EFEMP2 – Thoracic Aortic Aneurysm

Thoracic aortic aneurysm (TAA) can present in isolation or as part of syndromic cutis laxa; familial forms often follow an autosomal dominant pattern. A heterozygous EFEMP2 variant, c.247C>T (p.Arg83Cys), was identified by whole-exome sequencing in an Iranian kindred with nonsyndromic dominant TAA, supported by bioinformatic deleteriousness scores (CADD = 27.6) and conservation (PMID:38113391). A second proband with cutis laxa 1B and giant ascending aneurysm harbored homozygous c.409A>T (p.Ser137Cys) in EFEMP2 (PMID:38025136). These two case reports provide limited replication and no multi-family segregation.

Fibulin-4 (EFEMP2) is essential for collagen maturation in the aortic wall. Smooth muscle-specific Efemp2 knockout mice exhibit disrupted fibrillar collagen architecture and reduced lysyl oxidase activity in aortas, recapitulating human arterial fragility (PMID:26220971). Molecular dynamics and biochemical assays of fibulin-4 EGF domain mutants (p.Glu126Lys, p.Asp203Ala) reveal impaired extracellular assembly and increased protease susceptibility, further supporting a loss-of-function mechanism (PMID:31125616).

Key take-home: Limited clinical case data for EFEMP2 in TAA is supported by moderate functional evidence; targeted genetic testing can inform risk in affected families.

References

• Laboratory medicine • 2024 • Whole-exome sequencing uncovers a novel EFEMP2 gene variant (c.C247T) associated with dominant nonsyndromic thoracic aortic aneurysm. PMID:38113391
• European Heart Journal: Case Reports • 2023 • Giant ascending aortic aneurysm with impending rupture as presentation of cutis laxa 1B: a case report. PMID:38025136
• Human Molecular Genetics • 2015 • Loss of fibulin-4 disrupts collagen synthesis and maturation: implications for pathology resulting from EFEMP2 mutations. PMID:26220971
• Biochimica et Biophysica Acta. Proteins and Proteomics • 2019 • Molecular dynamics simulations on human fibulin-4 mutants D203A and E126K reveal conformational changes in EGF domains potentially responsible for enhanced protease lability and impaired extracellular matrix assembly. PMID:31125616

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