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(Circulation. 2005;112:200-206.)
© 2005 American Heart Association, Inc.

Genetics

Mapping of Familial Thoracic Aortic Aneurysm/Dissection With Patent Ductus Arteriosus to 16p12.2–p13.13

Philippe Khau Van Kien, MD^*; Flavie Mathieu, PhD^*; Limin Zhu, MD; Alain Lalande, PhD; Christine Betard, PhD; Mark Lathrop, MD, PhD; François Brunotte, MD, PhD; Jean-Eric Wolf, MD, PhD; Xavier Jeunemaitre, MD, PhD

From INSERM U36 and Collège de France; Département de Génétique, Hôpital Européen Georges Pompidou, Assistance Publique, Hôpitaux de Paris; and Faculté de Médecine Paris-Descartes, Paris (P.K.V.K., F.M., L.Z., K.J.); Laboratoire de Pharmacologie et de Physiopathologie Cardiovasculaire Expérimentale, CHU Dijon, and Université de Bourgogne, Dijon (P.K.V.K., F.B., J.-E.W.); Service de Cardiologie II (P.K.V.K., J.-E.W.) and Centre d’IRM (A.L., F.B.), CHU Dijon, Dijon; and Centre National de Génotypage, Evry (C.B., M.L.), France.

Correspondence to Xavier Jeunemaitre, MD, PhD, Collège de France, INSERM U36, 11, Place Marcelin Berthelot, 75005 Paris, France. E-mail xavier.jeunemaitre{at}college-de-france.fr or xavier.jeunemaitre@egp.aphp.fr

Received September 12, 2004; revision received March 8, 2005; accepted March 30, 2005.

	Abstract

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Background— Three loci have been shown to be responsible for nonsyndromic familial thoracic aortic aneurysms (TAAs) and aortic dissections (ADs). We recently described a large family in which TAA/AD associates with patent ductus arteriosus (PDA) and provided genetic arguments for a unique pathophysiological entity.

Methods and Results— Genome-wide scan was performed in 40 subjects belonging to 3 generations in this large pedigree. Using the 7 TAA/AD cases as affected, we observed positive 2-point LOD scores on adjacent markers at chromosome 16p, with a maximum LOD score value of 2.73 at =0, a value that increased to 3.56 when 5 PDA cases were included. Multipoint linkage analysis yielded a maximum LOD score of 4.14 in the vicinity of marker D16S3103. Fine mapping allowed the observation of recombinant haplotypes that delimited a critical 20-cM interval at 16p12.2-p13.13. Automatic determination of aortic compliance with cine MRI showed that all subjects bearing the disease haplotype, even asymptomatic, displayed a very low level of aortic compliance and distensibility. Aortic stiffness was strongly associated with disease haplotype with a marked effect of age, indicating subclinical and early manifestation of the disease.

Conclusions— Genetic analysis of this family identified a unique locus responsible for both TAA/AD and PDA at chromosome 16p12.2-p13.13 with aortic stiffness as an early hallmark of the disease. TAA/AD with PDA is a new monogenic entity among the genetically heterogeneous group of TAA/AD disease.

Key Words: aneurysm • aorta • ductus arteriosus • genetics • mapping

	Introduction

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Among thoracic aortic aneurysm (TAA) and/or aortic dissection (AD) cases, 15% to 20% may be familial.¹ Familial clustering of TAA/AD, however, is complex and heterogeneous. In addition to the classic mendelian connective tissue disorders such as Marfan or Ehlers-Danlos vascular-type syndromes,^2–4 several loci have been associated with nonsyndromic familial TAA/AD, namely TAAD1, TAAD2, and FAA1, which map to 5q13–q14, 3p24–p25, and 11q23.2–q24, respectively.^5–7 Identification of the causative genes should lead to new insights into the underlying mechanisms and to the detection of at-risk subjects who could benefit from early specific medical care.

