Exome sequencing in seven families and gene-based association studies indicate genetic heterogeneity and suggest possible candidates for fibromuscular dysplasia

J Hypertens. 2015 Sep;33(9):1802-10; discussion 1810. doi: 10.1097/HJH.0000000000000625.


Background: Fibromuscular dysplasia (FMD) is a nonatherosclerotic vascular disease leading to stenosis, aneurysm and dissection, mainly of renal arteries and carotids. FMD occurs predominantly in women with nearly four out of 1000 prevalence and cause hypertension, renal ischemia or stroke. The pathogenesis of FMD is unknown and a genetic origin is suspected given its demonstrated familial aggregation.

Method: We performed whole exome sequencing (WES) in 16 cases (seven families). Coding variants in 3971 genes were prioritized on frequency (minor allele frequency < 0.01) and in silico predicted functionality.

Results: No gene harbours variants that are shared among all affected members of at least three families. Variants from 16 genes of vascular and connective tissue diseases are excluded as causative in these families. Genes with at least four variants in the 16 patients and vascular genes were followed-up using genotypes from 249 unrelated cases and 689 controls. Gene-based association analyses using SKAT-O shows nominal significant association with multifocal FMD (N = 164) for myosin light chain kinase (MYLK, P = 0.01) previously involved in thoracic aortic aneurysm, obscurin (OBSCN), a sarcomeric protein (P = 0.003), dynein cytoplasmic heavy chain 1 (DYNC2H1, P = 0.02) and RNF213 previously associated with Moyamoya disease (P = 0.01).

Conclusion: Our study indicates genetic heterogeneity and the unlikely existence of a major gene for FMD and excludes the role of several vascular genes in familial FMD. We also suggest four possible candidate genes for multifocal FMD, though these findings need further genetic and functional confirmation. More powerful WES and association studies [e.g. genome-wide association study (GWAS)] will better decipher the genetic basis of FMD.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphatases
  • Aged
  • Calcium-Binding Proteins / genetics*
  • Case-Control Studies
  • Cytoplasmic Dyneins / genetics*
  • Exome
  • Female
  • Fibromuscular Dysplasia / genetics*
  • Genetic Association Studies
  • Genetic Heterogeneity
  • Genotype
  • Humans
  • Middle Aged
  • Myosin-Light-Chain Kinase / genetics*
  • Protein Serine-Threonine Kinases
  • Rho Guanine Nucleotide Exchange Factors / genetics*
  • Sequence Analysis, DNA
  • Ubiquitin-Protein Ligases / genetics*


  • Calcium-Binding Proteins
  • DYNC2H1 protein, human
  • Rho Guanine Nucleotide Exchange Factors
  • RNF213 protein, human
  • Ubiquitin-Protein Ligases
  • OBSCN protein, human
  • Protein Serine-Threonine Kinases
  • MYLK protein, human
  • Myosin-Light-Chain Kinase
  • Adenosine Triphosphatases
  • Cytoplasmic Dyneins