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| Rare syndromic craniosynostosis or isolated multisuture synostosis v4.149 | POLR2A |
Achchuthan Shanmugasundram gene: POLR2A was added gene: POLR2A was added to Rare syndromic craniosynostosis or isolated multisuture synostosis. Sources: Literature Mode of inheritance for gene: POLR2A was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: POLR2A were set to 35080095; 36980886 Phenotypes for gene: POLR2A were set to Neurodevelopmental disorder with hypotonia and variable intellectual and behavioral abnormalities, OMIM:618603; craniosynostosis, MONDO:0015469 Review for gene: POLR2A was set to RED Added comment: A de novo insertion was identified in the Norwegian sequencing study: c.4329_4330delinsAA; p.Ala1444Thr. The variant is absent from gnomAD (v.2.1.1) but is not predicted to affect a functional domain. The patient displayed metopic synostosis, impaired motor skills, hypospadias, hypermobile joints and hyperactive behaviour (PMID:35080095). Sources: Literature |
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| Rare syndromic craniosynostosis or isolated multisuture synostosis v3.4 | MAN2B1 |
Rebecca Tooze gene: MAN2B1 was added gene: MAN2B1 was added to Craniosynostosis. Sources: Literature Mode of inheritance for gene: MAN2B1 was set to BIALLELIC, autosomal or pseudoautosomal Review for gene: MAN2B1 was set to GREEN Added comment: • A Norwegian study of patients with craniosynostosis identified a homozygous missense variant in MAN2B1: c.1055 T>C; p.(Leu352Pro) (Tønne et al., 2021). • Compound heterozygous variant were identified through screening 114 families with craniosynostosis within the UK 100kGP: c.1830+1G>C; p.(?) and c.2248C>T; p.(Arg750Trp) (Hyder et al., 2021). • One patient out of 12 with recessive variants in MAN2B1 was described with craniosynostosis: c.2245C>T; p.(Arg749Trp), and c.2355G>A; p.(Thr785*) (Lipiński et al., 2022). Sources: Literature |
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| Rare syndromic craniosynostosis or isolated multisuture synostosis v2.49 | RNU12 | Eleanor Williams Phenotypes for gene: RNU12 were changed from CDAGS syndrome MIM#603116; Craniosynostosis, Delayed closure of the fontanelles, cranial defects, clavicular hypoplasia, Anal and Genitourinary malformations, and Skin manifestations to CDAGS syndrome, OMIM:603116; craniosynostosis-anal anomalies-porokeratosis syndrome, MONDO:001128 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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 v2.23 | RNU12 |
Zornitza Stark gene: RNU12 was added gene: RNU12 was added to Craniosynostosis. Sources: Literature Mode of inheritance for gene: RNU12 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: RNU12 were set to 34085356 Phenotypes for gene: RNU12 were set to CDAGS syndrome MIM#603116; Craniosynostosis, Delayed closure of the fontanelles, cranial defects, clavicular hypoplasia, Anal and Genitourinary malformations, and Skin manifestations Review for gene: RNU12 was set to GREEN Added comment: 5 CDAGS syndrome families with biallelic variants all including NC_000022.10:g.43011402C>T and another variant on the second allele. Whole transcriptome sequencing analysis of patient lymphoblastoid cells identified differentially expressed genes, and differential alternative splicing analysis indicated there was an enrichment of alternative splicing events. Craniosynostosis is a major feature of the condition. Sources: Literature |
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| Rare syndromic craniosynostosis or isolated multisuture synostosis v1.72 | SKI | Eleanor Williams Added phenotypes Shprintzen-Goldberg syndrome 182212 for gene: SKI | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Rare syndromic craniosynostosis or isolated multisuture synostosis v1.47 | SKI | Tracy Lester reviewed gene: SKI: Rating: GREEN; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: 23023332, 23103230, 24736733; Phenotypes: Shprintzen-Goldberg syndrome - 182212; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Rare syndromic craniosynostosis or isolated multisuture synostosis v1.46 | SKI | Eleanor Williams reviewed gene: SKI: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Rare syndromic craniosynostosis or isolated multisuture synostosis v1.45 | SKI |
Eleanor Williams Source NHS GMS was added to SKI. Rating Changed from Green List (high evidence) to Green List (high evidence) |
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