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A case of G1013R FBN1 mutation: A potential genotype-phenotype correlation in severe Marfan syndrome

Brooke R Willis¹, Mianne Lee¹, Kavitha Rethanavelu¹

¹LKS Faculty of Medicine, Department of Pediatrics & Adolescent Medicine, The University of Hong Kong, Hong Kong SAR, China.

American Journal of Medical Genetics. Part A

|March 22, 2020

Abstract:

Marfan Syndrome (MFS) is an autosomal dominant connective tissue disorder with a wide range of severities. Ninety-five percent of MFS probands have a mutation in the fibrillin-1 gene (FBN1); however, there are a high number of unique mutations complicating attempts at establishing any phenotype-genotype correlations for this disease (Tiecke et al., European Journal of Human Genetics, 2001, 9, 13-21). One of the few extant genotype-phenotype correlations is in exon 24-32 which have been associated with a severe pediatric presentation of neonatal MFS with predominately cardiovascular symptoms. We present a 24-year-old male patient with a heterozygous de novo variant NM_000138.4: c.3037G>A (p.G1013R) located in exon 25 of the FBN1 gene. The patient was found to have dysplastic mitral and tricuspid valves with dilated aortic root at 9 months of age. This is a notable case in that the location of this patient's mutation and his age of symptom onset would indicate a guarded prognosis. Further, this mutation, FBN1 G1013R, has been reported in the literature in four other unrelated patients all of whom presented at a young age with cardiac involvement and all of whom had relative longevity when compared to other patients with mutations in this exon 24-32 hot spot. These findings may represent a more specific genotype-phenotype correlation within this mutational hot spot.

Insights

Marfan syndrome (MFS) is a genetic disorder affecting connective tissue. A specific FBN1 gene mutation (G1013R) in exon 25 may correlate with a distinct cardiac presentation and potentially better longevity in MFS patients.

Area of Science:

Genetics
Cardiology
Connective Tissue Diseases

Background:

Marfan syndrome (MFS) is an autosomal dominant connective tissue disorder with variable severity.
Mutations in the fibrillin-1 gene (FBN1) cause MFS, but numerous unique mutations hinder genotype-phenotype correlations.
Exon 24-32 mutations are linked to severe neonatal MFS with cardiovascular issues.

Purpose of the Study:

To report a case of MFS with a de novo FBN1 variant in exon 25.
To investigate potential genotype-phenotype correlations within the FBN1 exon 24-32 hotspot.
To compare the clinical presentation and prognosis of this patient with previously reported cases.

Main Methods:

Case report of a 24-year-old male with MFS.
Genetic analysis identifying a heterozygous de novo variant NM_000138.4: c.3037G>A (p.G1013R) in FBN1 exon 25.
Review of literature for similar mutations and their clinical outcomes.

Main Results:

The patient presented at 9 months with dysplastic mitral/tricuspid valves and dilated aortic root.
The identified FBN1 G1013R mutation is in exon 25, a known MFS hotspot.
Four other patients with FBN1 G1013R had early cardiac involvement but relative longevity.

Conclusions:

The FBN1 G1013R mutation may represent a specific genotype-phenotype correlation within the exon 24-32 hotspot.
This mutation is associated with early-onset cardiac manifestations in Marfan syndrome.
Patients with this specific mutation may exhibit a more favorable prognosis regarding longevity compared to others in the hotspot.

Read full analysis

Keywords:

FBN1 Marfan syndrome genotype-phenotype correlation

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