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Abstract

Background

Visceral artery aneurysms (VAAs) can be fatal if ruptured. Although a relatively rare incident, it holds a contemporary mortality rate of approximately 12%. VAAs have multiple possible causes, one of which is genetic predisposition. Here, we present a striking family with seven individuals affected by VAAs, and one individual affected by a visceral artery pseudoaneurysm.

Methods

We exome sequenced the affected family members and the parents of the proband to find a possible underlying genetic defect. As exome sequencing did not reveal any feasible protein-coding variants, we combined whole-genome sequencing of two individuals with linkage analysis to find a plausible non-coding culprit variant. Variants were ranked by the deep learning framework DeepSEA.

Results

Two of seven top-ranking variants, NC_000013.11:g.108154659C>T and NC_000013.11:g.110409638C>T, were found in all VAA-affected individuals, but not in the individual affected by the pseudoaneurysm. The second variant is in a candidate cis-regulatory element in the fourth intron of COL4A2, proximal to COL4A1.

Conclusions

As type IV collagens are essential for the stability and integrity of the vascular basement membrane and involved in vascular disease, we conclude that COL4A1 and COL4A2 are strong candidates for VAA susceptibility genes.

Keywords

Aneurysm COL4A2 COL4A1 genetic susceptibility non-coding variants next-generation sequencing

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References

Sousa

Costa

Mansilha

. Visceral artery aneurysms: review on indications and current treatment strategies. Int Angiol 2019; 38: 381–394.

van Rijn

MJE

Ten Raa

Hendriks

, et al. Visceral aneurysms: old paradigms, new insights?. Best Pract Res Clin Gastroenterol 2017; 31: 97–104.

Pulli

Dorigo

Troisi

, et al. Surgical treatment of visceral artery aneurysms: a 25-year experience. J Vasc Surg 2008; 48: 334–342.

Regus

Lang

. Rupture risk and etiology of visceral artery aneurysms and pseudoaneurysms: a single-center experience. Vasc Endovascular Surg 2016; 50: 10–15.

Lee

Godfrey

Vitale

, et al. Linkage of Marfan syndrome and a phenotypically related disorder to two different fibrillin genes. Nature 1991; 352: 330–334.

Dietz

Cutting

Pyeritz

, et al. Marfan syndrome caused by a recurrent de novo missense mutation in the fibrillin gene. Nature 1991; 352: 337–339.

Maslen

Corson

Maddox

, et al. Partial sequence of a candidate gene for the Marfan syndrome. Nature 1991; 352: 334–337.

Zhang

Ramirez

. Developmental expression of fibrillin genes suggests heterogeneity of extracellular microfibrils. J Cell Biol 1995; 129: 1165–1176.

Superti-Furga

Gugler

Gitzelmann

, et al. Ehlers-Danlos syndrome type IV: a multi-exon deletion in one of the two COL3A1 alleles affecting structure, stability, and processing of type III procollagen. J Biol Chem 1988; 263: 6226–6232.

10.

Mettinger

Ericson

. Fibromuscular dysplasia and the brain. I. Observations on angiographic, clinical and genetic characteristics. Stroke 1982; 13: 46–52.

11.

Pannier-Moreau

Grimbert

Fiquet-Kempf

, et al. Possible familial origin of multifocal renal artery fibromuscular dysplasia. J Hypertens 1997; 15: 1797–1801.

12.

Shukla

Eid

Fish

, et al. Contemporary outcomes of intact and ruptured visceral artery aneurysms. J Vasc Surg 2015; 61: 1442–1447.

13.

Stanley

Thompson

Fry

. Splanchnic artery aneurysms. Arch Surg 1970; 101: 689–697.

14.

Sadat

Dar

Walsh

, et al. Splenic artery aneurysms in pregnancy--a systematic review. Int J Surg 2008; 6: 261–265.

15.

Jeanne

Labelle-Dumais

Jorgensen

, et al. COL4A2 mutations impair COL4A1 and COL4A2 secretion and cause hemorrhagic stroke. Am J Hum Genet 2012; 90: 91–101.

16.

Kuo

Labelle-Dumais

Gould

. COL4A1 and COL4A2 mutations and disease: insights into pathogenic mechanisms and potential therapeutic targets. Hum Mol Genet 2012; 21: R97–R110.

17.

Meuwissen

MEC

Halley

DJJ

Smit

, et al. The expanding phenotype of COL4A1 and COL4A2 mutations: clinical data on 13 newly identified families and a review of the literature. Genet Med 2015; 17: 843–853.

18.

Alavi

Mao

Pawlikowski

, et al. Col4a1 mutations cause progressive retinal neovascular defects and retinopathy. Sci Rep 2016; 6: 18602.

19.

Sadleir

Mandelstam

, et al. A mutation in COL4A2 causes autosomal dominant porencephaly with cataracts. Am J Med Genet A 2016; 170A: 1059–1063.

