Details of Disease

General Information of Disease (ID: DIS069FB)

• Disease Name: Familial thoracic aortic aneurysm and aortic dissection
• Synonyms: Erdheim cystic medial necrosis of aorta; familial thoracic aortic aneurysm and dissection; annuloaortic ectasia; familial aortic aneurysm; cystic medial necrosis of aorta; familial thoracic aortic aneurysm; familial TAAD; familial thoracic aortic aneurysm and aortic dissection; familial aortic dissection; FTAAD; Erdheim disease
• Definition: A rare genetic vascular disease characterized by the familial occurrence of thoracic aortic aneurysm, dissection or dilatation affecting one or more aortic segments (aortic root, ascending aorta, arch or descending aorta) in the absence of any other associated disease. Depending on the size, location and progression rate of dilatation/dissection, patients may be asymptomatic or may present dyspnea, cough, jaw, neck, chest or back pain, head, neck or upper limb edema, difficulty swallowing, voice hoarseness, pale skin, faint pulse and/or numbness/tingling in limbs. Patients have increased risk of presenting life threatening aortic rupture.
• Disease Hierarchy:
  DISYKSRF: Genetic disease
  DISVS67S: Vascular disease
  DIS069FB: Familial thoracic aortic aneurysm and aortic dissection
• Disease Identifiers:
  MONDO ID: MONDO_0019625
  UMLS CUI: C4707243
  MedGen ID: 1644766
  Orphanet ID: 91387
  SNOMED CT ID: 764965000

Molecular Interaction Atlas (MIA) of This Disease

This Disease Is Related to 25 DTT Molecule(s)

Gene Name	DTT ID	Evidence Level	Mode of Inheritance	REF
BGN	TT0JPVF	Limited	Autosomal dominant	[1]
BGN	TT0JPVF	Limited	Biomarker	[2]
FLNA	TTSTRZY	Limited	X-linked	[1]
FLNA	TTSTRZY	Limited	Biomarker	[3]
HCN4	TTQP04A	Limited	Autosomal dominant	[1]
HCN4	TTQP04A	Limited	Biomarker	[4]
MAT2A	TTSMPXQ	Limited	Biomarker	[5]
NOTCH1	TTB1STW	Limited	Autosomal dominant	[1]
NOTCH1	TTB1STW	Limited	Biomarker	[6]
TGFB3	TTWOMY8	Limited	Biomarker	[7]
TGFB3	TTWOMY8	Supportive	Autosomal dominant	[8]
LOX	TT4E26T	Strong	Autosomal dominant	[1]
LOX	TTQHNAM	Strong	Genetic Variation	[9]
MYLK	TT18ETS	Strong	Autosomal dominant	[1]
MYLK	TT18ETS	Strong	Biomarker	[10]
PRKG1	TT7IZSA	Strong	Autosomal dominant	[1]
PRKG1	TT7IZSA	Strong	Biomarker	[11]
SMAD3	TTHQZV7	Definitive	Autosomal dominant	[1]
SMAD3	TTHQZV7	Definitive	CausalMutation	[9]
TGFB2	TTY9TWO	Definitive	Autosomal dominant	[1]
TGFB2	TTI0KH6	Definitive	Biomarker	[12]
TGFBR1	TTP4520	Definitive	Autosomal dominant	[1]
TGFBR1	TTP4520	Definitive	Genetic Variation	[9]
TGFBR2	TTZE3P7	Definitive	Autosomal dominant	[1]
TGFBR2	TTZE3P7	Definitive	Genetic Variation	[9]

This Disease Is Related to 2 DTP Molecule(s)

Gene Name	DTP ID	Evidence Level	Mode of Inheritance	REF
SLC2A10	DT3BI6S	Limited	Autosomal dominant	[1]
SLC2A10	DT3BI6S	Limited	Biomarker	[13]

This Disease Is Related to 1 DME Molecule(s)

Gene Name	DME ID	Evidence Level	Mode of Inheritance	REF
MAT2A	DE76G8C	Limited	Autosomal dominant	[1]

This Disease Is Related to 29 DOT Molecule(s)

