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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 v4.157 | SH3BP4 |
Achchuthan Shanmugasundram gene: SH3BP4 was added gene: SH3BP4 was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature Mode of inheritance for gene: SH3BP4 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SH3BP4 were set to 35080095; 36980886 Phenotypes for gene: SH3BP4 were set to craniosynostosis, MONDO:0015469 Review for gene: SH3BP4 was set to RED Added comment: A patient was described with a recessive variant in SH3BP4 (c.128C>A; p.Pro43His) in the Norwegian craniosynostosis cohort. The variant has a CADD score of 33 and a gnomAD allele frequency of 9.6 x 10-5 (no homozygotes are reported in gnomAD). The patient presented with a Chiari I malformation, exophthalmos, eating difficulties as an infant, microcephaly, recurrent infections, dysmorphic features, Kabuki-like syndrome, and pan-synostosis. This patient also harbours two variants in KMT2D: c.11599C>A; p.Gln3867Lys (CADD = 22) and c.7182C>A; p.Ser2394Arg (CADD = 20); gnomAD frequency 1.2 x 10-5 and absent, respectively (PMID:35080095). Sources: Literature |
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| Rare syndromic craniosynostosis or isolated multisuture synostosis v4.154 | PUF60 |
Achchuthan Shanmugasundram gene: PUF60 was added gene: PUF60 was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature Mode of inheritance for gene: PUF60 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: PUF60 were set to 36367278; 36980886 Phenotypes for gene: PUF60 were set to craniosynostosis, MONDO:0015469 Review for gene: PUF60 was set to RED Added comment: A patient presenting with Verheij syndrome, characterised by craniofacial dysmorphism, multiple congenital anomalies and variable neurodevelopmental delay, was identified with a heterozygous variant in the splicing factor PUF60 (c.436C>T; p.Arg146Cys). They displayed fusion of the coronal and sagittal suture (PMID:36367278). Sources: Literature |
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| Rare syndromic craniosynostosis or isolated multisuture synostosis v4.141 | MED13L |
Achchuthan Shanmugasundram gene: MED13L was added gene: MED13L was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature Mode of inheritance for gene: MED13L was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: MED13L were set to 28371282; 36980886 Phenotypes for gene: MED13L were set to Impaired intellectual development and distinctive facial features with or without cardiac defects, OMIM:616789; craniosynostosis, MONDO:0015469 Review for gene: MED13L was set to RED Added comment: Two siblings exhibited an intragenic deletion of exons 3-14 resulting in MED13L haploinsufficiency syndrome (intellectual disability, developmental delay, heart defects and dysmorphic features). The deletion was inherited from their mother who showed low frequency mosaicism. The older sibling also presented with craniosynostosis (PMID:28371282). 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 v4.118 | DDX3X |
Achchuthan Shanmugasundram changed review comment from: A novel de novo missense variant was identified in the DDX3X gene (c.625C>G) by whole exome sequencing in a child with craniofacial dysmorphisms: brachycephaly and a flattened triangular-asymmetrical face characterized by micrognathia, mild hypertelorism, wide and prominent nose, short philtrum, thin lips and macroglossia (PMID:33789733). Exome-sequencing identified three distinct de novo heterozygous variants in DDX3X: c.1511G>A; p.(Gly504Glu) (Patient 1), c.1436_1439delinsTCTC; p.(Asp479Arg480delinsValSer) (Patient 2), and c.641_643delTCA; p.(Ile214del) (Patient 3). The patients showed severe intellectual disability/developmental disorders, microcephaly, and dysmorphic features. Plagiocephaly was observed in Patient 1 and Patient 2 was diagnosed with sensorineural hearing loss and trigonocephaly. However, craniosynostosis was only radiologically confirmed in Patient 2 (PMID:30936465). A de novo variant in DDX3X was identified in an additional patient with trigonocephaly, delay in speech acquisition and motor developmental delay: c.1616-2A>G; p.(?) (PMID:32530565). Sources: Literature; to: A novel de novo missense variant was identified in the DDX3X gene (c.625C>G) by whole exome sequencing in a child with craniofacial dysmorphisms: brachycephaly and a flattened triangular-asymmetrical face characterized by micrognathia, mild hypertelorism, wide and prominent nose, short philtrum, thin lips and macroglossia (PMID:33789733). Exome-sequencing identified three distinct de novo heterozygous variants in DDX3X: c.1511G>A; p.