We recently described the large 3-generation French "Bourgogne" family in which TAA/AD, patent ductus arteriosus (PDA), or both occurred and provided genetic arguments for a particular entity not linked to the previously described loci.⁸ To the best of our knowledge, only 1 American and 1 Canadian family have been reported that may also have this apparently rare disorder.^9,10

Here, we report on the identification of a single locus at 16p12.1–p13.2 that is responsible for this aortic disease. In addition, we demonstrate its association with a marked aortic stiffness, an abnormality that occurs even in nonsymptomatic subjects bearing the disease haplotype.

	Methods

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Subjects
The clinical description of the Bourgogne family (Supplemental Figure in the online-only Data Supplement) has been published.⁸ For the genome scan analysis, 40 first-degree nonconsanguineous relatives from 3 generations and 9 unrelated spouses were enrolled in this study after giving written consent form. Among these 40 subjects, 28 were investigated with cine MRI after determination of their aortic compliance and distensibility. Subsequently, 29 nonsymptomatic additional relatives were also investigated for the haplotype status (total, 69 subjects) and 20 for cine MRI measurements (total, 48 subjects). The study was approved by the local ethics committee (Comité Consultatif de Protection des Personnes dans la Recherche Biomédicale de Bourgogne No. 2000/15, 00/03/16) and the French Ministry of Health.

Procedures
Genome-Wide Genotyping
Genomic DNA was isolated from peripheral blood obtained from all subjects with classic methods. The whole-genome scan was performed by the Centre National de Génotypage with 382 well-defined highly polymorphic microsatellite markers distributed with an average spacing of 10 cM (ABI Prism Linkage Mapping Set 2, version 2.5, Applied Biosystems).

Linkage Analysis
MLINK from LINKAGE software package (version 5.2) was used for 2-point linkage analysis.¹¹ Classic affected-only-pedigree-members bipoint linkage analyses were performed under a dominant model of inheritance shown by segregation analysis, as described previously.⁸ Subjects were classified according to 2 phenotypes: First, TAA/AD cases only were considered affected, with others classified as unknown status; second, TAA/AD and PDA cases were considered affected, with others classified as unknown. For the first analysis, 7 TAA/AD (2 subjects with both TAA/AD and PDA) from 3 generations were considered. The second linkage analysis also included 5 PDA cases and was only performed for markers belonging to chromosome 16. Multipoint analysis was performed with the GENEHUNTER2.1 package.¹²

Parameters of Linkage Analysis
Allele frequencies for each of the 382 markers were estimated with the FBAT program¹³ from a sample of 70 white French nuclear families (as part of a genome-wide scan for loci predisposing to blood pressure salt sensitivity in hypertensive sibling pairs, Mathieu F. et al, personal data). Allele frequencies were thus compared with those estimated for unrelated subjects on the pedigree (ie, spouses); consistent results were obtained. The phenocopy rate was fixed at 4 per 100 000 for TAA/AD (average incidence in general population).^14,15 To account for the likely age-dependent penetrance of the disease,¹⁶ asymptomatic subjects were classified into 3 liability age classes, with empirically penetrance levels set as follows: 0% for those <20 years of age; 40% for those between 20 and 50 years of age, and 80% for those >50 years of age for TAA/AD. When including PDA cases in linkage analysis, we defined a supplemental liability class with a phenocopy rate fixed at 1 per 2000¹⁷ and a penetrance rate of 90%.

Refine Mapping and Haplotype Analysis
Sixteen markers within the 16p12–p13 region were used to refine mapping. Ten belonged to the ABI PRISM Linkage Mapping Set version 2.5; the remaining 6 markers (D16S519, D16S3035, D16S420, D16S3093, D16S3022, D16S3080) were selected to be evenly spaced within the critical region (http://research.marshfieldclinic.org/genetics/). GeneScan version 3.7 (ABI) and Genotyper version 3.7 (ABI) were used for gel analysis and genotype assignment, respectively.

