Clinical utility of a next generation sequencing panel assay for Marfan and Marfan-like syndromes featuring aortopathy

Whitney Wooderchak-Donahue, Chad Vansant-Webb, Tatiana Tvrdik, Parker Plant, Tracey Lewis, Jennifer Stocks, Joshua A. Raney, Lindsay Meyers, Alizabeth Berg, Alan F. Rope, Anji T. Yetman, Steven B. Bleyl, Rebecca Mesley, David A. Bull, R. Thomas Collins, Mayra Martinez Ojeda, Amy Roberts, Ronald Lacro, Audrey Woerner, Joan StolerPinar Bayrak-Toydemir

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

Aortopathy can be defined as aortic dilation, aneurysm, dissection, and tortuosity. Familial aortopathy may occur secondary to fibrillin-1 (FBN1) mutations in the setting of Marfan syndrome, or may occur as a result of other genetic defects with different, but occasionally overlapping, phenotypes. Because of the phenotypic overlap and genetic heterogeneity of disorders featuring aortopathy, we developed a next generation sequencing (NGS) assay and comparative genomic hybridization (CGH) array to detect mutations in 10 genes that cause thoracic aortic aneurysms (TAAs). Here, we report on the clinical and molecular findings in 175 individuals submitted for aortopathy panel testing at ARUP laboratories. Ten genes associated with heritable aortopathies were targeted using hybridization capture prior to sequencing. NGS results were analyzed, and variants were confirmed using Sanger sequencing. Array CGH was used to detect copy-number variation. Of 175 individuals, 18 had a pathogenic mutation and 32 had a variant of uncertain significance (VUS). Most pathogenic mutations (72%) were identified in FBN1. A novel large SMAD3 duplication and FBN1 deletion were identified. Over half who had TAAs or other aortic involvement tested negative for a mutation, suggesting that additional aortopathy genes exist. We anticipate that the clinical sensitivity of at least 10.3% will rise with VUS reclassification and as additional genes are identified and included in the panel. The aortopathy NGS panel aids in the timely molecular diagnosis of individuals with disorders featuring aortopathy and guides proper treatment.

Original languageEnglish (US)
Pages (from-to)1747-1757
Number of pages11
JournalAmerican Journal of Medical Genetics, Part A
Volume167
Issue number8
DOIs
StatePublished - Aug 1 2015
Externally publishedYes

Fingerprint

Marfan Syndrome
Mutation
Thoracic Aortic Aneurysm
Comparative Genomic Hybridization
Genes
Inborn Genetic Diseases
Genetic Heterogeneity
Aortic Aneurysm
Dissection
Dilatation
Phenotype
Fibrillin-1

Keywords

  • Aorta
  • Aortic aneurysm
  • Diagnosis
  • Dilation
  • Dissection
  • Ductus arteriosus
  • Marfan syndrome

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Wooderchak-Donahue, W., Vansant-Webb, C., Tvrdik, T., Plant, P., Lewis, T., Stocks, J., ... Bayrak-Toydemir, P. (2015). Clinical utility of a next generation sequencing panel assay for Marfan and Marfan-like syndromes featuring aortopathy. American Journal of Medical Genetics, Part A, 167(8), 1747-1757. https://doi.org/10.1002/ajmg.a.37085

Clinical utility of a next generation sequencing panel assay for Marfan and Marfan-like syndromes featuring aortopathy. / Wooderchak-Donahue, Whitney; Vansant-Webb, Chad; Tvrdik, Tatiana; Plant, Parker; Lewis, Tracey; Stocks, Jennifer; Raney, Joshua A.; Meyers, Lindsay; Berg, Alizabeth; Rope, Alan F.; Yetman, Anji T.; Bleyl, Steven B.; Mesley, Rebecca; Bull, David A.; Collins, R. Thomas; Ojeda, Mayra Martinez; Roberts, Amy; Lacro, Ronald; Woerner, Audrey; Stoler, Joan; Bayrak-Toydemir, Pinar.

In: American Journal of Medical Genetics, Part A, Vol. 167, No. 8, 01.08.2015, p. 1747-1757.

