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Pediatr Cardiol. 2017 Aug;38(6):1232-1240. doi: 10.1007/s00246-017-1650-5. Epub 2017 Jun 12.

Hypoplastic Left Heart Syndrome Sequencing Reveals a Novel NOTCH1 Mutation in a Family with Single Ventricle Defects.

Author information

1
Division of Neonatal-Perinatal Medicine, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.
2
Division of Cardiovascular Medicine, Departments of Medicine, Vanderbilt University School of Medicine, Nashville, TN, 37232, USA.
3
Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN, 37232, USA.
4
Department of Pediatric Cardiac Surgery, Vanderbilt University School of Medicine, Nashville, TN, 37232, USA.
5
Division of Cardiovascular Medicine, Departments of Medicine, Vanderbilt University School of Medicine, Nashville, TN, 37232, USA. charles.c.hong@vanderbilt.edu.
6
Research Medicine, Veterans Affairs Tennessee Valley Healthcare System, Nashville, TN, 37212, USA. charles.c.hong@vanderbilt.edu.
7
Vanderbilt University School of Medicine, 2220 Pierce Ave., PRB 383, Nashville, TN, 37232, USA. charles.c.hong@vanderbilt.edu.

Abstract

Hypoplastic left heart syndrome (HLHS) has been associated with germline mutations in 12 candidate genes and a recurrent somatic mutation in HAND1 gene. Using targeted and whole exome sequencing (WES) of heart tissue samples from HLHS patients, we sought to estimate the prevalence of somatic and germline mutations associated with HLHS. We performed Sanger sequencing of the HAND1 gene on 14 ventricular (9 LV and 5 RV) samples obtained from HLHS patients, and WES of 4 LV, 2 aortic, and 4 matched PBMC samples, analyzing for sequence discrepancy. We also screened for mutations in the 12 candidate genes implicated in HLHS. We found no somatic mutations in our HLHS cohort. However, we detected a novel germline frameshift/stop-gain mutation in NOTCH1 in a HLHS patient with a family history of both HLHS and hypoplastic right heart syndrome (HRHS). Our study, involving one of the first familial cases of single ventricle defects linked to a specific mutation, strengthens the association of NOTCH1 mutations with HLHS and suggests that the two morphologically distinct single ventricle conditions, HLHS and HRHS, may share a common molecular and cellular etiology. Finally, somatic mutations in the LV are an unlikely contributor to HLHS.

KEYWORDS:

Congenital heart disease; HAND1 and NOTCH1; Hypoplastic left heart syndrome; Somatic mutation; Whole exome sequencing

PMID:
28608148
PMCID:
PMC5577922
DOI:
10.1007/s00246-017-1650-5
[Indexed for MEDLINE]
Free PMC Article

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