(Gly504Glu) (Patient 1), c.1436_1439delinsTCTC; p.(Asp479Arg480delinsValSer) (Patient 2), and c.641_643delTCA; p.(Ile214del) (Patient 3). The patients showed severe intellectual disability/developmental disorders, microcephaly, and dysmorphic features. Plagiocephaly was observed in Patient 1 and Patient 2 was diagnosed with sensorineural hearing loss and trigonocephaly. However, craniosynostosis was only radiologically confirmed in Patient 2 (PMID:30936465). A de novo variant in DDX3X was identified in an additional patient with trigonocephaly, delay in speech acquisition and motor developmental delay: c.1616-2A>G (PMID:32530565). Sources: Literature |
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| Rare syndromic craniosynostosis or isolated multisuture synostosis v4.116 | DDX3X |
Achchuthan Shanmugasundram gene: DDX3X was added gene: DDX3X was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature Mode of inheritance for gene: DDX3X 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: DDX3X were set to 30936465; 32530565; 33789733; 36980886 Phenotypes for gene: DDX3X were set to craniosynostosis, MONDO:0015469 Review for gene: DDX3X was set to AMBER Added comment: A novel de novo missense variant was identified in the DDX3X gene (c.625C>G) by whole exome sequencing in a child with craniofacial dysmorphisms: brachycephaly and a flattened triangular-asymmetrical face characterized by micrognathia, mild hypertelorism, wide and prominent nose, short philtrum, thin lips and macroglossia (PMID:33789733). Exome-sequencing identified three distinct de novo heterozygous variants in DDX3X: c.1511G>A; p.(Gly504Glu) (Patient 1), c.1436_1439delinsTCTC; p.(Asp479Arg480delinsValSer) (Patient 2), and c.641_643delTCA; p.(Ile214del) (Patient 3). The patients showed severe intellectual disability/developmental disorders, microcephaly, and dysmorphic features. Plagiocephaly was observed in Patient 1 and Patient 2 was diagnosed with sensorineural hearing loss and trigonocephaly. However, craniosynostosis was only radiologically confirmed in Patient 2 (PMID:30936465). A de novo variant in DDX3X was identified in an additional patient with trigonocephaly, delay in speech acquisition and motor developmental delay: c.1616-2A>G; p.(?) (PMID:32530565). Sources: Literature |
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| Rare syndromic craniosynostosis or isolated multisuture synostosis v4.71 | IFT140 |
Achchuthan Shanmugasundram edited their review of gene: IFT140: Added comment: PMID:22503633 - two cases from a single family with craniosynostosis, scaphocephaly and facial dysmorphy. PMID:27874174 - single case with trigonocephaly and additional ciliopathy-related clinical features. PMID:28288023 - single case with evolving craniofacial phenotype, striking brachydactyly and sensenbrenner syndromeand it was not clear if craniosynostosis was radiologically confirmed (as reviewed by Rebecca Tooze). PMID:32007091 - single case with craniosynostosis and dolichocephaly.; Changed rating: GREEN; Changed publications to: 22503633, 27874174, 28288023, 32007091 |
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| Rare syndromic craniosynostosis or isolated multisuture synostosis v4.59 | DPH1 | Achchuthan Shanmugasundram Phenotypes for gene: DPH1 were changed from to Developmental delay with short stature, dysmorphic facial features, and sparse hair, OMIM:616901 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Rare syndromic craniosynostosis or isolated multisuture synostosis v4.56 | DPH1 | Achchuthan Shanmugasundram reviewed gene: DPH1: Rating: AMBER; Mode of pathogenicity: None; Publications: 26220823, 30877278; Phenotypes: Developmental delay with short stature, dysmorphic facial features, and sparse hair, OMIM:616901; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Rare syndromic craniosynostosis or isolated multisuture synostosis v4.25 | FBXO11 | Achchuthan Shanmugasundram Phenotypes for gene: FBXO11 were changed from to Intellectual developmental disorder with dysmorphic facies and behavioral abnormalities, OMIM:618089 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Rare syndromic craniosynostosis or isolated multisuture synostosis v4.23 | FBXO11 | Achchuthan Shanmugasundram reviewed gene: FBXO11: Rating: GREEN; Mode of pathogenicity: None; Publications: 30057029, 34429528; Phenotypes: Intellectual developmental disorder with dysmorphic facies and behavioral