FBN2

Gene Facts

• HGNC Symbol: FBN2 (HGNC:3604)
• HGNC Name: fibrillin 2
• Gene type: protein-coding gene
• Locus type: gene with protein product
• Previous symbols: CCA
• Alias symbols: DA9
• %HI: 21.09
• pLI: 1
• LOEUF: 0.31
• Cytoband: 5q23.3
• Genomic Coordinates:

  GRCh37/hg19:	chr5:127593601-127873938
  GRCh38/hg38:	chr5:128257909-128538245

• MANE Select Transcript: NM_001999.4 ENST00000262464.9
• Function: [Fibrillin-2]: Fibrillins are structural components of 10-12 nm extracellular calcium-binding microfibrils, which occur either in association with elastin or in elastin-free bundles. Fibrillin-2- containing microfibrils regulate the early process of elastic fiber assembly. Regulates osteoblast maturation by controlling TGF-beta bioavailability and calibrating TGF-beta and BMP levels, respectively. {ECO:0000250|UniProtKB:Q61555}. [Placensin]: Hormone secreted by trophoblasts that promotes trophob... (Source: Uniprot)

Dosage Sensitivity Summary (Gene)

• Dosage ID: ISCA-34479
• ClinGen Curation ID: CCID:007128
• Curation Status: Complete
• Issue Type: Dosage Curation - Gene
• Haploinsufficiency: No Evidence for Haploinsufficiency (0)
• Triplosensitivity: No Evidence for Triplosensitivity (0)
• Last Evaluated: 02/28/2024

Haploinsufficiency (HI) Score Details

• HI Score: 0
• HI Evidence Strength: No Evidence for Haploinsufficiency
• HI Evidence Comments: PMID 11754102: Gupta et al (2002) “screened exons 22 through 36 of FBN2 for mutations in 13 patients with classic Congenital Contractural Arachnodactyly (CCA) by single stranded conformational polymorphism analysis (SSCP) and then by direct sequencing.” Of the thirteen patients one patient was identified (subject GD1441) to have a nonsense variant, p.Y1421X detected in exon 33 of the FBN2 gene. This individual was diagnosed with CCA at age 6, without family history of CCA. She presented with abnormal ears (low set with crumpled helices), severe scoliosis, arachnodactyly, pectus carinatum, dilated aortic root and ascending aorta, and hypermobile thumbs. The effect of this FBN1 nonsense variant on RNA expression, protein expression, and function is unknown. PMID 24585410: Inbar-Feigenberg et al (2014) describes a 20-week gestation fetus (case 2) presenting with, “bilateral clenched fists with otherwise normal fetal anatomy and amniotic fluid volume. Movements in all other joints appeared normal.” “Follow-up ultrasound at 21-weeks’ gestation confirmed persistently clenched hands, and fetal echocardiography was normal.” Amniocentesis microarray was performed and a 103.3-kb deletion at 5q23.3 was identified, which includes a portion of the FBN2 gene (microarray results also reported in PMID 22467165, Shaffer et al 2012). Of note, overlapping deletions of FBN2 have been reported in DGV one of which is considered a DGV Gold Standard Loss (ID: gssvL102254). The effect of this deletion on FBN2 RNA expression, protein expression, and function is unknown. PMID 28762477: Lavillaureix et al (2017) reported a single individual with a mosaic intragenic deletion of the FBN2 gene presenting prenatally with hypokinesia, arthrogryposis and frequent respiratory movements suggesting fetal distress. Array-CGH identified a 116~135-kb mosaic intragenic deletion of the FBN2 gene (GRCh37/hg19: chr5:127663810-127779670_ chr5:127656238-127791139) which includes exon 7~8 to 34 of the 65 FBN2 exons (NM_001999.3). Fluorescence in situ hybridization (FISH) analysis confirmed the deletion in liver, muscle and skin tissue samples and showed that it was present in 55% to 70% of the nuclei examined. Parental testing was normal by both array-CGH and FISH. The authors speculate that this mosaic deletion is likely in-frame resulting in a drastically shorter protein disrupting the microfibrial assembly more severely and that this deletion and other similar intragenic deletions are more consistent with dominant negative mechanism. PMID 29907982: Overwater et al (2018) screened 810 patients of suspected of Hereditary Thoracic Aortic Disease (H-TAD) using a targeted NGS panel of 21 genes, including FBN2. Three patients were identified to have an FBN2 variant (patients 33-35) one of which was a frameshift variant (patient 35; c.7526_7527, del p.0) in 65 year old man who had an aneurysm and diagnosed aortic arch age the age of 64 years. The variant was absent in the patient’s brother who had an aneurysm and diagnosed aortic arch at age 39 years. The authors conclude that the variant is “NMD confirmed”, but data or results to support this were not presented. PMID 18767143: Frederic et al (20019) summarize several patients with CCA who have FBN2 variants. Within this paper the authors summarize several cases with FBN2 splice-site variants (Table 2) which demonstrate in-frame exon skipping. Intragenic deletions in patients are also believed to result in in-frame change. PMID 19006240: Callewaert et al (2009) also reports an individual with CCA who has a de novo splice site variant in FBN2 (c.4222+4_4222+5delAG) leading to skipping of exon 32. Most pathogenic FBN2 pathogenic variants observed in individuals with CCA cluster in a limited region of the gene, from exons 24-35, which is homologous to the region of FBN1 that harbors most pathogenic regions that lead to neonatal Marfan syndrome phenotype. Individuals with large deletion involving the FBN2 gene do not exhibit typical CCA phenotype (PMIDs: 24036431, 9605585, 25195018) and deletions involving the 5' end of the gene are observed in normal individuals (ExAC and DGV). This evidence supports a dominant negative mechanism and evidence of haploinsufficincy in individuals with CCA is very limited.

Triplosensitivity (TS) Score Details

• TS Score: 0
• TS Evidence Strength: No Evidence for Triplosensitivity
• TS Evidence Comments: no evidence suggesting triplosensitivity for FBN2 gene