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Compound heterozygous NOTCH1 mutations underlie impaired cardiogenesis in a patient with hypoplastic left heart syndrome

  • Theis, Jeanne L.1
  • Hrstka, Sybil C. L.2, 3
  • Evans, Jared M.4
  • O’Byrne, Megan M.4
  • de Andrade, Mariza4
  • O’Leary, Patrick W.5, 6
  • Nelson, Timothy J.5, 2, 3
  • Olson, Timothy M.1, 5, 6
  • 1 Mayo Clinic, Cardiovascular Genetics Research Laboratory, 200 First Street SW, Rochester, MN, 55905, USA , Rochester (United States)
  • 2 Mayo Clinic, Division of General Internal Medicine, Department of Internal Medicine, Rochester, MN, USA , Rochester (United States)
  • 3 Mayo Clinic, Center for Regenerative Medicine, Rochester, MN, USA , Rochester (United States)
  • 4 Mayo Clinic, Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Rochester, MN, USA , Rochester (United States)
  • 5 Mayo Clinic, Division of Pediatric Cardiology, Department of Pediatric and Adolescent Medicine, Rochester, MN, USA , Rochester (United States)
  • 6 Mayo Clinic, Division of Cardiovascular Diseases, Department of Internal Medicine, Rochester, MN, USA , Rochester (United States)
Published Article
Human Genetics
Publication Date
Jul 12, 2015
DOI: 10.1007/s00439-015-1582-1
Springer Nature


Hypoplastic left heart syndrome (HLHS) is a severe congenital heart defect (CHD) that necessitates staged, single ventricle surgical palliation. An increased frequency of bicuspid aortic valve (BAV) has been observed among relatives. We postulated number of mutant alleles as a molecular basis for variable CHD expression in an extended family comprised of an HLHS proband and four family members who underwent echocardiography and whole-genome sequencing (WGS). Dermal fibroblast-derived induced pluripotent stem cells (iPSC) were procured from the proband–parent trio and bioengineered into cardiomyocytes. Cardiac phenotyping revealed aortic valve atresia and a slit-like left ventricular cavity in the HLHS proband, isolated bicuspid pulmonary valve in his mother, BAV in a maternal 4° relative, and no CHD in his father or sister. Filtering of WGS for rare, functional variants that segregated with CHD and were compound heterozygous in the HLHS proband identified NOTCH1 as the sole candidate gene. An unreported missense mutation (P1964L) in the cytoplasmic domain, segregating with semilunar valve malformation, was maternally inherited and a rare missense mutation (P1256L) in the extracellular domain, clinically silent in the heterozygous state, was paternally inherited. Patient-specific iPSCs exhibited diminished transcript levels of NOTCH1 signaling pathway components, impaired myocardiogenesis, and a higher prevalence of heterogeneous myofilament organization. Extended, phenotypically characterized families enable WGS-derived variant filtering for plausible Mendelian modes of inheritance, a powerful strategy to discover molecular underpinnings of CHD. Identification of compound heterozygous NOTCH1 mutations and iPSC-based functional modeling implicate mutant allele burden and impaired myogenic potential as mechanisms for HLHS.

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