abnormalities, OMIM:618089; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Rare syndromic craniosynostosis or isolated multisuture synostosis v4.17 | CDK13 | Achchuthan Shanmugasundram Phenotypes for gene: CDK13 were changed from to Congenital heart defects, dysmorphic facial features, and intellectual developmental disorder, OMIM:617360; craniosynostosis, MONDO:0015469 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Rare syndromic craniosynostosis or isolated multisuture synostosis v4.16 | CDK13 | Achchuthan Shanmugasundram reviewed gene: CDK13: Rating: GREEN; Mode of pathogenicity: None; Publications: 28807008, 33288889, 34429528; Phenotypes: Congenital heart defects, dysmorphic facial features, and intellectual developmental disorder, OMIM:617360, craniosynostosis, MONDO:0015469; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Rare syndromic craniosynostosis or isolated multisuture synostosis v4.16 | BCL11B | Achchuthan Shanmugasundram Phenotypes for gene: BCL11B were changed from Craniosynostosis and global developmental delay to Intellectual developmental disorder with dysmorphic facies, speech delay, and T-cell abnormalities, OMIM:618092; Craniosynostosis, MONDO:0015469 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Rare syndromic craniosynostosis or isolated multisuture synostosis v4.13 | BCL11B | Achchuthan Shanmugasundram reviewed gene: BCL11B: Rating: GREEN; Mode of pathogenicity: None; Publications: 31067316, 34900871, 36275064, 36470856, 36512050, 36980886; Phenotypes: Intellectual developmental disorder with dysmorphic facies, speech delay, and T-cell abnormalities, OMIM:618092, Craniosynostosis, MONDO:0015469; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Rare syndromic craniosynostosis or isolated multisuture synostosis v3.4 | DPH1 |
Rebecca Tooze gene: DPH1 was added gene: DPH1 was added to Craniosynostosis. Sources: Literature Mode of inheritance for gene: DPH1 was set to BIALLELIC, autosomal or pseudoautosomal Review for gene: DPH1 was set to AMBER Added comment: • A patient was described with short stature, sagittal craniosynostosis and dysmorphic features including scaphocephaly, sparse hair, multiple dental anomalies, epicanthal folds and hypoplastic toenails to harbour a homozygous missense variant in DPH1: c.17T>A; p.(Met6Lys) (born to consanguineous parents). • A family with two affected siblings were described and one was confirmed to have metopic synostosis. They harboured a recessive c.335A>G; p.(Tyr112Cys) variant (Urreizti et al., 2020). 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 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 v2.23 | 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 v2.22 | B3GAT3 | Eleanor Williams Phenotypes for gene: B3GAT3 were changed from Craniosynostosis and bone fragility to Craniosynostosis and bone fragility; Multiple joint dislocations, short stature, craniofacial dysmorphism, with or without congenital heart defects OMIM:245600; Larsen-like syndrome, B3GAT3 type MONDO:0009511 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Rare syndromic craniosynostosis or isolated multisuture synostosis v2.16 | PTCH1 |
Andrew Wilkie gene: PTCH1 was added gene: PTCH1 was added to Craniosynostosis. Sources: Expert Review Mode of inheritance for gene: PTCH1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: PTCH1 were set to 31578813 Phenotypes for gene: PTCH1 were set to metopic craniosynostosis Penetrance for gene: PTCH1 were set to Incomplete Review for gene: PTCH1 was set to GREEN Added comment: Several lines of evidence support that heterozygous loss-of-function mutations in PTCH1, which cause the classical genetic disorder Gorlin (basal cell naevus) syndrome, rarely also cause metopic synostosis. It is especially important to recognise this association, given the implications for patient management from a diagnosis of Gorlin syndrome. (1) Beltrami et al (see PMID 31578813) described a frameshift variant in PTCH1 in a child with metopic synostosis. (2) At the ESHG conference 2020, Di Giovanni et al reported 2 cases of apparently isolated trigonocephaly found to have nonsense or frameshift varaints in PTCH1. The abstract is available on weblink: https://www.abstractsonline.com/pp8/#!/9102/presentation/1801. (3) Deletions of 9q22.3 including PTCH1 are well recognised to be associated with metopic synostosis (reviewed Yamada PMID:32028043), although genes additional to PTCH1 are included in the deleted region. (4) In the 100kGP, the submitter is aware of a case that was missed by GEL/GMC pipeline (found by research lab) because PTCH1 was not included in the Panel for craniosynostosis. (5) The consequence of PTCH1 loss-of-function mutations is to increase hedgehog (Hh) signalling through de-repression of Smoothened. Mutations in other genes associated with Hh overactivity, in the genes SMO, RAB23 and MEGF8, are all associated with craniosynostosis and are green panel app genes. A mice mutated in the Ptch1 orthologue, dogface-like, has lambdoid craniosynostosis (PMID:23897749). Hence, a clear biological mechanism exists accounting for craniosynostosis. Sources: Expert Review |
