Frequent intragenic microdeletions of elastin in familial supravalvular aortic stenosis

Satoshi Hayano, Yusuke Okuno, Makiko Tsutsumi, Hidehito Inagaki, Yoshie Fukasawa, Hiroki Kurahashi, Seiji Kojima, Yoshiyuki Takahashi, Taichi Kato

Research output: Contribution to journalArticle

Abstract

Background: Supravalvular aortic stenosis (SVAS) is a congenital heart disease affecting approximately 1:25,000 live births. SVAS may occur sporadically, be inherited in an autosomal dominant manner, or be associated with Williams-Beuren syndrome, a complex developmental disorder caused by a microdeletion of chromosome 7q11.23. ELN on 7q11.23, which encodes elastin, is the only known gene to be recurrently mutated in less than half of SVAS patients. Methods: Whole-exome sequencing (WES) was performed for seven familial SVAS families to identify other causative gene mutations of SVAS. Results: Three truncating mutations and three intragenic deletions affecting ELN were identified, yielding a diagnostic efficiency of 6/7 (85%). The deletions, which explained 3/7 of the present cohort, spanned 1–29 exons, which might be missed in the course of mutational analysis targeting point mutations. The presence of such deletions was validated by both WES-based copy number estimation and multiplex ligation-dependent probe amplification analyses, and their pathogenicity was reinforced by co-segregation with clinical presentations. Conclusions: The majority of familial SVAS patients appear to carry ELN mutations, which strongly indicates that elastin is the most important causative gene for SVAS. The frequency of intragenic deletions highlights the need for quantitative tests to analyze ELN for efficient genetic diagnosis of SVAS.

Original languageEnglish
Pages (from-to)290-295
Number of pages6
JournalInternational Journal of Cardiology
Volume274
DOIs
Publication statusPublished - 01-01-2019

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Supravalvular Aortic Stenosis
Elastin
Exome
Mutation
Williams Syndrome
Genes
Multiplex Polymerase Chain Reaction
Live Birth
Point Mutation
Virulence
Exons
Heart Diseases
Chromosomes

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine

Cite this

Hayano, Satoshi ; Okuno, Yusuke ; Tsutsumi, Makiko ; Inagaki, Hidehito ; Fukasawa, Yoshie ; Kurahashi, Hiroki ; Kojima, Seiji ; Takahashi, Yoshiyuki ; Kato, Taichi. / Frequent intragenic microdeletions of elastin in familial supravalvular aortic stenosis. In: International Journal of Cardiology. 2019 ; Vol. 274. pp. 290-295.
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Frequent intragenic microdeletions of elastin in familial supravalvular aortic stenosis. / Hayano, Satoshi; Okuno, Yusuke; Tsutsumi, Makiko; Inagaki, Hidehito; Fukasawa, Yoshie; Kurahashi, Hiroki; Kojima, Seiji; Takahashi, Yoshiyuki; Kato, Taichi.

In: International Journal of Cardiology, Vol. 274, 01.01.2019, p. 290-295.

Research output: Contribution to journalArticle

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T1 - Frequent intragenic microdeletions of elastin in familial supravalvular aortic stenosis

AU - Hayano, Satoshi

AU - Okuno, Yusuke

AU - Tsutsumi, Makiko

AU - Inagaki, Hidehito

AU - Fukasawa, Yoshie

AU - Kurahashi, Hiroki

AU - Kojima, Seiji

AU - Takahashi, Yoshiyuki

AU - Kato, Taichi

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N2 - Background: Supravalvular aortic stenosis (SVAS) is a congenital heart disease affecting approximately 1:25,000 live births. SVAS may occur sporadically, be inherited in an autosomal dominant manner, or be associated with Williams-Beuren syndrome, a complex developmental disorder caused by a microdeletion of chromosome 7q11.23. ELN on 7q11.23, which encodes elastin, is the only known gene to be recurrently mutated in less than half of SVAS patients. Methods: Whole-exome sequencing (WES) was performed for seven familial SVAS families to identify other causative gene mutations of SVAS. Results: Three truncating mutations and three intragenic deletions affecting ELN were identified, yielding a diagnostic efficiency of 6/7 (85%). The deletions, which explained 3/7 of the present cohort, spanned 1–29 exons, which might be missed in the course of mutational analysis targeting point mutations. The presence of such deletions was validated by both WES-based copy number estimation and multiplex ligation-dependent probe amplification analyses, and their pathogenicity was reinforced by co-segregation with clinical presentations. Conclusions: The majority of familial SVAS patients appear to carry ELN mutations, which strongly indicates that elastin is the most important causative gene for SVAS. The frequency of intragenic deletions highlights the need for quantitative tests to analyze ELN for efficient genetic diagnosis of SVAS.

AB - Background: Supravalvular aortic stenosis (SVAS) is a congenital heart disease affecting approximately 1:25,000 live births. SVAS may occur sporadically, be inherited in an autosomal dominant manner, or be associated with Williams-Beuren syndrome, a complex developmental disorder caused by a microdeletion of chromosome 7q11.23. ELN on 7q11.23, which encodes elastin, is the only known gene to be recurrently mutated in less than half of SVAS patients. Methods: Whole-exome sequencing (WES) was performed for seven familial SVAS families to identify other causative gene mutations of SVAS. Results: Three truncating mutations and three intragenic deletions affecting ELN were identified, yielding a diagnostic efficiency of 6/7 (85%). The deletions, which explained 3/7 of the present cohort, spanned 1–29 exons, which might be missed in the course of mutational analysis targeting point mutations. The presence of such deletions was validated by both WES-based copy number estimation and multiplex ligation-dependent probe amplification analyses, and their pathogenicity was reinforced by co-segregation with clinical presentations. Conclusions: The majority of familial SVAS patients appear to carry ELN mutations, which strongly indicates that elastin is the most important causative gene for SVAS. The frequency of intragenic deletions highlights the need for quantitative tests to analyze ELN for efficient genetic diagnosis of SVAS.

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