FBN2

Inheritance Pattern: AD

Disease ID:MONDO:0007363

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0007275

Submitter: Franklin by Genoox

A family in which CTS occurred in subsequent generations at an unusually young age underwent DNA examination which identified a heterozygous variant (c.5009T>G; p.Phe1670Cys) in the fibrillin-2 (FBN2) gene that co-segregated with the phenotype in the family. http://dx.doi.org/10.1136/jmedgenet-2020-107085

Inheritance Pattern: AD

Disease ID:MONDO:0014501

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0014501

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0007363

Submitter: ClinGen

*FBN2*, which encodes fibrillin-2, was first reported in association to autosomal dominant Congenital Contractural Arachnodactyly (CCA) in 1995 (PMID: 7773290). CCA is a connective tissue disorder characterized by the following: congenital joint contractures, arachnodactyly, crumpled ears, kyphoscoliosis, Marfanoid habitus, dolichostenomelia, micrognathia, highly arched palate, sternal deformities, and muscle hypoplasia (OMIM: 121050; PMID: 31316167). *FBN2* variants have also been reported in individuals with the following disease entities: thoracic aortic aneurysm and dissection (TAAD) and early-onset macular degeneration. Per criteria outlined by the ClinGen Lumping and Splitting Guidelines, CCA and TAAD have been lumped into a single disease entity, as no differences in molecular mechanism or inheritance pattern were identified, and both interfamilial and intrafamilial variability were observed. Given no evidence of overlap between early-onset macular degeneration and CCA and an unclear molecular mechanism, early-onset macular degeneration has been split and may be curated as a separate disease entity by the ClinGen Retinal GCEP in the future. Evidence supporting the gene-disease relationship between *FBN2* and CCA includes case-level, family segregation, functional, and experimental data. The majority of reported pathogenic variants cluster within exons 24–35, a region critical for microfibril assembly (PMID: 18767143). Notably, *FBN2* variants leading to premature termination are underrepresented, with only six nonsense variants reported as likely pathogenic or pathogenic in ClinVar to date. In contrast, there is an overrepresentation of pathogenic in-frame variants, including missense and splice-site, likely resulting in in-frame exon skipping. While the primary mechanism of disease is not yet well-established, a dominant negative effect is considered most likely. This curation describes 27 unique variants (16 missense, 10 splice site, and 1 nonsense) and 3 families with a combined LOD of 6.3 (PMIDs:7493032, 11754102, 17345643 19006240, 25975422, 35360850, 38326314, 31143044, 27912749, 33638605, 36936417). This gene-disease relationship is further supported by experimental data in the form of expression studies and mice models. FBN2 expression is highly specific to early embryonic development (PMID: 23715323, Accession phs000424.v10.p2). Fbn2 null mice models exhibit phenotypes consistent with CCA, including multiple joint contractures, supporting pathogenic equivalency between dominant-negative and loss-of-function variants (PMIDs:11470817, 20855508). Graded deficiency of Fbn1 and Fbn2 demonstrates that elastic tissue formation may be driven by the total amount of extracellular microfibrils and that fibrillin-2 containing microfibrils may play a functionally distinct role in organizing the embryonic matrix (PMID: 16407178). Aortic disease has been documented in individuals with pathogenic *FBN2* variants and clinically diagnosed CCA (PMIDs: 11754102, 25975422, 19006240). Perhaps most notable, is an adult male in a family of at least four affected individuals, with a splice site variant (*FBN2*:c.4222+5G>A), who passed at age 61yo due to an acute type A aortic dissection (PMID: 25975422). The risk of thoracic aortic aneurysm is approximately 10-15% among this population (GeneReviews, Callewaert, 2022). However, without routine screening for cardiovascular disease, the prevalence may be underreported. Given the potential risks, screening for TAAD should be considered. Currently, there is no evidence for gene-specific surgical management guidelines. In summary, there is definitive evidence to support this gene-disease relationship with replication over time. Although additional functional studies could further elucidate the molecular mechanism(s), no convincing evidence has emerged that contradicts the above evidence regarding *FBN2*-related CCA. This classification was approved by the ClinGen Heritable Thoracic Aortic Aneurysm and Dissection subgroup of the Hereditary Cardiovascular Disease GCEP on 11/7/2025 (SOP Version 11).

Inheritance Pattern: AD

Disease ID:MONDO:0007363

Submitter: Genomics England PanelApp

Inheritance Pattern: AR

Disease ID:MONDO:0007363

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0007363

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0007363

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0007363

Submitter: G2P

Inheritance Pattern: AD

Disease ID:MONDO:0014501

Submitter: Labcorp Genetics (formerly Invitae)