A mutational hotspot in AMOTL1 defines a new syndrome of orofacial clefting, cardiac anomalies, and tall stature

Am J Med Genet A. 2023 May;191(5):1227-1239. doi: 10.1002/ajmg.a.63130. Epub 2023 Feb 7.


AMOTL1 encodes angiomotin-like protein 1, an actin-binding protein that regulates cell polarity, adhesion, and migration. The role of AMOTL1 in human disease is equivocal. We report a large cohort of individuals harboring heterozygous AMOTL1 variants and define a core phenotype of orofacial clefting, congenital heart disease, tall stature, auricular anomalies, and gastrointestinal manifestations in individuals with variants in AMOTL1 affecting amino acids 157-161, a functionally undefined but highly conserved region. Three individuals with AMOTL1 variants outside this region are also described who had variable presentations with orofacial clefting and multi-organ disease. Our case cohort suggests that heterozygous missense variants in AMOTL1, most commonly affecting amino acid residues 157-161, define a new orofacial clefting syndrome, and indicates an important functional role for this undefined region.

Keywords: YAP; cleft lip; cleft palate; congenital heart disease; exome sequencing; genome sequencing.

Publication types

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

MeSH terms

  • Angiomotins
  • Cleft Lip* / diagnosis
  • Cleft Lip* / genetics
  • Cleft Palate* / diagnosis
  • Cleft Palate* / genetics
  • Heart Defects, Congenital* / diagnosis
  • Heart Defects, Congenital* / genetics
  • Humans
  • Mutation
  • Mutation, Missense / genetics


  • AMOTL1 protein, human
  • Angiomotins