ELN – Supravalvular Aortic Stenosis

ELN encodes tropoelastin, the core structural protein of elastic fibers in large vessels. Heterozygous loss-of-function variants in ELN cause autosomal dominant supravalvular aortic stenosis (SVAS), characterized by progressive narrowing of the ascending aorta and branch pulmonary arteries, leading to left ventricular outflow tract obstruction and risk of sudden cardiac events. Familial and sporadic cases exhibit incomplete penetrance and variable expressivity, underscoring the need for genetic testing in both syndromic and non-syndromic presentations.

Linkage studies first mapped SVAS to chromosome 7q11.23, co-localizing with ELN (lod 5.9 at D7S371/ELN) in two kindreds ([PMID:8475063]). Subsequent mutation screens identified point mutations co-segregating with disease in four familial and three sporadic cases, including nonsense, frameshift, and splice site alterations, confirming ELN as the causal gene ([PMID:9215670]).

A broad mutational spectrum was described in a cohort of 100 SVAS patients, with 35 individuals harboring ELN variants: 24 frameshift/nonsense mutations, 4 missense changes, and 7 splice site alterations ([PMID:11175284]). These findings established haploinsufficiency via null alleles as the principal pathogenic mechanism. More recently, whole-exome sequencing and MLPA in seven familial SVAS families uncovered intragenic deletions spanning 1–29 ELN exons in 6/7 families, emphasizing the importance of dosage analysis for comprehensive genetic diagnosis ([PMID:30228022]).

Functional assays in patient fibroblasts demonstrate that premature termination codon (PTC) mutations trigger nonsense-mediated mRNA decay, reducing ELN transcript levels by >50% and diminishing tropoelastin synthesis and secretion ([PMID:10942104]). Mutations disrupting self-association domains impair elastic fiber assembly, confirming that reduced elastin dosage leads to arterial wall stiffening and luminal narrowing.

Collectively, genetic and experimental data converge on elastin haploinsufficiency as the unifying mechanism for SVAS. The high yield of heterozygous ELN variants in familial and sporadic cases supports a Strong gene–disease association. Genetic evidence is Strong based on >35 unrelated probands with loss-of-function ELN variants and multi-family co-segregation. Functional evidence is Moderate, with consistent in vitro NMD and fiber assembly defects paralleling human vascular pathology.

Routine sequencing and deletion/duplication analysis of ELN should be integrated into diagnostic workflows for congenital arteriopathies. Early molecular diagnosis enables risk stratification, cascade testing, and tailored surveillance to mitigate life-threatening cardiovascular complications.

Key Take-home: ELN haploinsufficiency underlies autosomal dominant SVAS; comprehensive mutational and dosage analysis facilitates precise diagnosis, family counseling, and management.

References

• Proceedings of the National Academy of Sciences of the United States of America • 1993 • A human vascular disorder, supravalvular aortic stenosis, maps to chromosome 7. PMID:8475063
• Human Molecular Genetics • 1997 • Elastin point mutations cause an obstructive vascular disease, supravalvular aortic stenosis. PMID:9215670
• European journal of human genetics : EJHG • 2000 • Elastin: mutational spectrum in supravalvular aortic stenosis. PMID:11175284
• International journal of cardiology • 2019 • Frequent intragenic microdeletions of elastin in familial supravalvular aortic stenosis. PMID:30228022
• Human Genetics • 2000 • Isolated supravalvular aortic stenosis: functional haploinsufficiency of the elastin gene as a result of nonsense-mediated decay. PMID:10942104

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