Rare syndromic craniosynostosis or isolated multisuture synostosis
Gene: FBN1
Comment on list classification: As reviewed by Rebecca Tooze (University of Oxford), there is sufficient evidence (>3 unrelated cases) for this gene to be promoted to GREEN in the next GMS update.Created: 10 May 2023, 1:31 p.m. | Last Modified: 10 May 2023, 1:31 p.m.
Panel Version: 4.23
PMID:16596670 reported two cases that had heterozygous FBN1 variants. One had scaphocephaly with indistinct coronal sutures and partial sagittal synostosis. Second had plagiocephaly with patent coronal, lambdoid and sagittal sutures. A third case had FBN1 deletion with dolichocephaly.
PMID:24039054 reported a girl with severe congenital lipodystrophy and a neonatal progeroid appearance. She exhibited an accelerated growth in height with a discrepant poor weight gain and a characteristic facial appearance with craniosynostosis. She was identified with the variant c.8175_8182del8bp/ p.Arg2726Glufs*9 in FBN1 gene.
PMID:27884935 reported the identification of a de novo splice variant in FBN1gene (c.8226+5G>A) in a patient with craniosynostosis.
PMID:29168297 reported two probands with variants in FBN1 (proband 1: c.1169C>T/ p.(Ser390Phe) & c.8149G>A/ p.(Glu2717Lys); proband 2: c.7661G>A/ p.(Arg2554Gln)) presenting with me topic (proband 1) and sagittal (proband 2) craniosynostosis.
PMID:31754721 reported a patient with Marfan syndrome identified with c.4096G>A/ p.(Glu1366Lys) variant in FBN1 gene. This patient presented with sagittal and bilambdoidal craniosynostosis.
This gene has been associated with relevant phenotypes in both OMIM and Gene2Phenotype databases.Created: 10 May 2023, 1:26 p.m. | Last Modified: 10 May 2023, 1:29 p.m.
Panel Version: 4.19
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes
Marfan syndrome, OMIM:154700; Marfan lipodystrophy syndrome, OMIM:616914; craniosynostosis, MONDO:0015469
Publications
• Two variants reported in the Clarke paper but both detailed in gnomAD v2.1.1: c.1169C>T; p.(Ser390Phe) with an allele frequency of 2.40e-5, and c.8149G>A; p.(Glu2717Lys) with an allele frequency of 1.35e-4 (Clarke et al., 2018).
• Two recurrent novel heterozygous FBN1 mutations were found in two patients with Marfan syndrome (MFS) and abnormal cranial dura: a de novo c.3302G>A; p.(Tyr1101Cys) and a de novo c.3217G > A; p.(Glu1073Lys) variant (Adès et al., 2006).
• A de novo c.8226+5G>A; p.(?) splicing variant was identified in one individual with sagittal and metopic synostosis (Miller et al., 2017).
• Mutation analysis identified a c.8175_8182del8bp; p.(Arg2726Glufs*9) variant in exon 64 of the FBN1 gene (pLI score of 1) in an individual with overgrowth and craniosynostosis (Takenouchi et al., 2013).
• Interstitial deletions involving the chromosomal band 15q15 are described in five prior cases and a further case was identified by Hiraki and colleagues in an individual with coronal, metopic and sagittal synostosis, resulting in the deletion of FBN1 (Hiraki et al., 2008).
• A further patient with Marfan syndrome and a familial variant in FBN1 was identified: c.4096G>A; p.(Glu1366Lys) (not reported in gnomAD) (Yoon et al., 2020).Created: 2 Mar 2023, 1:25 p.m. | Last Modified: 2 Mar 2023, 1:25 p.m.
Panel Version: 3.4
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Ades et al 2006 report cases with MFS and CSS (Furlong syndrome), phenotypically similar to Shprintzen-Goldberg. 2 cases had FBN1 mutations - one had scaphocephaly w indistinct coronal sutures & partial sagittal synostosis. Second had plagiocephaly with patent coronal, lambdoid and sagittal sutures. A third case had FBN1 deletion with dolichocephaly. Further case with craniosynostosis reported in Miller et al (2017) ; Review on behalf of Tracy Lester and Andrew WilkieCreated: 5 Mar 2019, 11:33 a.m.
Phenotypes
Marfan syndrome
The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.Created: 11 Oct 2023, 11:55 a.m. | Last Modified: 11 Oct 2023, 11:55 a.m.
Panel Version: 4.174
PMID: 16596670 - Ades et al 2006 - report 2 patients with heterozygous FBN1 mutations (Patients 1 and 2) and a patient with a heterozygous FBN1 deletion (Patient 5). Patient 1 had Marfan syndrome with scaphocephaly, unusually rounded orbital rims and recession of the right orbital and frontal regions. Coronal sutures were indistinct. The anterior half of the sagittal suture was fused. Patient 2 had severe early onset Marfan sydnrome and plagiocephaly with coronal, lambdoid, and sagittal sutures. Patient 5 had marfanoid (MD) features, mental retardation (MR), and dolichocephaly.
PMID: 27884935 - Miller et al 2017 - report a case of a patient with craniosynostosis and a de novo splice variant affecting FBN1. c.8226+5G>A.Created: 10 Nov 2019, 11:38 p.m. | Last Modified: 10 Nov 2019, 11:38 p.m.
Panel Version: 2.0
This gene was part of an initial gene list collated by Tracy Lester, Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust, February 2019 on behalf of the GMS Musculoskeletal Specialist Group; Gene symbol submitted: FBN1; Suggested initial gene rating: amberCreated: 5 Mar 2019, 11:21 a.m.
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Very rare association. Only likely to be significant if other features of Marfan syndrome presentCreated: 14 Sep 2015, 12:20 p.m.
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes
Marfan syndrome
Publications
Tag Q2_23_promote_green was removed from gene: FBN1.
Source Expert Review Green was added to FBN1. Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Tag Q2_23_promote_green tag was added to gene: FBN1.
Gene: fbn1 has been classified as Amber List (Moderate Evidence).
Phenotypes for gene: FBN1 were changed from Marfan syndrome to Marfan syndrome, OMIM:154700; Marfan lipodystrophy syndrome, OMIM:616914; craniosynostosis, MONDO:0015469
Publications for gene: FBN1 were set to
Mode of inheritance for gene: FBN1 was changed from to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Added phenotypes Marfan syndrome for gene: FBN1
Source NHS GMS was added to FBN1.
This gene has been classified as Red List (Low Evidence).
FBN1 was added to Craniosynostosis syndromespanel. Sources: Expert list