EVIDENCE: PMID: 20683987 - Mefford et al 2010 - Evaluated 186 individuals with single-suture craniosynostosis for submicroscopic deletions and duplications using whole-genome array CGH. They identified a heterozygous inverted 1.1 Mb duplication including the entire sequence of RUNX2, MIR586, and some of CLIC5 and SUPT3H in two affected cousins (1007 and 1019) with metopic synostosis and hypodontia. The duplication was inherited from the mother of one individual and it is presumed the father of the second individual (DNA not available, mother does not have the duplication). Both carrier parents have hypodontia by report, but neither is known to have had synostosis suggesting incomplete penetrance for that phenotype. The grandfather of 1007 and 1019 is described as having an abnormal head shape with a narrow forehead and several missing teeth; DNA was not available from this individual. They state that this CNV was not found in 2,493 control individuals [Itsara et al., 2009]. They compared RUNX2 expression levels in osteoblasts from these two individuals to expression levels in osteoblasts from unaffected individuals (n = 6) and individuals with synostosis but without duplication of RUNX2 (n = 22). The average expression of RUNX2 in the samples from the two individuals was higher than all affected and unaffected cell lines but it was not a statistically significant difference so should be interpreted with caution. PMID: 23307468 - Varvagiannis et al 2013 - a girl with a de novo trisomy 6p12.3-p21.1 who showed craniosynostosis, manifested by the premature fusion of the right coronal and sagittal sutures, and also facial anomalies, psychomotor delay, and recurrent respiratory tract infections. MLPA analysis suggested a duplication of the entire RUNX2 gene. MLPA analysis indicated that the duplication was not present in parental blood samples. SNP array analysis identified the duplication was 6.9 Mb in size and mapped to 6p12.3–p21.1 (chr6: 40,797,975–47,701,961 NCBI Build 35; May 2004), thus encompassing 163 ENSEMBL genes. The finding of abnormal fontanelles and/or abnormal sutures, either manifested as craniosynostosis or not, has been documented in 5 cases in patients with pure partial trisomy 6p. No analysis of RUNX2 expression was performed. PMID: 23348268 - Greives et al 2013 - present a case study of a boy with an atypical skull deformity with pan-craniosynostosis whose microarray analysis revealed 4 copies of a 1.24-Mb region from 6p12.3 to 6p21.1 containing the RUNX2 gene. He presented as an infant with airway obstruction from choanal atresia. He was diagnosed with a closed anterior fontanelle, ventricular septal defect, restricted range of motion in his elbows, mild conductive hearing loss, and developmental delays. They note that his multisutural craniosynostosis is the most extensive associated with RUNX2. No segregation analysis given. PMID:25899668 - Molin et al 2015 - report on a family with an affected mother and three affected children. The four patients carried a 285 kb duplication identified by array comparative genomic hybridization. The duplication includes the entire sequence of RUNX2 and the 5' half of SUPT3H. We confirmed the duplication by real-time quantitative PCR in the four patients. Two children presented with the association of metopic craniosynostosis and oligo/hypodontia previously described, confirming the phenotype caused by RUNX2 duplication. The mother and one child had isolated hypodontia without craniosynostosis. The clinical presentation shown by syndromic patients IV‐1 and IV‐3 appears radically different from MDMHB, but shares a few similarities with previously duplication patients, including as hypodontia and craniosynostosis. Isolated hypodontia observed in Patients III‐2 and IV‐2 highlights a wider clinical spectrum associated with RUNX2 duplication, in addition to isolated and syndromic craniosynostosis and MDMHB. Decipher - there are 6 patients with RUNX2 duplications over 1 kb in size. None mention craniosynostosis as a feature, although abnormality of the face/triangular face is listed for the patient with the 3.59 Mb duplication. https://decipher.sanger.ac.uk/gene/RUNX2#variants/RUNX2/patient-overlap/cnvs Mouse models: PMIDs: 11581292 (Liu et al 2001) and 12167715 (Geoffroy et al 2002) - both surprisingly report transgenic mice overexpressing Cbfa1 (runx2) developed severe osteopenia. PMID: 21807129 - Maeno et al 2011 - report that in mice early onset of Runx2 expression in the cranial mesenchyme induced mineralization on E13.0, when no mineralization was observed in wild-type mice, and resulted in craniosynostosis. PMID: 23300083 McGee-Lawrence et al 2013 - Runx2-deficient mice die at birth because of a lack of skeletal ossification. Axin2-deficient mice develop craniosynostosis because of high β-catenin activity. Runx2 represses transcription of Axin2 mRNA. They state that their data are consistent with the idea that Runx2 plays a central role in the etiologies of several different forms of