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Thoracic aortic aneurysm or dissection (GMS) v5.4 FBN1 Ida Ertmanska commented on gene: FBN1: Comment on mode of inheritance: There are numerous individuals with Marfan syndrome reported with both heterozygous and biallelic FBN1 variants - though biallelic cases are known to present with more severe features, and with higher disease penetrance. Hence, the MOI on Thoracic aortic aneurysm or dissection (GMS) should be changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal.
Thoracic aortic aneurysm or dissection (GMS) v5.4 FBN1 Ida Ertmanska Publications for gene: FBN1 were set to 26888179; 20082464; 7762551
Thoracic aortic aneurysm or dissection (GMS) v5.3 FBN1 Ida Ertmanska Tag Q2_26_MOI tag was added to gene: FBN1.
Thoracic aortic aneurysm or dissection (GMS) v5.3 FBN1 Ida Ertmanska changed review comment from: PMID: 23278365 Hogue et al., 2013
Report of a proband (Mexican-American woman, consanguineous parents) + literature review of 4 additional unrelated families with biallelic FBN1 variants and severe Marfan syndrome - heterozygous parents were either asymptomatic or had a milder form of Marfan syndrome. Mostly biallelic missense, one instance of missense + deletion in 2 sibs. Proband presented with scoliosis, arachnodactyly, dislocated lenses, mitral valve prolapse, aortic dilatation, dural ectasias.

PMID: 27582083 Arnaud et al., 2017
In a large cohort of Marfan syndrome patients, 4 probands were homozygous and 22 potentially comp het for FBN1 variants (5 confirmed to be in trans). All 4 homozygous individuals harboured missense variants; comp het cases either had biallelic missense FBN1 variants, or missense + nonsense. Heterozygous carriers usually also diagnosed with MFS, sometimes very mild e.g., isolated mild skeletal features in women. The severity of symptoms and age of onset varied a lot, both between biallelic and among monoallelic cases.

PMID: 31950671 McInerney-Leo et al., 2020
Report of a pedigree with Marfan syndrome (ectopia lentis, though the skeletal phenotype is variable, and not all have aortic dilatation) - some individuals with monoallelic and some with biallelic FBN1 variants.
All subjects with Marfan syndrome harboured p.Tyr754Cys in FBN1. An additional variant (p.Met2273Thr), previously associated with 'incomplete' MFS, was identified in three siblings. These three compound heterozygous individuals had aortic dilatation at early age (all <30 years): one also had cerebral and ocular aneurysms; and one, who had undergone surgical repair aged 18 years, died from aortic dissection at 31 years.
The heterozygous father (p.Tyr754Cys) with MFS died at 57 years (myocardial infarction) without requiring surgical intervention and one heterozygous (p.Tyr754Cys) sibling has aortic dilatation presenting >40 years but not requiring surgical intervention. Another heterozygous (p.Tyr754Cys) sibling did require aortic root repair (28 years). The heterozygous (p.Met2273Thr) mother had aortic dilatation diagnosed at age 68 years but has not required surgical repair.; to: PMID: 23278365 Hogue et al., 2013
Report of a proband (Mexican-American woman, consanguineous parents) + literature review of 4 additional unrelated families with biallelic FBN1 variants and severe Marfan syndrome - heterozygous parents were either asymptomatic or had a milder form of Marfan syndrome. Mostly biallelic missense, one instance of missense + deletion in 2 sibs. Proband presented with scoliosis, arachnodactyly, dislocated lenses, mitral valve prolapse, aortic dilatation, dural ectasias.

PMID: 27582083 Arnaud et al., 2017
In a large cohort of Marfan syndrome patients, 4 probands were homozygous and 22 potentially comp het for FBN1 variants (5 confirmed to be in trans). All 4 homozygous individuals harboured missense variants; comp het cases either had biallelic missense FBN1 variants, or missense + nonsense. Heterozygous carriers usually also diagnosed with MFS, sometimes very mild e.g., isolated mild skeletal features in women. The severity of symptoms and age of onset varied a lot, both between biallelic and among monoallelic cases.

PMID: 31950671 McInerney-Leo et al., 2020
Report of a pedigree with Marfan syndrome (ectopia lentis, though the skeletal phenotype is variable, and not all have aortic dilatation) - some individuals with monoallelic and some with biallelic FBN1 variants.
All subjects with Marfan syndrome harboured p.Tyr754Cys in FBN1. An additional variant (p.Met2273Thr), previously associated with 'incomplete' MFS, was identified in three siblings. These three compound heterozygous individuals had aortic dilatation at early age (all <30 years): one also had cerebral and ocular aneurysms; and one, who had undergone surgical repair aged 18 years, died from aortic dissection at 31 years.
The heterozygous father (p.Tyr754Cys) with MFS died at 57 years (myocardial infarction) without requiring surgical intervention and one heterozygous (p.Tyr754Cys) sibling has aortic dilatation presenting >40 years but not requiring surgical intervention. Another heterozygous (p.Tyr754Cys) sibling did require aortic root repair (28 years). The heterozygous (p.Met2273Thr) mother had aortic dilatation diagnosed at age 68 years but has not required surgical repair.

The association between FBN1 and Marfan syndrome is rated as Definitive in Gene2Phenotype, both for the AD and AR inheritance patterns.
Thoracic aortic aneurysm or dissection (GMS) v5.3 FBN1 Ida Ertmanska reviewed gene: FBN1: Rating: GREEN; Mode of pathogenicity: None; Publications: 23278365, 27582083, 31950671; Phenotypes: Marfan syndrome, OMIM:154700, Marfan syndrome, MONDO:0007947; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Thoracic aortic aneurysm or dissection (GMS) v0.35 FBN1 Ivone Leong reviewed gene: FBN1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Thoracic aortic aneurysm or dissection (GMS) v0.30 FBN1 Matthew Edwards reviewed gene: FBN1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Marfan syndrome; Mode of inheritance: None; Current diagnostic: yes
Thoracic aortic aneurysm or dissection (GMS) v0.12 FBN1 Ivone Leong Publications for gene: FBN1 were set to
Thoracic aortic aneurysm or dissection (GMS) v0.5 FBN1 Alison Callaway reviewed gene: FBN1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Marfan syndrome, Ectopia lentis; Mode of inheritance: None; Current diagnostic: yes
Thoracic aortic aneurysm or dissection (GMS) v0.0 FBN1 Ellen McDonagh gene: FBN1 was added
gene: FBN1 was added to GMS FTAAD placeholder panel. Sources: Expert Review Green,London South GLH,South West GLH,North West GLH
Mode of inheritance for gene: FBN1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: FBN1 were set to Weill-Marchesani syndrome 2, dominant, (608328); Marfan syndrome (154700); Ectopia lentis, familial (129600); Marfan lipodystrophy syndrome (616914); MASS syndrome (604308); Stiff skin syndrome (184900); Geleophysic dysplasia 2 (614185); Marfan Syndrome; Aortic aneurysm, ascending, and dissection; ongenital contracturalarachnodactyly; Acromicric dysplasia (102370)