Pulmonary hypertension in patients with 9q34.3 microdeletion-associated Kleefstra syndrome

Am J Med Genet A. 2018 Aug;176(8):1773-1777. doi: 10.1002/ajmg.a.38852. Epub 2018 Jul 31.


Kleefstra Syndrome is a rare genetic disorder caused by mutations in EHMT1, Euchromatin Histone Methyl Transferase 1, or deletions encompassing EHMT1 on 9q34.3. Congenital heart defects are among the major findings in patients with 9q34.3 microdeletion/Kleefstra Syndrome along with recognizable facial appearance, developmental delay/intellectual disability including severely delayed or absent speech, hypotonia, seizures, behavioral and sleep abnormalities. Pulmonary hypertension (PH) is a rare condition associated with increased pulmonary artery and right heart pressures that can lead to right heart failure and death if untreated. PH can be idiopathic, heritable, or associated with co-morbid conditions including congenital heart disease (CHD), lung diseases and other metabolic disorders. Genetic factors play important roles in heritable and idiopathic PH development and are particularly relevant but more diverse in etiology in children. PH is also reported in some chromosomal disorders such as Down syndrome in which congenital heart defects are common; however, PH has rarely been reported in patients with 9q34.3 microdeletion/Kleefstra Syndrome. Here, we present three patients with 9q34.3 microdeletions with CHD and PH along with review of five similar cases reported in the literature and discuss the potential association of PH with Kleefstra syndrome.

Keywords: 9q34.3 microdeletion; Kleefstra Syndrome; congenital heart disease (CHD); microarray; pulmonary hypertension (PH).

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Child, Preschool
  • Chromosome Deletion
  • Chromosomes, Human, Pair 9 / genetics
  • Craniofacial Abnormalities / complications
  • Craniofacial Abnormalities / genetics*
  • Craniofacial Abnormalities / physiopathology
  • Down Syndrome / genetics
  • Down Syndrome / physiopathology
  • Female
  • Heart Defects, Congenital / complications
  • Heart Defects, Congenital / genetics*
  • Heart Defects, Congenital / physiopathology
  • Histone-Lysine N-Methyltransferase / genetics*
  • Humans
  • Hypertension, Pulmonary / complications
  • Hypertension, Pulmonary / genetics*
  • Hypertension, Pulmonary / physiopathology
  • Infant
  • Intellectual Disability / complications
  • Intellectual Disability / genetics*
  • Intellectual Disability / physiopathology
  • Language Development Disorders / complications
  • Language Development Disorders / genetics
  • Language Development Disorders / physiopathology
  • Male
  • Mutation
  • Prenatal Diagnosis


  • EHMT1 protein, human
  • Histone-Lysine N-Methyltransferase

Supplementary concepts

  • Kleefstra Syndrome