craniosynostosis. Summary: Loss of function variants, partial duplication of the the RUNX2 gene and full duplication of the RUNX2 gene appear to result in different phenotypes. With regards to full duplication, there are 4 cases reported in separate publications of duplications fully covering the RUNX2 gene and patients with a craniosynostosis phenotype. The smallest duplication is 285 kb and includes RUNX2 and the 5' half of SUPT3H. However, there appears to be incomplete penetrance with some carriers having a less severe phenotype. Mefford et al state the CNV they report was not found in 2,493 control individuals. Mouse models give conflicting evidence. Mouse models of runx2 over-expression surprisingly found they developed severe osteopenia. However, early onset of Runx2 expression resulted in craniosynostosis, and Runx2 was found to repress Axin2, low levels of which can result in craniosynostosis. |
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| Rare syndromic craniosynostosis or isolated multisuture synostosis v1.123 | RUNX2 |
Eleanor Williams changed review comment from: Loss of functional mutations associated with CLEIDOCRANIAL DYSPLASIA in Gene2Phenotype (confirmed). In OMIM loss of function mutations are associated with several phenotypes including Cleidocranial dysplasia. A heterozygous duplication of some exons of RUNX2 is associated with Metaphyseal dysplasia with maxillary hypoplasia with or without brachydactyly . However, craniosynostosis is not listed as a feature of this disorder (PMID: 23290074, 25311905, 29891876 CNV EVIDENCE: PMID: 20683987 - Mefford et al 2010 - Evaluated 186 individuals with single-suture craniosynostosis for submicroscopic deletions and duplications using whole-genome array CGH. They identified a heterozygous inverted 1.1 Mb duplication including the entire sequence of RUNX2, MIR586, and some of CLIC5 and SUPT3H in two affected cousins (1007 and 1019) with metopic synostosis and hypodontia. The duplication was inherited from the mother of one individual and it is presumed the father of the second individual (DNA not available, mother does not have the duplication). Both carrier parents have hypodontia by report, but neither is known to have had synostosis suggesting incomplete penetrance for that phenotype. The grandfather of 1007 and 1019 is described as having an abnormal head shape with a narrow forehead and several missing teeth; DNA was not available from this individual. They state that this CNV was not found in 2,493 control individuals [Itsara et al., 2009]. They compared RUNX2 expression levels in osteoblasts from these two individuals to expression levels in osteoblasts from unaffected individuals (n = 6) and individuals with synostosis but without duplication of RUNX2 (n = 22). The average expression of RUNX2 in the samples from the two individuals was higher than all affected and unaffected cell lines but it was not a statistically significant difference in RUNX2 expression levels so should be interpreted with caution. PMID: 23307468 - Varvagiannis et al 2013 - a girl with a de novo trisomy 6p12.3-p21.1 who showed craniosynostosis, manifested by the premature fusion of the right coronal and sagittal sutures, and also facial anomalies, psychomotor delay, and recurrent respiratory tract infections. MLPA analysis suggested a duplication of the entire RUNX2 gene. MLPA analysis indicated that the duplication was not present in parental blood samples. SNP array analysis identified the duplication was 6.9 Mb in size and mapped to 6p12.3–p21.1 (chr6: 40,797,975–47,701,961 NCBI Build 35; May 2004), thus encompassing 163 ENSEMBL genes. The finding of abnormal fontanelles and/or abnormal sutures, either manifested as craniosynostosis or not, has been documented in 5 cases in patients with pure partial trisomy 6p. No analysis of RUNX2 expression was performed. PMID: 23348268 - Greives et al 2013 - present a case study of a boy with an atypical skull deformity with pan-craniosynostosis whose microarray analysis revealed 4 copies of a 1.24-Mb region from 6p12.3 to 6p21.1 containing the RUNX2 gene. He presented as an infant with airway obstruction from choanal atresia. He was diagnosed with a closed anterior fontanelle, ventricular septal defect, restricted range of motion in his elbows, mild conductive hearing loss, and developmental delays. They note that his multisutural craniosynostosis is the most extensive associated with RUNX2. No segregation analysis given. PMID:25899668 - Molin et al 2015 - report on a family with an affected mother and three affected children. The four patients carried a 285 kb duplication identified by array comparative genomic hybridization. The duplication includes the entire sequence of RUNX2 and the 5' half of SUPT3H. We confirmed the duplication by real-time quantitative PCR in the four patients. Two children presented with the association of metopic craniosynostosis and oligo/hypodontia previously described, confirming the phenotype caused by RUNX2 duplication. The mother and