Gene Name	DOT ID	Evidence Level	Mode of Inheritance	REF
BGN	OT3AV6IF	Limited	Autosomal dominant	[1]
ELN	OTFSO7PG	Limited	Genetic Variation	[14]
FBN2	OT3KYJQL	Limited	Autosomal dominant	[1]
FLNA	OTYZ9JXM	Limited	X-linked	[1]
HCN4	OTPH3RRX	Limited	Autosomal dominant	[1]
MAT2A	OTFJMIQR	Limited	Autosomal dominant	[1]
NOTCH1	OTI1WADQ	Limited	Autosomal dominant	[1]
SLC2A10	OTL32QH7	Limited	Autosomal dominant	[1]
HEY2	OTU4J3ZI	Supportive	Autosomal dominant	[15]
SMAD4	OTWQWCKG	Supportive	Autosomal dominant	[16]
TGFB3	OT2LOUQ1	Supportive	Autosomal dominant	[8]
EFEMP2	OT0I2B4J	Moderate	Autosomal recessive	[1]
FOXE3	OTAUDKC1	Moderate	Autosomal dominant	[1]
MFAP5	OT46VXSG	Moderate	Autosomal dominant	[1]
SMAD2	OTC6VB4K	Moderate	Autosomal dominant	[1]
THSD4	OTXDBMDC	Moderate	Autosomal dominant	[17]
LOX	OT1C2HIU	Strong	Autosomal dominant	[1]
MYLK	OT78QB4A	Strong	Autosomal dominant	[1]
PRKG1	OTPAS4LF	Strong	Autosomal dominant	[1]
SRFBP1	OTI8518R	Strong	Genetic Variation	[18]
STAMBPL1	OTI4CYTF	Strong	CausalMutation	[19]
ACTA2	OTEDLG8E	Definitive	Autosomal dominant	[1]
COL3A1	OTT1EMLM	Definitive	Biomarker	[20]
FBN1	OTYCJT63	Definitive	Autosomal dominant	[1]
MYH11	OTVNVWY3	Definitive	Autosomal dominant	[1]
SMAD3	OTNA96MR	Definitive	Autosomal dominant	[1]
TGFB2	OTC0TXEP	Definitive	Autosomal dominant	[1]
TGFBR1	OT40S1SJ	Definitive	Autosomal dominant	[1]
TGFBR2	OT3P7GZP	Definitive	Autosomal dominant	[1]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [2] Loss-of-function mutations in the X-linked biglycan gene cause a severe syndromic form of thoracic aortic aneurysms and dissections. Genet Med. 2017 Apr;19(4):386-395. doi: 10.1038/gim.2016.126. Epub 2016 Sep 15.
• [3] Smooth muscle filamin A is a major determinant of conduit artery structure and function at the adult stage.Pflugers Arch. 2016 Jul;468(7):1151-1160. doi: 10.1007/s00424-016-1813-x. Epub 2016 Mar 29.
• [4] Dilation of the Aorta Ascendens Forms Part of the Clinical Spectrum of HCN4 Mutations.J Am Coll Cardiol. 2016 May 17;67(19):2313-2315. doi: 10.1016/j.jacc.2016.01.086.
• [5] MAT2A mutations predispose individuals to thoracic aortic aneurysms.Am J Hum Genet. 2015 Jan 8;96(1):170-7. doi: 10.1016/j.ajhg.2014.11.015. Epub 2014 Dec 31.
• [6] Cardiovascular malformations caused by NOTCH1 mutations do not keep left: data on 428 probands with left-sided CHD and their families.Genet Med. 2016 Sep;18(9):914-23. doi: 10.1038/gim.2015.193. Epub 2016 Jan 28.
• [7] Mutations in a TGF- ligand, TGFB3, cause syndromic aortic aneurysms and dissections.J Am Coll Cardiol. 2015 Apr 7;65(13):1324-1336. doi: 10.1016/j.jacc.2015.01.040.
• [8] A mutation in TGFB3 associated with a syndrome of low muscle mass, growth retardation, distal arthrogryposis and clinical features overlapping with Marfan and Loeys-Dietz syndrome. Am J Med Genet A. 2013 Aug;161A(8):2040-6. doi: 10.1002/ajmg.a.36056. Epub 2013 Jul 3.
• [9] Next-generation sequencing of 32 genes associated with hereditary aortopathies and related disorders of connective tissue in a cohort of 199 patients.Genet Med. 2019 Aug;21(8):1832-1841. doi: 10.1038/s41436-019-0435-z. Epub 2019 Jan 24.
• [10] Autoregulatory Control of Smooth Muscle Myosin Light Chain Kinase Promoter by Notch Signaling.J Biol Chem. 2016 Feb 5;291(6):2988-99. doi: 10.1074/jbc.M115.679803. Epub 2015 Dec 24.
• [11] PRKG1 and genetic diagnosis of early-onset thoracic aortic disease.Eur J Clin Invest. 2016 Sep;46(9):787-94. doi: 10.1111/eci.12662. Epub 2016 Aug 18.
• [12] A 1-bp duplication in TGFB2 in three family members with a syndromic form of thoracic aortic aneurysm.Eur J Hum Genet. 2014 Jul;22(7):944-8. doi: 10.1038/ejhg.2013.252. Epub 2013 Nov 6.
• [13] Mitochondrial GLUT10 facilitates dehydroascorbic acid import and protects cells against oxidative stress: mechanistic insight into arterial tortuosity syndrome.Hum Mol Genet. 2010 Oct 1;19(19):3721-33. doi: 10.1093/hmg/ddq286. Epub 2010 Jul 16.
• [14] ELN gene triplication responsible for familial supravalvular aortic aneurysm.Cardiol Young. 2015 Apr;25(4):712-7. doi: 10.1017/S1047951114000766. Epub 2014 Jun 16.
• [15] Germline variants in HEY2 functional domains lead to congenital heart defects and thoracic aortic aneurysms. Genet Med. 2021 Jan;23(1):103-110. doi: 10.1038/s41436-020-00939-4. Epub 2020 Aug 21.
• [16] SMAD4 rare variants in individuals and families with thoracic aortic aneurysms and dissections. Eur J Hum Genet. 2019 Jul;27(7):1054-1060. doi: 10.1038/s41431-019-0357-x. Epub 2019 Feb 26.
• [17] Pathogenic variants in THSD4, encoding the ADAMTS-like 6 protein, predispose to inherited thoracic aortic aneurysm. Genet Med. 2021 Jan;23(1):111-122. doi: 10.1038/s41436-020-00947-4. Epub 2020 Aug 28.
• [18] LOX Mutations Predispose to Thoracic Aortic Aneurysms and Dissections. Circ Res. 2016 Mar 18;118(6):928-34. doi: 10.1161/CIRCRESAHA.115.307130. Epub 2016 Jan 12.
• [19] Neonatal stroke and progressive leukoencephalopathy in a child with an ACTA2 mutation.J Child Neurol. 2013 Apr;28(4):531-4. doi: 10.1177/0883073812446631. Epub 2012 Jun 29.
• [20] Performant Mutation Identification Using Targeted Next-Generation Sequencing of 14 Thoracic Aortic Aneurysm Genes.Hum Mutat. 2015 Aug;36(8):808-14. doi: 10.1002/humu.22802. Epub 2015 Jun 13.