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ADAMTS19-associated heart valve defects: Novel genetic variants consolidating a recognizable cardiac phenotype

Salam Massadeh1,2, Amal Alhashem3,4, Ingrid M B H van de Laar5

  • 1Department of Developmental Medicine, King Abdullah International Medical Research Center, King Saud Bin Abdulaziz University for Health Sciences, King Abdulaziz Medical City, Ministry of National Guard Health Affairs, Riyadh, Saudi Arabia.

Clinical Genetics
|April 24, 2020
PubMed

Insights

Genetic variants in ADAMTS19 cause autosomal recessive heart valve disease (HVD), affecting aortic and pulmonary valves. Testing is recommended for patients with valve abnormalities and subaortic membrane.

Area of Science:

  • Genetics
  • Cardiology
  • Molecular Biology

Background:

  • ADAMTS19 was recently identified as a novel gene linked to heart valve disease (HVD).
  • Autosomal recessive inheritance patterns are observed in affected families.
  • The primary affected valves are the aortic and pulmonary valves.

Purpose of the Study:

  • To identify and characterize novel loss-of-function (LoF) variants in ADAMTS19.
  • To delineate the cardiac phenotype associated with ADAMTS19 mutations.
  • To establish ADAMTS19 as a causative gene for a specific form of HVD.

Main Methods:

  • Exome sequencing was utilized to identify patients with ADAMTS19 variants.
  • Analysis of a patient data repository (CentoMD) aided variant discovery.
  • SNP array homozygosity was used to identify a third affected family.

Main Results:

  • Three novel LoF variants in ADAMTS19 were identified in six patients across three families.
  • All patients exhibited aortic/pulmonary valve anomalies, including thickening, stenosis, and insufficiency.
  • Subaortic membrane was observed in three patients, suggesting a link between ADAMTS19 and discrete subaortic stenosis.

Conclusions:

  • Biallelic LoF variants in ADAMTS19 cause a distinct and recognizable cardiac phenotype.
  • ADAMTS19 genetic testing should be considered in patients with multiple semilunar valve abnormalities, especially with subaortic membrane.
  • Further screening is needed to determine the prevalence of ADAMTS19-related HVD phenotypes.

Keywords:
ADAMTS19aortic valve stenosispulmonary stenosissubaortic membrane

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