one child had isolated hypodontia without craniosynostosis. The clinical presentation shown by syndromic patients IV‐1 and IV‐3 appears radically different from MDMHB, but shares a few similarities with previously duplication patients, including as hypodontia and craniosynostosis. Isolated hypodontia observed in Patients III‐2 and IV‐2 highlights a wider clinical spectrum associated with RUNX2 duplication, in addition to isolated and syndromic craniosynostosis and MDMHB. Decipher - there are 6 patients with RUNX2 duplications over 1 kb in size. None mention craniosynostosis as a feature, although abnormality of the face/triangular face is listed for the patient with the 3.59 Mb duplication. https://decipher.sanger.ac.uk/gene/RUNX2#variants/RUNX2/patient-overlap/cnvs Mouse models: PMIDs: 11581292 (Liu et al 2001) and 12167715 (Geoffroy et al 2002) - both surprisingly report transgenic mice overexpressing Cbfa1 (runx2) developed severe osteopenia. PMID: 21807129 - Maeno et al 2011 - report that in mice early onset of Runx2 expression in the cranial mesenchyme induced mineralization on E13.0, when no mineralization was observed in wild-type mice, and resulted in craniosynostosis. PMID: 23300083 McGee-Lawrence et al 2013 - Runx2-deficient mice die at birth because of a lack of skeletal ossification. Axin2-deficient mice develop craniosynostosis because of high β-catenin activity. Runx2 represses transcription of Axin2 mRNA. They state that their data are consistent with the idea that Runx2 plays a central role in the etiologies of several different forms of craniosynostosis. Summary: Loss of function variants, partial duplication of the the RUNX2 gene and full duplication of the RUNX2 gene appear to result in different phenotypes. With regards to full duplication, there are 4 cases reported in separate publications of duplications fully covering the RUNX2 gene and patients with a craniosynostosis phenotype. The smallest duplication is 285 kb and includes RUNX2 and the 5' half of SUPT3H. However, there appears to be incomplete penetrance with some carriers having a less severe phenotype. Mefford et al state the CNV they report was not found in 2,493 control individuals. Mouse models give conflicting evidence. Mouse models of runx2 over-expression surprisingly found they developed severe osteopenia. However, early onset of Runx2 expression resulted in craniosynostosis, and Runx2 was found to repress Axin2, low levels of which can result in craniosynostosis. ; to: Loss of functional mutations associated with CLEIDOCRANIAL DYSPLASIA in Gene2Phenotype (confirmed). In OMIM loss of function mutations are associated with several phenotypes including Cleidocranial dysplasia. A heterozygous duplication of some exons of RUNX2 is associated with Metaphyseal dysplasia with maxillary hypoplasia with or without brachydactyly . However, craniosynostosis is not listed as a feature of this disorder (PMID: 23290074, 25311905, 29891876 CNV EVIDENCE: PMID: 20683987 - Mefford et al 2010 - Evaluated 186 individuals with single-suture craniosynostosis for submicroscopic deletions and duplications using whole-genome array CGH. They identified a heterozygous inverted 1.1 Mb duplication including the entire sequence of RUNX2, MIR586, and some of CLIC5 and SUPT3H in two affected cousins (1007 and 1019) with metopic synostosis and hypodontia. The duplication was inherited from the mother of one individual and it is presumed the father of the second individual (DNA not available, mother does not have the duplication). Both carrier parents have hypodontia by report, but neither is known to have had synostosis suggesting incomplete penetrance for that phenotype. The grandfather of 1007 and 1019 is described as having an abnormal head shape with a narrow forehead and several missing teeth; DNA was not available from this individual. They state that this CNV was not found in 2,493 control individuals [Itsara et al., 2009]. They compared RUNX2 expression levels in osteoblasts from these two individuals to expression levels in osteoblasts from unaffected individuals (n = 6) and individuals with synostosis but without duplication of RUNX2 (n = 22). The average expression of RUNX2 in the samples from the two individuals was higher than all affected and unaffected cell lines but it was not a statistically significant difference in RUNX2 expression levels so should be interpreted with caution. PMID: 23307468 - Varvagiannis et al 2013 - a girl with a de novo trisomy 6p12.3-p21.1 who showed craniosynostosis, manifested by the premature fusion of the right coronal and sagittal sutures, and also facial anomalies, psychomotor delay, and recurrent respiratory tract infections. MLPA analysis suggested a duplication of the entire RUNX2 gene. MLPA analysis indicated that the duplication was not present in parental blood samples. SNP array analysis identified the duplication was 6.9 Mb in size and mapped to 6p12.3–p21.1 (chr6: 40,797,975–47,701,961 NCBI Build 35; May 2004), thus encompassing 163 