Heart and Vessels

, Volume 34, Issue 4, pp 658–668 | Cite as

ISL1 loss-of-function mutation contributes to congenital heart defects

  • Lan Ma
  • Juan Wang
  • Li Li
  • Qi Qiao
  • Ruo-Min Di
  • Xiu-Mei Li
  • Ying-Jia Xu
  • Min Zhang
  • Ruo-Gu Li
  • Xing-Biao Qiu
  • Xun LiEmail author
  • Yi-Qing YangEmail author
Original Article


Congenital heart defect (CHD) is the most common form of birth deformity and is responsible for substantial morbidity and mortality in humans. Increasing evidence has convincingly demonstrated that genetic defects play a pivotal role in the pathogenesis of CHD. However, CHD is a genetically heterogeneous disorder and the genetic basis underpinning CHD in the vast majority of cases remains elusive. This study was sought to identify the pathogenic mutation in the ISL1 gene contributing to CHD. A cohort of 210 unrelated patients with CHD and a total of 256 unrelated healthy individuals used as controls were registered. The coding exons and splicing boundaries of ISL1 were sequenced in all study subjects. The functional effect of an identified ISL1 mutation was evaluated using a dual-luciferase reporter assay system. A novel heterozygous ISL1 mutation, c.409G > T or p.E137X, was identified in an index patient with congenital patent ductus arteriosus and ventricular septal defect. Analysis of the proband’s pedigree revealed that the mutation co-segregated with CHD, which was transmitted in the family in an autosomal dominant pattern with complete penetrance. The nonsense mutation was absent in 512 control chromosomes. Functional analysis unveiled that the mutant ISL1 protein failed to transactivate the promoter of MEF2C, alone or in synergy with TBX20. This study firstly implicates ISL1 loss-of-function mutation with CHD in humans, which provides novel insight into the molecular mechanism of CHD, implying potential implications for genetic counseling and individually tailored treatment of CHD patients.


Congenital heart defect Patent ductus arteriosus Molecular genetics Transcription factor ISL1 Reporter gene assay 



We are sincerely thankful to the study participants for their dedication to the investigation.


This study was funded by the grants from the National Natural Science Foundation of China (81470372, 81400244, and 81370400), the Medicine Guided Program of Shanghai, China (17411971000), the Experimental Animal Program of Shanghai, China (17140902400), the Clinical Research Plan of SHDC, Shanghai, China (16CR3005A), the Project Foundation of Health and Family Planning Commission of Shanghai, China (M20170348), and the Fundamental Research Funds for the Central Universities.

Compliance with ethical standards

Conflict of interest

The authors declare that no conflict of interest exists.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study or their legal guardians.


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Copyright information

© Springer Japan KK, part of Springer Nature 2018

Authors and Affiliations

  • Lan Ma
    • 1
    • 2
  • Juan Wang
    • 3
  • Li Li
    • 4
  • Qi Qiao
    • 5
  • Ruo-Min Di
    • 5
  • Xiu-Mei Li
    • 5
  • Ying-Jia Xu
    • 5
  • Min Zhang
    • 6
  • Ruo-Gu Li
    • 6
  • Xing-Biao Qiu
    • 6
  • Xun Li
    • 1
    Email author
  • Yi-Qing Yang
    • 5
    • 7
    • 8
    Email author
  1. 1.Department of CardiologyThe First Affiliated Hospital of Soochow UniversitySuzhouChina
  2. 2.Department of Ultrasound, Shanghai Chest HospitalShanghai Jiao Tong UniversityShanghaiChina
  3. 3.Department of Cardiovascular Medicine, East HospitalTongji University School of MedicineShanghaiChina
  4. 4.Key Laboratory of Arrhythmias of the Ministry of Education of China, East HospitalTongji University School of MedicineShanghaiChina
  5. 5.Department of Cardiology, The Fifth People′s Hospital of ShanghaiFudan UniversityShanghaiChina
  6. 6.Department of Cardiology, Shanghai Chest HospitalShanghai Jiao Tong UniversityShanghaiChina
  7. 7.Department of Cardiovascular Research Laboratory, The Fifth People′s Hospital of ShanghaiFudan UniversityShanghaiChina
  8. 8.Department of Central Laboratory, The Fifth People′s Hospital of ShanghaiFudan UniversityShanghaiChina

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