Research output: Contribution to journalArticle

Wooderchak-Donahue, W, Vansant-Webb, C, Tvrdik, T, Plant, P, Lewis, T, Stocks, J, Raney, JA, Meyers, L, Berg, A, Rope, AF, Yetman, AT, Bleyl, SB, Mesley, R, Bull, DA, Collins, RT, Ojeda, MM, Roberts, A, Lacro, R, Woerner, A, Stoler, J & Bayrak-Toydemir, P 2015, 'Clinical utility of a next generation sequencing panel assay for Marfan and Marfan-like syndromes featuring aortopathy', American Journal of Medical Genetics, Part A, vol. 167, no. 8, pp. 1747-1757. https://doi.org/10.1002/ajmg.a.37085
Wooderchak-Donahue, Whitney ; Vansant-Webb, Chad ; Tvrdik, Tatiana ; Plant, Parker ; Lewis, Tracey ; Stocks, Jennifer ; Raney, Joshua A. ; Meyers, Lindsay ; Berg, Alizabeth ; Rope, Alan F. ; Yetman, Anji T. ; Bleyl, Steven B. ; Mesley, Rebecca ; Bull, David A. ; Collins, R. Thomas ; Ojeda, Mayra Martinez ; Roberts, Amy ; Lacro, Ronald ; Woerner, Audrey ; Stoler, Joan ; Bayrak-Toydemir, Pinar. / Clinical utility of a next generation sequencing panel assay for Marfan and Marfan-like syndromes featuring aortopathy. In: American Journal of Medical Genetics, Part A. 2015 ; Vol. 167, No. 8. pp. 1747-1757.
@article{618d145b582846c688321f47e6817b8f,
title = "Clinical utility of a next generation sequencing panel assay for Marfan and Marfan-like syndromes featuring aortopathy",
abstract = "Aortopathy can be defined as aortic dilation, aneurysm, dissection, and tortuosity. Familial aortopathy may occur secondary to fibrillin-1 (FBN1) mutations in the setting of Marfan syndrome, or may occur as a result of other genetic defects with different, but occasionally overlapping, phenotypes. Because of the phenotypic overlap and genetic heterogeneity of disorders featuring aortopathy, we developed a next generation sequencing (NGS) assay and comparative genomic hybridization (CGH) array to detect mutations in 10 genes that cause thoracic aortic aneurysms (TAAs). Here, we report on the clinical and molecular findings in 175 individuals submitted for aortopathy panel testing at ARUP laboratories. Ten genes associated with heritable aortopathies were targeted using hybridization capture prior to sequencing. NGS results were analyzed, and variants were confirmed using Sanger sequencing. Array CGH was used to detect copy-number variation. Of 175 individuals, 18 had a pathogenic mutation and 32 had a variant of uncertain significance (VUS). Most pathogenic mutations (72{\%}) were identified in FBN1. A novel large SMAD3 duplication and FBN1 deletion were identified. Over half who had TAAs or other aortic involvement tested negative for a mutation, suggesting that additional aortopathy genes exist. We anticipate that the clinical sensitivity of at least 10.3{\%} will rise with VUS reclassification and as additional genes are identified and included in the panel. The aortopathy NGS panel aids in the timely molecular diagnosis of individuals with disorders featuring aortopathy and guides proper treatment.",
keywords = "Aorta, Aortic aneurysm, Diagnosis, Dilation, Dissection, Ductus arteriosus, Marfan syndrome",
author = "Whitney Wooderchak-Donahue and Chad Vansant-Webb and Tatiana Tvrdik and Parker Plant and Tracey Lewis and Jennifer Stocks and Raney, {Joshua A.} and Lindsay Meyers and Alizabeth Berg and Rope, {Alan F.} and Yetman, {Anji T.} and Bleyl, {Steven B.} and Rebecca Mesley and Bull, {David A.} and Collins, {R. Thomas} and Ojeda, {Mayra Martinez} and Amy Roberts and Ronald Lacro and Audrey Woerner and Joan Stoler and Pinar Bayrak-Toydemir",
year = "2015",
month = "8",
day = "1",
doi = "10.1002/ajmg.a.37085",
language = "English (US)",
volume = "167",
pages = "1747--1757",
journal = "American Journal of Medical Genetics, Part A",
issn = "1552-4825",
publisher = "Wiley-Liss Inc.",
number = "8",

}

TY - JOUR

T1 - Clinical utility of a next generation sequencing panel assay for Marfan and Marfan-like syndromes featuring aortopathy

AU - Wooderchak-Donahue, Whitney

AU - Vansant-Webb, Chad

AU - Tvrdik, Tatiana

AU - Plant, Parker

AU - Lewis, Tracey

AU - Stocks, Jennifer

AU - Raney, Joshua A.