ENSEMBL genes. The finding of abnormal fontanelles and/or abnormal sutures, either manifested as craniosynostosis or not, has been documented in 5 cases in patients with pure partial trisomy 6p. No analysis of RUNX2 expression was performed. PMID: 23348268 - Greives et al 2013 - present a case study of a boy with an atypical skull deformity with pan-craniosynostosis whose microarray analysis revealed 4 copies of a 1.24-Mb region from 6p12.3 to 6p21.1 containing the RUNX2 gene. He presented as an infant with airway obstruction from choanal atresia. He was diagnosed with a closed anterior fontanelle, ventricular septal defect, restricted range of motion in his elbows, mild conductive hearing loss, and developmental delays. They note that his multisutural craniosynostosis is the most extensive associated with RUNX2. No segregation analysis given. PMID:25899668 - Molin et al 2015 - report on a family with an affected mother and three affected children. The four patients carried a 285 kb duplication identified by array comparative genomic hybridization. The duplication includes the entire sequence of RUNX2 and the 5' half of SUPT3H. We confirmed the duplication by real-time quantitative PCR in the four patients. Two children presented with the association of metopic craniosynostosis and oligo/hypodontia previously described, confirming the phenotype caused by RUNX2 duplication. The mother and one child had isolated hypodontia without craniosynostosis. The clinical presentation shown by syndromic patients IV‐1 and IV‐3 appears radically different from MDMHB, but shares a few similarities with previously duplication patients, including as hypodontia and craniosynostosis. Isolated hypodontia observed in Patients III‐2 and IV‐2 highlights a wider clinical spectrum associated with RUNX2 duplication, in addition to isolated and syndromic craniosynostosis and MDMHB. Decipher - there are 6 patients with RUNX2 duplications over 1 kb in size. None mention craniosynostosis as a feature, although abnormality of the face/triangular face is listed for the patient with the 3.59 Mb duplication. https://decipher.sanger.ac.uk/gene/RUNX2#variants/RUNX2/patient-overlap/cnvs Mouse models: PMIDs: 11581292 (Liu et al 2001) and 12167715 (Geoffroy et al 2002) - both surprisingly report transgenic mice overexpressing Cbfa1 (runx2) developed severe osteopenia. PMID: 21807129 - Maeno et al 2011 - report that in mice early onset of Runx2 expression in the cranial mesenchyme induced mineralization on E13.0, when no mineralization was observed in wild-type mice, and resulted in craniosynostosis. PMID: 23300083 McGee-Lawrence et al 2013 - Runx2-deficient mice die at birth because of a lack of skeletal ossification. Axin2-deficient mice develop craniosynostosis because of high β-catenin activity. Runx2 represses transcription of Axin2 mRNA. They state that their data are consistent with the idea that Runx2 plays a central role in the etiologies of several different forms of craniosynostosis. Summary: Loss of function variants, partial duplication of the the RUNX2 gene and full duplication of the RUNX2 gene appear to result in different phenotypes. With regards to full duplication, there are 4 cases reported in separate publications of duplications fully covering the RUNX2 gene and patients with a craniosynostosis phenotype. The smallest duplication is 285 kb and includes RUNX2 and the 5' half of SUPT3H. However, there appears to be incomplete penetrance with some carriers having a less severe phenotype. Mefford et al state the CNV they report was not found in 2,493 control individuals. Mouse models give conflicting evidence. Mouse models of runx2 over-expression surprisingly found they developed severe osteopenia. However, early onset of Runx2 expression resulted in craniosynostosis, and Runx2 was found to repress Axin2, low levels of which can result in craniosynostosis. |
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| Rare syndromic craniosynostosis or isolated multisuture synostosis v1.123 | RUNX2 |
Eleanor Williams changed review comment from: Loss of functional mutations associated with CLEIDOCRANIAL DYSPLASIA in Gene2Phenotype (confirmed). In OMIM loss of function mutations are associated with several phenotypes including Cleidocranial dysplasia. A heterozygous duplication of some exons of RUNX2 is associated with Metaphyseal dysplasia with maxillary hypoplasia with or without brachydactyly . However, craniosynostosis is not listed as a feature of this disorder (PMID: 23290074, 25311905, 29891876 CNV EVIDENCE: PMID: 20683987 - Mefford et al 2010 - Evaluated 186 individuals with single-suture craniosynostosis for submicroscopic deletions and duplications using whole-genome array CGH. They identified a heterozygous inverted 1.1 Mb duplication including the entire sequence of RUNX2, MIR586, and some of CLIC5 and SUPT3H in two affected cousins (1007 and 1019) with metopic synostosis and hypodontia. The duplication was inherited from the mother of one individual and it is