Loss of ADAMTS19 causes progressive non-syndromic heart valve disease

Nat Genet. 2020 Jan;52(1):40-47. doi: 10.1038/s41588-019-0536-2. Epub 2019 Dec 16.


Valvular heart disease is observed in approximately 2% of the general population1. Although the initial observation is often localized (for example, to the aortic or mitral valve), disease manifestations are regularly observed in the other valves and patients frequently require surgery. Despite the high frequency of heart valve disease, only a handful of genes have so far been identified as the monogenic causes of disease2-7. Here we identify two consanguineous families, each with two affected family members presenting with progressive heart valve disease early in life. Whole-exome sequencing revealed homozygous, truncating nonsense alleles in ADAMTS19 in all four affected individuals. Homozygous knockout mice for Adamts19 show aortic valve dysfunction, recapitulating aspects of the human phenotype. Expression analysis using a lacZ reporter and single-cell RNA sequencing highlight Adamts19 as a novel marker for valvular interstitial cells; inference of gene regulatory networks in valvular interstitial cells positions Adamts19 in a highly discriminatory network driven by the transcription factor lymphoid enhancer-binding factor 1 downstream of the Wnt signaling pathway. Upregulation of endocardial Krüppel-like factor 2 in Adamts19 knockout mice precedes hemodynamic perturbation, showing that a tight balance in the Wnt-Adamts19-Klf2 axis is required for proper valve maturation and maintenance.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADAMTS Proteins / genetics
  • ADAMTS Proteins / metabolism*
  • Animals
  • Family
  • Female
  • Gene Expression Regulation, Developmental*
  • Heart Valve Diseases / etiology*
  • Heart Valve Diseases / pathology
  • Humans
  • Kruppel-Like Transcription Factors / genetics
  • Kruppel-Like Transcription Factors / metabolism
  • Male
  • Mice
  • Mice, Knockout
  • Pedigree
  • Single-Cell Analysis
  • Wnt Signaling Pathway


  • KLF2 protein, human
  • Klf2 protein, mouse
  • Kruppel-Like Transcription Factors
  • ADAMTS Proteins
  • ADAMTS19 protein, human
  • Adamts2 protein, mouse