AU - Meyers, Lindsay

AU - Berg, Alizabeth

AU - Rope, Alan F.

AU - Yetman, Anji T.

AU - Bleyl, Steven B.

AU - Mesley, Rebecca

AU - Bull, David A.

AU - Collins, R. Thomas

AU - Ojeda, Mayra Martinez

AU - Roberts, Amy

AU - Lacro, Ronald

AU - Woerner, Audrey

AU - Stoler, Joan

AU - Bayrak-Toydemir, Pinar

PY - 2015/8/1

Y1 - 2015/8/1

N2 - Aortopathy can be defined as aortic dilation, aneurysm, dissection, and tortuosity. Familial aortopathy may occur secondary to fibrillin-1 (FBN1) mutations in the setting of Marfan syndrome, or may occur as a result of other genetic defects with different, but occasionally overlapping, phenotypes. Because of the phenotypic overlap and genetic heterogeneity of disorders featuring aortopathy, we developed a next generation sequencing (NGS) assay and comparative genomic hybridization (CGH) array to detect mutations in 10 genes that cause thoracic aortic aneurysms (TAAs). Here, we report on the clinical and molecular findings in 175 individuals submitted for aortopathy panel testing at ARUP laboratories. Ten genes associated with heritable aortopathies were targeted using hybridization capture prior to sequencing. NGS results were analyzed, and variants were confirmed using Sanger sequencing. Array CGH was used to detect copy-number variation. Of 175 individuals, 18 had a pathogenic mutation and 32 had a variant of uncertain significance (VUS). Most pathogenic mutations (72%) were identified in FBN1. A novel large SMAD3 duplication and FBN1 deletion were identified. Over half who had TAAs or other aortic involvement tested negative for a mutation, suggesting that additional aortopathy genes exist. We anticipate that the clinical sensitivity of at least 10.3% will rise with VUS reclassification and as additional genes are identified and included in the panel. The aortopathy NGS panel aids in the timely molecular diagnosis of individuals with disorders featuring aortopathy and guides proper treatment.

AB - Aortopathy can be defined as aortic dilation, aneurysm, dissection, and tortuosity. Familial aortopathy may occur secondary to fibrillin-1 (FBN1) mutations in the setting of Marfan syndrome, or may occur as a result of other genetic defects with different, but occasionally overlapping, phenotypes. Because of the phenotypic overlap and genetic heterogeneity of disorders featuring aortopathy, we developed a next generation sequencing (NGS) assay and comparative genomic hybridization (CGH) array to detect mutations in 10 genes that cause thoracic aortic aneurysms (TAAs). Here, we report on the clinical and molecular findings in 175 individuals submitted for aortopathy panel testing at ARUP laboratories. Ten genes associated with heritable aortopathies were targeted using hybridization capture prior to sequencing. NGS results were analyzed, and variants were confirmed using Sanger sequencing. Array CGH was used to detect copy-number variation. Of 175 individuals, 18 had a pathogenic mutation and 32 had a variant of uncertain significance (VUS). Most pathogenic mutations (72%) were identified in FBN1. A novel large SMAD3 duplication and FBN1 deletion were identified. Over half who had TAAs or other aortic involvement tested negative for a mutation, suggesting that additional aortopathy genes exist. We anticipate that the clinical sensitivity of at least 10.3% will rise with VUS reclassification and as additional genes are identified and included in the panel. The aortopathy NGS panel aids in the timely molecular diagnosis of individuals with disorders featuring aortopathy and guides proper treatment.

KW - Aorta

KW - Aortic aneurysm

KW - Diagnosis

KW - Dilation

KW - Dissection

KW - Ductus arteriosus

KW - Marfan syndrome

UR - http://www.scopus.com/inward/record.url?scp=84937977490&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84937977490&partnerID=8YFLogxK

U2 - 10.1002/ajmg.a.37085

DO - 10.1002/ajmg.a.37085

M3 - Article

C2 - 25944730

AN - SCOPUS:84937977490

VL - 167

SP - 1747

EP - 1757

JO - American Journal of Medical Genetics, Part A

JF - American Journal of Medical Genetics, Part A

SN - 1552-4825

IS - 8

ER -