presumed the father of the second individual (DNA not available, mother does not have the duplication). Both carrier parents have hypodontia by report, but neither is known to have had synostosis suggesting incomplete penetrance for that phenotype. The grandfather of 1007 and 1019 is described as having an abnormal head shape with a narrow forehead and several missing teeth; DNA was not available from this individual. They compared RUNX2 expression levels in osteoblasts from these two individuals to expression levels in osteoblasts from unaffected individuals (n = 6) and individuals with synostosis but without duplication of RUNX2 (n = 22). The average expression of RUNX2 in the samples from the two individuals was higher than all affected and unaffected cell lines but it was not a statistically significant difference in RUNX2 expression levels so should be interpreted with caution. PMID: 23307468 - Varvagiannis et al 2013 - a girl with a de novo trisomy 6p12.3-p21.1 who showed craniosynostosis, manifested by the premature fusion of the right coronal and sagittal sutures, and also facial anomalies, psychomotor delay, and recurrent respiratory tract infections. MLPA analysis suggested a duplication of the entire RUNX2 gene. MLPA analysis indicated that the duplication was not present in parental blood samples. SNP array analysis identified the duplication was 6.9 Mb in size and mapped to 6p12.3–p21.1 (chr6: 40,797,975–47,701,961 NCBI Build 35; May 2004), thus encompassing 163 ENSEMBL genes. The finding of abnormal fontanelles and/or abnormal sutures, either manifested as craniosynostosis or not, has been documented in 5 cases in patients with pure partial trisomy 6p. No analysis of RUNX2 expression was performed. PMID: 23348268 - Greives et al 2013 - present a case study of a boy with an atypical skull deformity with pan-craniosynostosis whose microarray analysis revealed 4 copies of a 1.24-Mb region from 6p12.3 to 6p21.1 containing the RUNX2 gene. He presented as an infant with airway obstruction from choanal atresia. He was diagnosed with a closed anterior fontanelle, ventricular septal defect, restricted range of motion in his elbows, mild conductive hearing loss, and developmental delays. No segregation analysis given. PMID: McGee-Lawrence et al 2013 - Axin2-deficient mice develop craniosynostosis because of high β-catenin activity. Runx2 represses transcription of Axin2 mRNA. To determine whether Runx2 contributes to the etiology of Axin2 deficiency-induced craniosynostosis, they generated Axin2(-/-):Runx2(+/-) mice. These double mutant mice had longer skulls than Axin2(-/-) mice, indicating that Runx2 haploinsufficiency rescued the craniosynostosis phenotype of Axin2(-/-) mice PMID:25899668 - Molin et al 2015 - report on a family with an affected mother and three affected children. The four patients carried a 285 kb duplication identified by array comparative genomic hybridization. The duplication includes the entire sequence of RUNX2 and the 5' half of SUPT3H. We confirmed the duplication by real-time quantitative PCR in the four patients. Two children presented with the association of metopic craniosynostosis and oligo/hypodontia previously described, confirming the phenotype caused by RUNX2 duplication. The mother and one child had isolated hypodontia without craniosynostosis. The clinical presentation shown by syndromic Patients IV‐1 and IV‐3 appears radically different from MDMHB, but shares a few similarities with previously duplication patients, including as hypodontia and craniosynostosis. Isolated hypodontia observed in Patients III‐2 and IV‐2 highlights a wider clinical spectrum associated with RUNX2 duplication, in addition to isolated and syndromic craniosynostosis and MDMHB. Decipher - there are 6 patients with RUNX2 duplications over 1 kb in size. None mention craniosynostosis as a feature, although abnormality of the face/triangular face is listed for the patient with the 3.59 Mb duplication. https://decipher.sanger.ac.uk/gene/RUNX2#variants/RUNX2/patient-overlap/cnvs Summary: Loss of function variants, partial duplication of the the RUNX2 gene and full duplication of the RUNX2 gene appear to result in different phenotypes. With regards to full duplication, there are 4 cases reported in separate publications of duplications fully covering the RUNX2 gene and patients with a craniosynostosis phenotype. The smallest duplication is 285 kb and includes RUNX2 and the 5' half of SUPT3H. However, there appears to be incomplete penetrance with some carriers having a less severe phenotype. Frequency of CNVs covering this region in the general population have not been reported.; to: Loss of functional mutations associated with CLEIDOCRANIAL DYSPLASIA in Gene2Phenotype (confirmed). In OMIM loss of function mutations are associated with several phenotypes including Cleidocranial dysplasia. A heterozygous duplication of some exons of RUNX2 is associated with Metaphyseal dysplasia with maxillary hypoplasia with or without brachydactyly . However, craniosynostosis is not listed as a feature of this disorder (PMID: 23290074, 25311905, 29891876 CNV EVIDENCE: PMID: 20683987 - Mefford et al 2010 - Evaluated 186 individuals with single-suture craniosynostosis for submicroscopic deletions and duplications using whole-genome array CGH. They identified a heterozygous inverted 1.1 Mb duplication including the entire sequence of RUNX2, MIR586, and some of CLIC5 and SUPT3H in two affected cousins (1007 and 1019) with metopic synostosis and hypodontia. The duplication was inherited from the mother of one individual and it is presumed the father of the second individual (DNA not available, mother does not have the duplication). Both carrier parents have hypodontia by report, but neither is known to have had synostosis suggesting incomplete penetrance for that phenotype. The grandfather of 1007 and 1019 is described as having an abnormal head shape with a narrow forehead and several missing teeth; DNA was not available from this individual. They state that this CNV was not found in 2,493 control individuals [Itsara et al., 2009]. They compared RUNX2 expression levels in osteoblasts from these two individuals to expression levels in osteoblasts from unaffected individuals (n = 6) and individuals with synostosis but without duplication of RUNX2 (n = 22). The average expression of RUNX2 in the samples from the two individuals was higher than all affected and unaffected cell lines but it was not a statistically significant difference in RUNX2 expression levels so should be interpreted with caution. PMID: 23307468 - Varvagiannis et al 2013 - a girl with a de novo trisomy 6p12.3-p21.1 who showed craniosynostosis, manifested by the premature fusion of the right coronal and sagittal sutures, and also facial anomalies, psychomotor delay, and recurrent respiratory tract infections. MLPA analysis suggested a duplication of the entire RUNX2 gene. MLPA analysis indicated that the duplication was not present in parental blood samples. SNP array analysis identified the duplication was 6.9 Mb in size and mapped to 6p12.3–p21.1 (chr6: 40,797,975–47,701,961 NCBI Build 35; May 2004), thus encompassing 163 ENSEMBL genes. The finding of abnormal fontanelles and/or abnormal sutures, either manifested as craniosynostosis or not, has been documented in 5 cases in patients with pure partial trisomy 6p. No analysis of RUNX2 expression was performed. PMID: 23348268 - Greives et al 2013 - present a case study of a boy with an atypical skull deformity with pan-craniosynostosis whose microarray analysis revealed 4 copies of a 1.24-Mb region from 6p12.3 to 6p21.1 containing the RUNX2 gene. He presented as an infant with airway obstruction from choanal atresia. He was diagnosed with a closed anterior fontanelle, ventricular septal defect, restricted range of motion in his elbows, mild conductive hearing loss, and developmental delays. They note that his multisutural craniosynostosis is the most extensive associated with RUNX2. No segregation analysis given. PMID:25899668 - Molin et al 2015 - report on a family with an affected mother and three affected children. The four patients carried a 285 kb duplication identified by array comparative genomic hybridization. The duplication includes the entire sequence of RUNX2 and the 5' half of SUPT3H. We confirmed the duplication by real-time quantitative PCR in the four patients. Two children presented with the association of metopic craniosynostosis and oligo/hypodontia previously described, confirming the phenotype caused by RUNX2 duplication. The mother and one child had isolated hypodontia without craniosynostosis. The clinical presentation shown by syndromic patients IV‐1 and IV‐3 appears radically different from MDMHB, but shares a few similarities with previously duplication patients, including as hypodontia and craniosynostosis. Isolated hypodontia observed in Patients III‐2 and IV‐2 highlights a wider clinical spectrum associated with RUNX2 duplication, in addition to isolated and syndromic craniosynostosis and MDMHB. Decipher - there are 6 patients with RUNX2 duplications over 1 kb in size. None mention craniosynostosis as a feature, although abnormality of the face/triangular face is listed for the patient with the 3.59 Mb duplication. https://decipher.sanger.ac.uk/gene/RUNX2#variants/RUNX2/patient-overlap/cnvs Mouse models: PMIDs: 11581292 (Liu et al 2001) and 12167715 (Geoffroy et al 2002) - both surprisingly report transgenic mice overexpressing Cbfa1 (runx2) developed severe osteopenia. PMID: 21807129 - Maeno et al 2011 - report that in mice early onset of Runx2 expression in the cranial mesenchyme induced mineralization on E13.0, when no mineralization was observed in wild-type mice, and resulted in craniosynostosis. PMID: 23300083 McGee-Lawrence et al 2013 - Runx2-deficient mice die at birth because of a lack of skeletal ossification. Axin2-deficient mice develop craniosynostosis because of high β-catenin activity. Runx2 represses transcription of Axin2 mRNA. They state