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

Jeanne L. Theis, Sybil C L Hrstka, Jared M. Evans, Megan M. O’Byrne, Mariza De Andrade, Patrick W. O’Leary, Timothy J Nelson, Timothy Mark Olson

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1003-1011
Number of pages9
JournalHuman Genetics
Volume134
Issue number9
DOIs
StatePublished - Sep 10 2015

Fingerprint

Hypoplastic Left Heart Syndrome
Congenital Heart Defects
Mutation
Induced Pluripotent Stem Cells
Genome
Missense Mutation
Alleles
Mothers
Pulmonary Valve
Myofibrils
Aortic Valve
Mitral Valve
Cardiac Myocytes
Fathers
Echocardiography
Siblings
Organizations
Skin
Genes

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics

Cite this

Compound heterozygous NOTCH1 mutations underlie impaired cardiogenesis in a patient with hypoplastic left heart syndrome. / Theis, Jeanne L.; Hrstka, Sybil C L; Evans, Jared M.; O’Byrne, Megan M.; De Andrade, Mariza; O’Leary, Patrick W.; Nelson, Timothy J; Olson, Timothy Mark.

In: Human Genetics, Vol. 134, No. 9, 10.09.2015, p. 1003-1011.

Research output: Contribution to journalArticle

Theis, Jeanne L. ; Hrstka, Sybil C L ; Evans, Jared M. ; O’Byrne, Megan M. ; De Andrade, Mariza ; O’Leary, Patrick W. ; Nelson, Timothy J ; Olson, Timothy Mark. / Compound heterozygous NOTCH1 mutations underlie impaired cardiogenesis in a patient with hypoplastic left heart syndrome. In: Human Genetics. 2015 ; Vol. 134, No. 9. pp. 1003-1011.
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