Analysis of Candidate Genes
Three positional genes that were confined at the disease locus were analyzed: NOMO1 encoding the NODAL modulator 1 protein (NM_014287) that was previously called PM5,^18,19 ABCC6 encoding ATP-binding cassette subfamily C member 6 (NM_001171.2),^20,21 and BFAR (bifunctional apoptosis regulator) encoding the bifunctional apoptosis regulator (NM_016561).²² Direct sequencing with the Sanger method (BigDye Terminator Cycle Sequencing Kit, Applied Biosystems) was performed to search for mutation. For the NOMO1 gene, the entire cDNA was sequenced after reverse transcription from RNA extracted from cultured skin fibroblasts. For the ABCC6 and BFAR genes, all the exons were sequenced after amplification with polymerase chain reaction from genomic DNA. Intron-based, exon-specific primers were designed according to the genomic sequence (available on request). The Sequencher 4.0.5 program (Gene Codes Corp) was used to identify differences between sequences. For each gene, we analyzed peripheral DNA from 2 affected subjects carrying the disease haplotype (1 with TAA, 1 with PDA). As controls, we used DNA from 1 unaffected individual of the family not carrying the disease haplotype and from 1 unrelated white normal volunteer.

Automatic Determination of Aortic Compliance With Cine MRI
Aortic compliance was analyzed in 48 subjects of the French Bourgogne kindred (28 subjects among the 40 genotyped for genome-wide linkage analysis and 20 additional relatives). It was measured by MRI with automatic detection of the contour of the aorta over the whole cardiac cycle as previously described.²³ Ascending aorta was imaged in the transverse plane at the level of the pulmonary trunk with a cine MRI sequence (ECG-gated cine FISP sequence) with a repetition time of 15 milliseconds. Forty to 60 images of a single slice were acquired, thereby covering the whole cardiac cycle. Cross-sectional area of the aorta was computed with an automatic contouring method, and a surface-versus-time curve was obtained for each patient. Compliance (C in mm²/mm Hg) and aortic distensibility (D in mm Hg^–1) of the ascending aorta were defined as follows: C=S/P and D=S/(PxSmin) respectively, where S is aortic surface (mm²) and P is blood pressure (mm Hg) as described elsewhere.^23,24

Statistical Analysis of Aortic Compliance and Distensibility
Values of aortic compliance and aortic distensibility in subjects without the disease haplotype (H–), affected subjects with TAA/AD or PDA (H+, symptomatic), and asymptomatic carriers of the disease haplotype (H+, asymptomatic) were compared by use of a classic ANOVA. Similar significant results were obtained with the nonparametric Mann-Whitney test. Statview statistical software (release 6.0, Abacus Concept) was used for statistical analysis. Data are expressed as mean and SD. A value of P<0.05 was considered significant.

	Results

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Genome-Wide Screen and Linkage Analysis
Results of the genome-wide linkage scan are indicated in Figure 1. In the first analysis in which only TAA/AD cases were considered affected, LOD scores 1.5 were detected for several adjacent markers on chromosome 16, with a maximum value of 2.73 at =0 for marker D16S3068 (the Table). No other suggestive chromosomal region was detected. If the 5 PDA cases are considered affected, stronger values were observed at this region, with a maximum LOD score of 3.56 for marker D16S3075 (the Table and Figure 1). Multipoint analysis showed a peak LOD score of 4.14 near marker D16S3103. Consequently, the linkage analysis provided evidence suggestive of linkage for the TAA/AD only status and significant evidence of linkage when for TAA/AD and PDA status according to the standard thresholds proposed by Lander and Kruglyak.²⁵

View larger version (40K): [in this window] [in a new window]   Figure 1. Results of genome-wide scan in Bourgogne family. Blue curves correspond to results of bipoint linkage analysis obtained with TAA/AD affected–only model. Red curves correspond to results obtained TAA/AD and PDA subjects are considered affected. Only in 16p region were significant LOD scores obtained.

View this table: [in this window] [in a new window]   Bipoint Linkage Analysis at Chromosome 16

When pedigrees ascertained for a disease contain founders with unknown marker phenotypes, misspecification of the allele frequencies of the marker locus might lead to an increased rate of false-positive linkage findings.²⁶ To test for the robustness of our linkage results, linkage analyses were repeated with allele frequencies of 1/n. This resulted in a loss of statistical significance for the 2-point analyses, which no longer established linkage. For the D16S3075 marker, the LOD score was equal to 1.19 and reached 2.54 when PDA cases were included. The multipoint analysis, however, continued to detect significant linkage, with a maximal LOD score of 3.88.