that their data are consistent with the idea that Runx2 plays a central role in the etiologies of several different forms of craniosynostosis. Summary: Loss of function variants, partial duplication of the the RUNX2 gene and full duplication of the RUNX2 gene appear to result in different phenotypes. With regards to full duplication, there are 4 cases reported in separate publications of duplications fully covering the RUNX2 gene and patients with a craniosynostosis phenotype. The smallest duplication is 285 kb and includes RUNX2 and the 5' half of SUPT3H. However, there appears to be incomplete penetrance with some carriers having a less severe phenotype. Mefford et al state the CNV they report was not found in 2,493 control individuals. Mouse models give conflicting evidence. Mouse models of runx2 over-expression surprisingly found they developed severe osteopenia. However, early onset of Runx2 expression resulted in craniosynostosis, and Runx2 was found to repress Axin2, low levels of which can result in craniosynostosis. |
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| Rare syndromic craniosynostosis or isolated multisuture synostosis v1.123 | RUNX2 |
Eleanor Williams commented on gene: RUNX2: Loss of functional mutations associated with CLEIDOCRANIAL DYSPLASIA in Gene2Phenotype (confirmed). In OMIM loss of function mutations are associated with several phenotypes including Cleidocranial dysplasia. A heterozygous duplication of some exons of RUNX2 is associated with Metaphyseal dysplasia with maxillary hypoplasia with or without brachydactyly . However, craniosynostosis is not listed as a feature of this disorder (PMID: 23290074, 25311905, 29891876 CNV EVIDENCE: PMID: 20683987 - Mefford et al 2010 - Evaluated 186 individuals with single-suture craniosynostosis for submicroscopic deletions and duplications using whole-genome array CGH. They identified a heterozygous inverted 1.1 Mb duplication including the entire sequence of RUNX2, MIR586, and some of CLIC5 and SUPT3H in two affected cousins (1007 and 1019) with metopic synostosis and hypodontia. The duplication was inherited from the mother of one individual and it is presumed the father of the second individual (DNA not available, mother does not have the duplication). Both carrier parents have hypodontia by report, but neither is known to have had synostosis suggesting incomplete penetrance for that phenotype. The grandfather of 1007 and 1019 is described as having an abnormal head shape with a narrow forehead and several missing teeth; DNA was not available from this individual. They compared RUNX2 expression levels in osteoblasts from these two individuals to expression levels in osteoblasts from unaffected individuals (n = 6) and individuals with synostosis but without duplication of RUNX2 (n = 22). The average expression of RUNX2 in the samples from the two individuals was higher than all affected and unaffected cell lines but it was not a statistically significant difference in RUNX2 expression levels so should be interpreted with caution. PMID: 23307468 - Varvagiannis et al 2013 - a girl with a de novo trisomy 6p12.3-p21.1 who showed craniosynostosis, manifested by the premature fusion of the right coronal and sagittal sutures, and also facial anomalies, psychomotor delay, and recurrent respiratory tract infections. MLPA analysis suggested a duplication of the entire RUNX2 gene. MLPA analysis indicated that the duplication was not present in parental blood samples. SNP array analysis identified the duplication was 6.9 Mb in size and mapped to 6p12.3–p21.1 (chr6: 40,797,975–47,701,961 NCBI Build 35; May 2004), thus encompassing 163 ENSEMBL genes. The finding of abnormal fontanelles and/or abnormal sutures, either manifested as craniosynostosis or not, has been documented in 5 cases in patients with pure partial trisomy 6p. No analysis of RUNX2 expression was performed. PMID: 23348268 - Greives et al 2013 - present a case study of a boy with an atypical skull deformity with pan-craniosynostosis whose microarray analysis revealed 4 copies of a 1.24-Mb region from 6p12.3 to 6p21.1 containing the RUNX2 gene. He presented as an infant with airway obstruction from choanal atresia. He was diagnosed with a closed anterior fontanelle, ventricular septal defect, restricted range of motion in his elbows, mild conductive hearing loss, and developmental delays. No segregation analysis given. PMID: McGee-Lawrence et al 2013 - Axin2-deficient mice develop craniosynostosis because of high β-catenin activity. Runx2 represses transcription of Axin2 mRNA. To determine whether Runx2 contributes to the etiology of Axin2 deficiency-induced craniosynostosis, they generated Axin2(-/-):Runx2(+/-) mice. These double mutant mice had longer skulls than Axin2(-/-) mice, indicating that Runx2 haploinsufficiency rescued the craniosynostosis phenotype of Axin2(-/-) mice PMID:25899668 - Molin et al 2015 - report on a family with an affected mother and three affected children. The four patients carried a 285 kb