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| Rare syndromic craniosynostosis or isolated multisuture synostosis v2.9 | B3GAT3 | Zornitza Stark reviewed gene: B3GAT3: Rating: GREEN; Mode of pathogenicity: None; Publications: 31438591; Phenotypes: Multiple joint dislocations, short stature, craniofacial dysmorphism, with or without congenital heart defects, MIM# 245600; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Rare syndromic craniosynostosis or isolated multisuture synostosis v1.127 | TMCO1 | Eleanor Williams Phenotypes for gene: TMCO1 were changed from MR syndrome; Cerebrofaciothoracic dysplasia/ craniofacial dysmorphism; skeletal anomalies to MR syndrome; Cerebrofaciothoracic dysplasia/ craniofacial dysmorphism; skeletal anomalies; Craniofacial dysmorphism, skeletal anomalies, and mental retardation syndrome, 213980 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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 v1.80 | 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 | TMCO1 | Eleanor Williams Added phenotypes MR syndrome; Cerebrofaciothoracic dysplasia/ craniofacial dysmorphism; skeletal anomalies for gene: TMCO1 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Rare syndromic craniosynostosis or isolated multisuture synostosis v1.47 | TMCO1 | Tracy Lester reviewed gene: TMCO1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Cerebrofaciothoracic dysplasia/ craniofacial dysmorphism, skeletal anomalies and MR syndrome; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Rare syndromic craniosynostosis or isolated multisuture synostosis v1.47 | SMO | Tracy Lester reviewed gene: SMO: Rating: GREEN; Mode of pathogenicity: Other - please provide details in the comments; Publications: 27236920; Phenotypes: Curry-Jones syndrome, somatic mosaic, 601707; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Rare syndromic craniosynostosis or isolated multisuture synostosis v1.46 | SMO | Eleanor Williams reviewed gene: SMO: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Rare syndromic craniosynostosis or isolated multisuture synostosis v1.45 | SMO |
Eleanor Williams Source NHS GMS was added to SMO. Rating Changed from Green List (high evidence) to Green List (high evidence) |
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| Rare syndromic craniosynostosis or isolated multisuture synostosis v1.40 | SMO | Rebecca Foulger Added comment: Comment on mode of inheritance: Changed MOI from 'Other' in order to capture variants within this gene in our current tiering pipeline. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Rare syndromic craniosynostosis or isolated multisuture synostosis v1.40 | SMO | Rebecca Foulger Mode of inheritance for gene: SMO was changed from Other - please specifiy in evaluation comments to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Rare syndromic craniosynostosis or isolated multisuture synostosis | SMO | Louise Daugherty commented on SMO | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Rare syndromic craniosynostosis or isolated multisuture synostosis | SMO | Louise Daugherty classified SMO as green | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Rare syndromic craniosynostosis or isolated multisuture synostosis | SMO | Louise Daugherty edited their review of SMO | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Rare syndromic craniosynostosis or isolated multisuture synostosis | SMO | Louise Daugherty classified SMO as amber | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Rare syndromic craniosynostosis or isolated multisuture synostosis | SMO | Louise Daugherty commented on SMO | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Rare syndromic craniosynostosis or isolated multisuture synostosis | SMO | Andrew Wilkie added SMO to panel | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Rare syndromic craniosynostosis or isolated multisuture synostosis | SMO | Andrew Wilkie reviewed SMO | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||