Fine Mapping and Haplotype Analysis
Sixteen microsatellite markers allowed the observation of 2 recombinant haplotypes that delimited a critical interval to a 20-cM region (sex-averaged) bordered by the centromeric marker D16S519 and the telomeric marker D16S403 (http://research.marshfieldclinic.org/genetics/). This recombinant region was shared by all the 12 subjects with TAA/AD or PDA. Among them, 2 other crossovers (subjects III-1 and IV-5) were observed close to each boundary of the critical interval. Thus, a unique genetic locus was responsible for both TAA/AD and PDA (Figure 2 and online-only Data Supplement Figure).

View larger version (30K): [in this window] [in a new window]   Figure 2. Haplotype analysis at disease locus. Top, Simplified pedigree of Bourgogne family. For simplicity, only data concerning symptomatic TAA/AD (black solid symbols) or PDA (gray solid symbols) subjects are represented. Genotypes for TAA/AD and PDA locus microsatellites are shown below. TAA/AD with PDA disease haplotype is boxed. Bottom, Critical TAA/AD or PDA interval. It is defined by 2 critical recombination events (subjects IV-1 and IV-5). Critical interval is closely surrounded by 2 other crossovers (subjects III-1 and IV-5).

Among the remaining 57 subjects of this large family, haplotype analysis led us to identify 9 carriers of the disease haplotype without TAA/AD or PDA, 33 noncarriers, and 15 subjects with a recombinant haplotype. Consequently, the overall observed penetrance of TAA/AD or PDA disease could be estimated at 57%. If TAA/AD and PDA were separated, the observed penetrance for the TAA/AD trait could be estimated to be 0% at age <20 years (0 affected, 7 asymptomatic), 43% at age between 20 and 50 years (3 subjects affected, 5 asymptomatic), and 66% after 50 years of age (4 affected, 2 asymptomatic). For PDA, the observed penetrance of 33% (7 PDAs for a total of 21 carriers) has to be taken even more cautiously because most of the children of the family have not been systematically explored and because PDA can be transient and asymptomatic.

Automatic Determination of Aortic Compliance With Cine MRI
We hypothesized that asymptomatic subjects bearing the disease haplotype could display abnormalities in aortic compliance or distensibility. Indeed, aortic MRI performed in the first subjects showed a strong decrease in the amplitude of variation of the aortic cross-sectional area during a cardiac cycle (Figure 3a). When all individuals were compared according to their phenotypic and haplotypic status, a marked reduction in aortic compliance and distensibility was observed in all haplotype-positive individuals, both symptomatic and asymptomatic (Figure 3b and 3c). A marked effect of age was present in subjects with normal haplotype but not in the group bearing the disease haplotype. The effect of the genotype was particularly strong in young adult subjects (Figure 3d through 3f). In individuals <35 years of age (symptomatic or not), aortic compliance values did not overlap between carriers (n=7; range, 0.43 to 1.28 mm²/mm Hg; mean, 0.82 mm²/mm Hg) and noncarriers (n=19; range, 1.32 to 2.96 mm²/mm Hg; mean, 2.10 mm²/mm Hg) of the disease haplotype. Thus, altered aortic compliance and distensibility that result in aortic stiffness were an early hallmark of the disease.

