Discovery of a novel mutation F184S (c.551T>C) in GATA4 gene causing congenital heart disease in a consanguineous Saudi family
Mahmood Rasool,
Peter Natesan Pushparaj,
Absarul Haque,
Ayat Mohammed Shorbaji,
Loubna Siraj Mira,
Sherin Bakhashab,
Mohamed Nabil Alama,
Muhammad Farooq,
Sajjad Karim,
Lars Allan Larsen
Affiliations
Mahmood Rasool
Center of Excellence in Genomic Medicine Research, Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia; Corresponding author.
Peter Natesan Pushparaj
Center of Excellence in Genomic Medicine Research, Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
Absarul Haque
King Fahd Medical Research Center, Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
Ayat Mohammed Shorbaji
Center of Excellence in Genomic Medicine Research, Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia; Department of Biochemistry, King Abdulaziz University, Jeddah, Saudi Arabia
Loubna Siraj Mira
Center of Excellence in Genomic Medicine Research, Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
Sherin Bakhashab
Center of Excellence in Genomic Medicine Research, Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia; Department of Biochemistry, King Abdulaziz University, Jeddah, Saudi Arabia
Mohamed Nabil Alama
Department of Cardiology, King Abdulaziz University Hospital, Jeddah, Saudi Arabia
Muhammad Farooq
Department of Bioinformatics and Biotechnology, Government College University, Faisalabad, Pakistan
Sajjad Karim
Center of Excellence in Genomic Medicine Research, Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
Lars Allan Larsen
Department of Cellular and Molecular Medicine, University of Copenhagen, Denmark
Background & aim: Congenital heart disease (CHD) is the most common cause of non-infectious deaths in infants worldwide. However, the molecular mechanisms underlying CHD remain unclear. Approximately 30 % of the causes are believed to be genetic mutations and chromosomal abnormalities. In this study, we aimed to identify the genetic causes of CHD in consanguineous families. Methods: Fourth-generation pedigrees with CHD were recruited. The main cardiac features of the patient included absence of the right pulmonary artery and a large dilated left pulmonary artery. To determine the underlying genetic cause, whole-exome sequencing was performed and subsequently confirmed using Sanger sequencing and different online databases to study the pathogenesis of the identified gene mutation. An in-silico homology model was created using the Alphafold homology model structure of GATA4 (AF-P43694-F1). The missense3D online program was used to evaluate the structural alterations. Results: We identified a deleterious mutation c.551T > C (p.Phe184Ser) in GATA4. GATA4 is a highly conserved zinc-finger transcription factor, and its continuous expression is essential for cardiogenesis during embryogenesis. The in-silico model suggested a compromised binding efficiency with other proteins. Several variant interpretation algorithms indicated that the F184S missense variant in GATA4 is damaging, whereas HOPE analysis indicated the functional impairment of DNA binding of transcription factors and zinc-ion binding activities of GATA4. Conclusion: The variant identified in GATA4 appears to cause recessive CHD in the family. In silico analysis suggested that this variant was damaging and caused multiple structural and functional aberrations. This study may support prenatal screening of the fetus in this family to prevent diseases in new generations.