duplication identified by array comparative genomic hybridization. The duplication includes the entire sequence of RUNX2 and the 5' half of SUPT3H. We confirmed the duplication by real-time quantitative PCR in the four patients. Two children presented with the association of metopic craniosynostosis and oligo/hypodontia previously described, confirming the phenotype caused by RUNX2 duplication. The mother and one child had isolated hypodontia without craniosynostosis. The clinical presentation shown by syndromic Patients IV‐1 and IV‐3 appears radically different from MDMHB, but shares a few similarities with previously duplication patients, including as hypodontia and craniosynostosis. Isolated hypodontia observed in Patients III‐2 and IV‐2 highlights a wider clinical spectrum associated with RUNX2 duplication, in addition to isolated and syndromic craniosynostosis and MDMHB. Decipher - there are 6 patients with RUNX2 duplications over 1 kb in size. None mention craniosynostosis as a feature, although abnormality of the face/triangular face is listed for the patient with the 3.59 Mb duplication. https://decipher.sanger.ac.uk/gene/RUNX2#variants/RUNX2/patient-overlap/cnvs Summary: Loss of function variants, partial duplication of the the RUNX2 gene and full duplication of the RUNX2 gene appear to result in different phenotypes. With regards to full duplication, there are 4 cases reported in separate publications of duplications fully covering the RUNX2 gene and patients with a craniosynostosis phenotype. The smallest duplication is 285 kb and includes RUNX2 and the 5' half of SUPT3H. However, there appears to be incomplete penetrance with some carriers having a less severe phenotype. Frequency of CNVs covering this region in the general population have not been reported. |
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| Rare syndromic craniosynostosis or isolated multisuture synostosis v1.80 | SEC24D |
Eleanor Williams commented on gene: SEC24D: Associated with Cole-Carpenter syndrome 2 #616294 in OMIM and probable association with SYNDROMIC OSTEOGENESIS IMPERFECTA in Gene2Phenotype. PMID: 25683121 - Garbes et al 2015 - 7 year old boy with a syndromic form of OI that clinically classified as Cole-Carpenter syndrome, based on the history of multiple pre- and postnatal fractures and the presence of distinct craniofacial malformations. Compound heterozygosity for a SEC24D nonsense mutation (c.613C>T [p.Gln205*]) and for a missense mutation (c.3044C>T [p.Ser1015Phe]). The medaka mutant vbi, caused by a sec24d nonsense mutation, is characterized by short body length, OI, and craniofacial malformations—including an impaired ossification of the neurocranium (note, Sec24d-null mice are embryonic lethal prior to skeletal development). Fetuses with suspected to be affected by a severe type of OI from second family are likely compound heterozygous for SEC24D mutations c.3044C>T (p.Ser1015Phe) and c.2933A>C (p.Gln978Pro). PMID: 30462379 - Takeyari et al 2018 - Japanese boy with syndromic OI. His features include a short trunk, and craniofacial abnormalities including ocular proptosis, marked frontal bossing, midface hypoplasia, and micrognathia. He was compound heterogzyous for 2 variants in the SEC24D gene (NM_014822:c.1450C>T:p.Arg484* and c.938G>A:p.Arg313His) . PMID: 27942778 - Zhang et al 2017 - 2 unrelated families with individuals with osteogenesis imperfecta. Compound heterozygous variants in SEC24D were found in both. Family 1 - c.2723G>A (p. Cys908Tyr) and c.2842T>C (p. Ser948Pro). Family 2 - c.938G>A (p. Arg313His) and c.875C>T (p. Pro292Leu). Proband from family 1 showed skull deformities associated with a broad frontoapical ossification defect, a widened sagittal suture, and Wormian bones. In the proband from family 2 the anterior fontanel was not closed, and he did not have obvious facial dysmorphism. Consulting with the Genomics England Team with respect to the relevance to craniosynostosis of these phenotypes. |
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| Rare syndromic craniosynostosis or isolated multisuture synostosis v1.72 | IDUA | Eleanor Williams Added phenotypes Mucopolysaccharidosis Ih/s (Hurler syndrome) 607014; 607016 for gene: IDUA | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Rare syndromic craniosynostosis or isolated multisuture synostosis v1.47 | IDUA | Tracy Lester reviewed gene: IDUA: Rating: GREEN; Mode of pathogenicity: ; Publications: 23917744; Phenotypes: Mucopolysaccharidosis Ih/s (Hurler syndrome) 607014, 607016; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Rare syndromic craniosynostosis or isolated multisuture synostosis v1.46 | IDUA | Eleanor Williams reviewed gene: IDUA: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Rare syndromic craniosynostosis or isolated multisuture synostosis v1.45 | IDUA |
Eleanor Williams Source NHS GMS was added to IDUA. Rating Changed from Green List (high evidence) to Green List (high evidence) |
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