View larger version (17K): [in this window] [in a new window]   Figure 3. Genotype-phenotype relationships. a, Changes in cross-sectional area (S) of ascending aorta during cardiac cycle. Gray line corresponds to typical result obtained in wild-type subject (H–); black line, that obtained in subject without TAA/AD or PDA but who exhibits disease haplotype (H+). H+ subject had markedly reduced systolic dilatation of aorta (S=29 vs 148 mm2 for subject H–) and subsequent differences in aortic compliance (0.45 vs 2.96 mm2/mm Hg, respectively). Both subjects were similar for variables known to influence aortic compliance: age (25 versus 24 years), body surface area (1.72 versus 1.74 m2), blood pressure (123/59 versus 116/66 mm Hg), absence of tobacco exposure, dyslipidemia, and diabetes mellitus. b, c, Aortic compliance (b) or distensibility (c) values in subjects without disease haplotype (H–; open symbols), affected subjects with TAA/AD or PDA (H+, symptomatic; solid symbols), and asymptomatic carriers of disease haplotype (H+, asymptomatic; gray symbols). For each group, means and SDs are indicated to right of individual values. Groups did not differ in sex ratio, age, and blood pressure. d–f, Marked effect of age with decreased of aortic compliance (d) or distensibility (e) was observed in subjects without disease haplotype (H– subjects; open symbols). This was not the case in subjects harboring disease haplotype (H+), symptomatic (TAA/AD and/or PDA; solid symbols) or not (gray symbols). In this last group, subjects <35 years of age (f) had such marked decrease in aortic compliance that values did not overlap between carriers (n=7; range, 0.43 to 1.28 mm2/mm Hg; mean, 0.82 mm2/mm Hg) and noncarriers (n=19; range, 1.32 to 2.96 mm2/mm Hg; mean, 2.10 mm2/mm Hg) of disease haplotype. Limit of 1.3 (dotted line) seems to differentiate carriers and noncarriers of haplotype susceptibility.

Candidate Gene Analysis
A large number of genes (86 known or predicted genes on Human May 2004 assembly, http://genome.ucsc.edu/) are contained within this region. As a first effort to identify the causative gene, we analyzed 3 attractive positional candidates. Negative results were obtained on NOMO1, encoding a novel protein that shares DNA homology with conserved regions of the collagenase gene family.¹⁹ Several single nucleotide polymorphisms (11 silent, 2 coding) were observed on the NOMO1 cDNA from the 2 affected and the 2 control subjects. Presence of these variants in different parts of the cDNA at the heterozygous state excluded a microdeletion or a nonsense mutation with mRNA decay. The ABCC6 gene was also an attractive candidate because it causes pseudoxathoma elasticum, a disease with arterial complications.^20,21 However, we did not observe any mutation but 3 heterozygous SNPs (c.1864TC, c.1913CG, c.1919CA) in both affected and unaffected subjects. Finally, no mutation but 1 synonymous SNP (c.1365AG) was observed on BFAR, a gene thought to be at the intersection between the extrinsic (ie, TGF-ß receptors) and intrinsic (ie, BCL-2 family protein) pathways for induction of apoptosis,²² a mechanism known to occur during PDA closure²⁷ and Marfan syndrome.²⁸

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
We chose a 2-step approach with first a stringent phenotype (TAA/AD alone) and then a larger one (TAA/AD and/or PDA) as a positive disease status. Initially, positive LOD scores were obtained with several adjacent markers at chromosome 16 using 7 TAA/AD cases on 3 generations. No other suggestive region was observed, in agreement with our previous segregation and candidate gene/loci analysis.⁸ Using the 5 PDA cases as additional affected subjects, we obtained significant positive bipoint and multipoint LOD scores for the same 16p12.2–p13.13 region, which definitely assessed a true linkage.²⁹ Thus, the genetic analysis of this family identified a unique genetic locus responsible for both TAA/AD and PDA, illustrating the interest in deciphering particular mendelian traits among a more complex group of heterogeneous diseases. The size of the Bourgogne family allowed this finding without genetic heterogeneity.

Until now, TAA/AD with PDA seemed to be a rare recognizable entity, described only in an American family and possibly a Canadian family.^9,10 In our study, 6 of 11 PDA cases were first discovered by our echo Doppler screening in nonsymptomatic subjects without auscultatory signs.⁸ These results provide argument for a systematic search of PDA when screening aortic abnormalities in familial or apparently sporadic TAA/AD cases. It is interesting to note that in the case of TAA/AD, a periodic imaging of the aortic root is recommended that does not allow identification of PDA.^30,31 Consequently, the proportion of this recognizable entity among the genetically heterogeneous familial TAA/AD may be underestimated. Personal or family history of either TAA/AD or PDA should indicate the possibility of this particular entity and consequently suggest an appropriate screening in relatives.