20.

Jones

Bailey

Murray

, et al. ER stress and basement membrane defects combine to cause glomerular and tubular renal disease resulting from Col4a1 mutations in mice. Dis Model Mech 2016; 9: 165–176.

21.

Guiraud

Migeon

Ferry

, et al. HANAC Col4a1 mutation in mice leads to skeletal muscle alterations due to a primary vascular defect. Am J Pathol 2017; 187: 505–516.

22.

Labelle-Dumais

Schuitema

Hayashi

, et al. COL4A1 mutations cause neuromuscular disease with tissue-specific mechanistic heterogeneity. Am J Hum Genet 2019; 104: 847–860.

23.

Haniel

Welge-Lüssen

Kühn

, et al. Identification and characterization of a novel transcriptional silencer in the human collagen type IV gene COL4A2. J Biol Chem 1995; 270: 11209–11215.

24.

Favor

Gloeckner

Janik

, et al. Type IV procollagen missense mutations associated with defects of the eye, vascular stability, the brain, kidney function and embryonic or postnatal viability in the mouse, Mus musculus: an extension of the Col4a1 allelic series and the identification of the first two Col4a2 mutant alleles. Genetics 2007; 175: 725–736.

25.

Kuo

Labelle-Dumais

Mao

, et al. Allelic heterogeneity contributes to variability in ocular dysgenesis, myopathy and brain malformations caused by Col4a1 and Col4a2 mutations. Hum Mol Genet 2014; 23: 1709–1722.

26.

Abecasis

Cherny

Cookson

, et al. Merlin--rapid analysis of dense genetic maps using sparse gene flow trees. Nat Genet 2002; 30: 97–101.

27.

Kong

Cox

. Allele-sharing models: LOD scores and accurate linkage tests. Am J Hum Genet 1997; 61: 1179–1188.

28.

Katainen

Donner

Cajuso

, et al. Discovery of potential causative mutations in human coding and noncoding genome with the interactive software BasePlayer. Nat Protoc 2018; 13: 2580–2600.

29.

Zhou

Troyanskaya

. Predicting effects of noncoding variants with deep learning-based sequence model. Nat Methods 2015; 12: 931–934.

30.

Marion

Jorgensen

Gould Douglas

. Molecular and genetic analyses of collagen type IV mutant mouse models of spontaneous intracerebral hemorrhage identify mechanisms for stroke prevention. Circulation 2015; 131: 1555–1565.

31.

Rannikmäe

Davies

Thomson

, et al. Common variation in COL4A1/COL4A2 is associated with sporadic cerebral small vessel disease. Neurology 2015; 84: 918–926.

32.

Verbeek

Meuwissen

MEC

Verheijen

, et al. COL4A2 mutation associated with familial porencephaly and small-vessel disease. Eur J Hum Genet 2012; 20: 844–851.

33.

Pollner

Schmidt

Fischer

, et al. Cooperative and competitive interactions of regulatory elements are involved in the control of divergent transcription of human Col4A1 and Col4A2 genes. FEBS Lett 1997; 405: 31–36.

34.

Gould

Phalan

Breedveld

, et al. Mutations in Col4a1 cause perinatal cerebral hemorrhage and porencephaly. Science 2005; 308: 1167–1171.

35.

Gould

Phalan

van Mil

, et al. Role of COL4A1 in small-vessel disease and hemorrhagic stroke. N Engl J Med 2006; 354: 1489–1496.

36.

Plaisier

Gribouval

Alamowitch

, et al. COL4A1 mutations and hereditary angiopathy, nephropathy, aneurysms, and muscle cramps. N Engl J Med 2007; 357: 2687–2695.

37.

Zenteno

Crespí

Buentello-Volante

, et al. Next generation sequencing uncovers a missense mutation in COL4A1 as the cause of familial retinal arteriolar tortuosity. Graefes Arch Clin Exp Ophthalmol 2014; 252: 1789–1794.

38.

Xia

X-Y

Cao

, et al. A novel COL4A1 gene mutation results in autosomal dominant non-syndromic congenital cataract in a Chinese family. BMC Med Genet 2014; 15: 97.

39.

ENCODE Project Consortium . An integrated encyclopedia of DNA elements in the human genome. Nature 2012; 489: 57–74.

40.

Pöschl

Schlötzer-Schrehardt

Brachvogel

, et al. Collagen IV is essential for basement membrane stability but dispensable for initiation of its assembly during early development. Development 2004; 131: 1619–1628.

41.

Jana

Shen

, et al. Extracellular matrix, regional heterogeneity of the aorta, and aortic aneurysm. Exp Mol Med 2019; 51: 1–15.

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Next-generation sequencing in a large pedigree segregating visceral artery aneurysms suggests potential role of COL4A1/COL4A2 in disease etiology

Abstract

Background

Methods

Results

Conclusions

Keywords

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References

Supplementary Material