Novel ELN mutation in a family with supravalvular aortic stenosis and intracranial aneurysm

Abstract

Pathogenic germline mutations in ELN can be detected in patients with supravalvular aortic stenosis. The mutation might occur de novo or be inherited following an autosomal dominant pattern of inheritance. In this report we describe a three-generation family suffering from supravalvular aortic stenosis, various other arterial stenoses, sudden death, and intracranial aneurysms. A frameshift mutation in exon 12, not described before, was detected in the affected family members. This report emphasises the importance of family history, genetic counselling, and demonstrates the great variability in the phenotype within a single SVAS family.

Double heterozygosity of novel variants found in patients with severe clinical phenotype of cardiovascular disorders

“…Seven novel mutations were detected in 31 familial and sporadic cases of nonsyndromic SVAS, including five frameshift mutations and two donor splice site mutations in intron 3 and 28 resulting in premature stop codons [14]. In another study of a family suffering from SVAS, arterial stenosis, sudden death and intracranial aneurysm, a frameshift mutation was detected in exon 12 of ELN in the affected members [15].…”

<p>A Novel Splice-Site Mutation in the <em>ELN</em> Gene Suggests an Alternative Mechanism for Vascular Elastinopathies</p>

“…The molecular mechanism proposed for the pathogenesis of SVAS is ELN haploinsufficiency, explained by premature termination codon mutations (PTCs), extensively described in affected patients. 8 , 11 , 12 , 15 PTCs lead to insufficient expression of ELN because mutant mRNA is presumably degraded by the nonsense mediated decay (NMD) pathway. 10 A reduction in ELN expression has also been found in skin fibroblasts and aortic smooth muscle cells of SVAS affected patients, thus supporting ELN haploinsufficiency as the mechanism involved in the pathogenesis of the vasculopathy.…”

“…Mutations in the elastin gene are associated with diverse forms of elastinopathies, including supravalvular aortic stenosis (SVAS), autosomal dominant cutis laxa (ADCL) and pulmonic stenosis. 1,[5][6][7][8][9][10][11] Supravalvular aortic stenosis (SVAS) (OMIM 185500) is a congenital narrowing of the lumen of the ascending aorta with an estimated incidence of 1 in 20.000 live births 6,12 This condition can present in both syndromic and nonsyndromic forms. The syndromic form is usually associated with Williams-Beuren syndrome (WBS) (OMIM 194050), which shows an autosomal dominant inheritance pattern and is caused by a deletion in 7q11.…”

Prevalence of Intracranial Aneurysm in Patients with Aortopathy: A Systematic Review with Meta-Analyses

“…10,[22][23][24][25] Furthermore, the genetic relation of IA and aortopathy has been examined in researches. [26][27][28][29][30][31][32][33][34] Multiple types of gene mutation play a critical role in this relationship: single nucleotide polymorphisms, 27,35 frameshift mutations in exons, 28 and translocations of chromosome, 29 which demonstrates that the gene- Values are presented as mean±standard deviation or number (number of intracranial aneurysm per person). BAV, bicuspid aortic valve; CoA, coarctation of the aorta; AD, aortic dissection; AA, aortic aneurysm; TAA, thoracic aortic aneurysm; AAA, abdominal aortic aneurysm; IA, intracranial aneurysm; Ant-IA, IA in anterior circulation arteries after bifurcation of the internal carotid artery; ACA, anterior cerebral artery; ACoA, anterior communicating artery; MCA, middle cerebral artery; ICA-IA, IA in internal carotid artery and branches except for Ant-IA; ICA, internal carotid artery; AChoA, anterior choroidal artery; SHA, superior hypophyseal artery; OA, ophthalmic artery; Post-IA, IA in posterior circulation artery; PCoA, posterior communicating artery; PCA, posterior cerebral artery; SCA, superior cerebellar artery; PICA, posterior inferior communicating artery; VA, vertebral artery; BA, basilar artery.…”