The identification of the locus involved in the Bourgogne family gave the possibility of an individual indirect genetic test. Whereas 33 of the 69 subjects did not carry the disease haplotype, 9 asymptomatic subjects carried the at-risk haplotype. Investigation performed after written informed consent to our research protocol showed the absence of PDA or TAA in these individuals. To obtain further insight into the possibility of subclinical vascular abnormalities, aortic compliance was measured in 48 individuals (42 asymptomatic, 6 TAA/PDA) with MRI, a very precise, noninvasive technique.²³ Our results show that aortic stiffness is an early hallmark of the disease, occurring in all subjects harboring the disease haplotype compared with their normal relatives.

The severity of the disease in some members of the family,⁸ the possibility of an indirect genetic diagnosis in relatives, and the strong decrease in aortic distensibility in positive subjects argue for the indication of a lifelong ß-blockade therapy to prevent TAA/AD in that particular disease. This treatment is now recommended for prevention of aortic dissection in inherited diseases such as Marfan syndrome, Ehlers-Danlos syndrome, and annuloaortic ectasia.³¹ It is interesting to note that aortic stiffness has been shown to be an early and independent predictor of TAA/AD development in Marfan disease^24,32 and is reduced by ß-blockade therapy. MRI is well suited to detect these changes.³³ In that regard, noninvasive measurement of aortic stiffness derivatives such as aortic compliance and distensibility should help to assess and monitor the individual risk of aortic dilatation and rupture.²⁴

An accurate genetic test will need identification of the disease gene. Until now, we restricted the locus to a 20-cM interval, defined proximally by marker D16S519 and distally by marker D16S403. Among the 15 subjects harboring a recombinant haplotype, only 4 were investigated with cine MRI to allow determination of their aortic compliance or distensibility. Among them, a 30-year-old woman had a normal aortic compliance. Taking a complete penetrance of the disease on this biomarker would define the interval more distally by marker D16S3041 and thus restrict it to 18 cM. Values obtained for the 3 other individuals were either intermediate or difficult to interpret because of age and associated diseases and treatment. It is therefore difficult to restrict the locus on the sole assumption of a complete penetrance of the disease gene on aortic compliance and on the value observed in 1 individual. MRI investigation in other individuals with recombinant haplotypes should help to refine mapping and to identify the causative gene.

In conclusion, identification of TAA/AD causative genetic defects should open avenues to an understanding of the underlying mechanisms thought to be complex and heterogeneous. Recent advances in Marfan disease have brought novel arguments for a targeted treatment of the disease.²⁹ Among the heterogeneous inherited aortic diseases, we provide here arguments for a recognizable entity associating aortic stiffness, TAA/AD, and PDA, which maps to 16p12.2–p13.13. Further analysis may identify its genetic basis and might contribute to promote new strategies for clinical management and treatment of thoracic aortic diseases.

	Acknowledgments

 
Dr Khau Van Kien is supported by the Association de Cardiologie de Bourgogne. Dr Zhu receives support from the Association Claude Bernard. We thank all affected individuals and their families who participated in this study and the clinical researchers of CHU Dijon, the Conseil Régional de Bourgogne, the Fondation pour la Recherche Médicale, the Fondation de France, and the Association Claude Bernard for their support. We thank the technicians of the Department of Genetics of the Hôpital Européen Georges Pompidou for DNA extraction and technical help, as well as Dr Annie Nivelon-Chevallier, Dr Nicolas Salvé, Dr Annie Petit, Dr Arnaud Dellinger, Dr Gaëtan Lesca, Dr Catherine Bonaïti-Pelié, and Pr Michel David for their advice.

	Footnotes

 
*Drs Khau Van Kien and Mathieu contributed equally to this article.

The online-only Data Supplement can be found with this article at http://circ.ahajournals.org/cgi/content/full/CIRCULATIONAHA.104.506345/DC1.

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