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, 26 (12), 1759-1772

Association of Modifiers and Other Genetic Factors Explain Marfan Syndrome Clinical Variability

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Association of Modifiers and Other Genetic Factors Explain Marfan Syndrome Clinical Variability

Melodie Aubart et al. Eur J Hum Genet.

Abstract

Marfan syndrome (MFS) is a rare autosomal dominant connective tissue disorder related to variants in the FBN1 gene. Prognosis is related to aortic risk of dissection following aneurysm. MFS clinical variability is notable, for age of onset as well as severity and number of clinical manifestations. To identify genetic modifiers, we combined genome-wide approaches in 1070 clinically well-characterized FBN1 disease-causing variant carriers: (1) an FBN1 eQTL analysis in 80 fibroblasts of FBN1 stop variant carriers, (2) a linkage analysis, (3) a kinship matrix association study in 14 clinically concordant and discordant sib-pairs, (4) a genome-wide association study and (5) a whole exome sequencing in 98 extreme phenotype samples.Three genetic mechanisms of variability were found. A new genotype/phenotype correlation with an excess of loss-of-cysteine variants (P = 0.004) in severely affected subjects. A second pathogenic event in another thoracic aortic aneurysm gene or the COL4A1 gene (known to be involved in cerebral aneurysm) was found in nine individuals. A polygenic model involving at least nine modifier loci (named gMod-M1-9) was observed through cross-mapping of results. Notably, gMod-M2 which co-localizes with PRKG1, in which activating variants have already been described in thoracic aortic aneurysm, and gMod-M3 co-localized with a metalloprotease (proteins of extra-cellular matrix regulation) cluster. Our results represent a major advance in understanding the complex genetic architecture of MFS and provide the first steps toward prediction of clinical evolution.

Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

Fig. 1
Fig. 1
Study design. Three different samples (skin fibroblasts, EPS and sibpairs) were studied by five different approaches (eQTL, WES, GWAS, linkage analysis, kinship matrix GWAS). Cross mapping of results from the five approaches revealed modifier loci while WES showed rare coding variants in known TAA genes
Fig. 2
Fig. 2
FBN1 eQTL Results, focus on chromosome 11. a FBN1 expression was studied in skin fibroblasts of 80 FBN1 variant-carriers and associated with their genotyping array results in an eQTL study. On the Manhattan Plot, red line represents the significant threshold at 8 × 10−8, blue line represents P-value 1 × 10−5. One SNP had significant P-value (rs11212346), with three others SNPs (rs12294839, rs11212330, rs7946302) in linkage disequilibrium (LD). LD is determined according to R2 in Haploview (Black squares correspond to R2 = 100%). b Expression of FBN1 in skin fibroblasts of FBN1 variant-carriers according to rs11212346 genotype (boxplot: box from first to third quartile shift by the median, extreme lines showing the highest and lowest value, except if they are superior to a default range of 1.5 interquartile)
Fig. 3
Fig. 3
Examples of segregation of rare modifier variants. a Segregation of a SMAD3 rare variant in a family with a FBN1 de novo variant-carrier. Individual III-1 is the proband of the family with a clinical diagnosis of MFS (bilateral ectopia lentis with surgery at 13 y.o., severe and early-onset TAA with preventive surgery at 16 y.o., MFS facial features, cleft palate, pectus carinatum, arachnodactyly, dolichostenomelia, hypermobility with Beighton score of 9/9, pes planus, 30° scoliosis, spondylolisthesis, dural ectasia, striae) and osteoarthritis features (early-onset osteophytosis at 30 y.o. and genu valgum surgery at 10 y.o.). His mother, individual III-2, has no ectopia lentis, no TAA but has severe lumbar and shoulder ostéo-arthritis and medical history of disc surgery. Sudden death of unknown origin occurred at 55 y.o. in individual II-1. Individual III-4 is an obligate carrier with no clinical information available but her daughter (IV-3) has pectus excavatum, scoliosis less than 20°, hand (fingers and wrist) pain, medical history of Scheuermann disease but no TAA. Individual III-6 has a medical history of surgery for hernia, hypermobility, cleft palate and striae. Individual II-7 has wrist and leg pains without MFS symptoms. Abdominal aortic aneurysm surgery has been performed in individual III-9 at 50 y.o. This individual has also a TAA with an aortic root measured at 49 mm at Valsalva level by CT-scan and cardiac ultrasound (+3DS), tortuosity of carotid and vertebral arteries, pectus carinatum, spinal osteoarthritis, lumbar scoliosis measured at 22°, toe and ankle surgery. This individual has cardiovascular risk factors (smoking and hypercholesterolemia). His daughter (IV-11) has no TAA but a mitral valve prolapse, a pectus excavatum, a 22° scoliosis and medical history of multiple sprains (knee and ankle). Individual III-11 died suddenly at 20 y.o. without diagnosis. b Segregation of a COL4A1 rare variant in a family carrying a FBN1 variant. Individual II-5 had preventive aortic surgery at diagnosis of MFS (43 years-old). Individual III-8 had preventive aortic surgery at 17 years-old. Individuals IV-7 (7 y.o.) and IV-8 (4 y.o.) had aortic roots diameters at 3.1 and 2.7 SD, respectively. Individuals II-1, II-3, III-1, III-3 carry the FBN1 pathogenic variant but not the COL4A1 variant and have clinical features of MFS but no TAA (aortic root diameter <2 SD). Individuals I-1, III-10 and III-11 (carrying the COL4A1 variant but not the FBN1 variant) have no features of MFS and no history of cerebral haemorrhage, but no cerebral investigations have been performed. Individual I-2 had a clinical diagnosis of MFS and died at 44 years-old from internal haemorrhage
Fig. 4
Fig. 4
Graphic representation of crossmapping results. Crossmapped modifier loci are overlayed on a karyotype cartoon. In red are represented the three major modifier loci (crossmapping of three analysis or of two analyses and strong arguments in litterature), in blue the six putative modifier loci (crossmapping in two analyses and no good regional candidate), in yellow excellent candidate genes in a region found in only one analysis, in green genes in which convincing rare coding variants have been found in EPS
Fig. 5
Fig. 5
Modifier regions identified by cross-mapping of genome-wide strategies. a gMod-M1; b gMod-M2; c gMod-M3. For each figure, upper panel shows regional results for eQTL and/or association studies from LocusZoom (http://locuszoom.sph.umich.edu). Genome build and LD population are from Hg19/1000Genomes (Nov 2014 EUR). Each point represents the nominal P-value (left y axis). SNPs are colored according to their pairwise correlation (r2) with the major regional SNP (rs with purple circle). SNPs with missing LD information are shown in grey. Overlaid are recombination rates (right y axis) represented as blue lines. Middle panel provides location of regional genes with respect to upper panel coordinates. The best candidate gene(s) are highlighted. Lower panel shows results of regional linkage analysis in sibpairs: black curve represents hLod-score (left y axis), blue line represents the Hlod 1.5 threshold; red curve represents ALPHA (heterogeneity) (right y axis)
Fig. 5
Fig. 5
Modifier regions identified by cross-mapping of genome-wide strategies. a gMod-M1; b gMod-M2; c gMod-M3. For each figure, upper panel shows regional results for eQTL and/or association studies from LocusZoom (http://locuszoom.sph.umich.edu). Genome build and LD population are from Hg19/1000Genomes (Nov 2014 EUR). Each point represents the nominal P-value (left y axis). SNPs are colored according to their pairwise correlation (r2) with the major regional SNP (rs with purple circle). SNPs with missing LD information are shown in grey. Overlaid are recombination rates (right y axis) represented as blue lines. Middle panel provides location of regional genes with respect to upper panel coordinates. The best candidate gene(s) are highlighted. Lower panel shows results of regional linkage analysis in sibpairs: black curve represents hLod-score (left y axis), blue line represents the Hlod 1.5 threshold; red curve represents ALPHA (heterogeneity) (right y axis)

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