The expanding clinical phenotype of germline ABL1-associated congenital heart defects and skeletal malformations syndrome

Hum Mutat. 2020 Oct;41(10):1738-1744. doi: 10.1002/humu.24075. Epub 2020 Jul 19.


Congenital heart defects and skeletal malformations syndrome (CHDSKM) is a rare autosomal dominant disorder characterized by congenital heart disease, skeletal abnormalities, and failure to thrive. CHDSKM is caused by germline mutations in ABL1. To date, three variants have been in association with CHDSKM. In this study, we describe three de novo missense variants, c.407C>T (p.Thr136Met), c.746C>T (p.Pro249Leu), and c.1573G>A (p.Val525Met), and one recurrent variant, c.1066G>A (p.Ala356Thr), in six patients, thereby expanding the phenotypic spectrum of CHDSKM to include hearing impairment, lipodystrophy-like features, renal hypoplasia, and distinct ocular abnormalities. Functional investigation of the three novel variants showed an increased ABL1 kinase activity. The cardiac findings in additional patients with p.Ala356Thr contribute to the accumulating evidence that patients carrying either one of the recurrent variants, p.Tyr245Cys and p.Ala356Thr, have a high incidence of cardiac abnormalities. The phenotypic expansion has implications for the clinical diagnosis of CHDSKM in patients with germline ABL1 variants.

Keywords: CHDSKM; congenital heart defects; hearing impairment; renal hypoplasia; skeletal malformations.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abnormalities, Multiple* / diagnosis
  • Abnormalities, Multiple* / genetics
  • Germ Cells
  • Heart Defects, Congenital* / genetics
  • Humans
  • Phenotype
  • Syndrome