A Pathogenic Homozygous Mutation in The Pleckstrin Homology Domain of RASA1 Is Responsible for Familial Tricuspid Atresia in An Iranian Consanguineous Family


Ahoura Nozari, M.Sc, 1Ehsan Aghaei-Moghadam, M.D, 2Aliakbar Zeinaloo, M.D, 2Afagh Alavi, Ph.D, 1Saghar Ghasemi Firouzabdi, Ph.D., 1Shohre Minaee, B.Sc., 2Marzieh Eskandari Hesari, B.Sc., 2Farkhondeh Behjati, Ph.D., 1,*
Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran
Department of Pediatrics Cardiology, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran
Department of Pediatrics Cardiology, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
*Corresponding Address: P.O.Box: 1985713871 Genetics Research Center University of Social Welfare and Rehabilitationz Sciences Tehran Iran Email:f_behjati@uswr.ac.ir
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Nozari Ahoura, Aghaei-Moghadam Ehsan, Zeinaloo Aliakbar, Alavi Afagh, Ghasemi Firouzabdi Saghar, Minaee Shohre, Eskandari Hesari Marzieh, Behjati Farkhondeh. A Pathogenic Homozygous Mutation in The Pleckstrin Homology Domain of RASA1 Is Responsible for Familial Tricuspid Atresia in An Iranian Consanguineous Family. Cell J. 2019; 21(1): 70-77.

Abstract

Objective

Tricuspid atresia (TA) is a rare life-threatening form of congenital heart defect (CHD). The genetic mechanisms underlying TA are not clearly understood. According to previous studies, the endocardial cushioning event, as the primary sign of cardiac valvulogenesis, is governed by several overlapping signaling pathways including Ras/ ERK pathway. RASA1, a regulator of cardiovascular development, is involved in this pathway and its haploinsufficiency (due to heterozygous mutations) has been identified as the underlying etiology of the autosomal dominant capillary malformation/arteriovenous malformation (CM/AVM).

Materials and Methods

In this prospective study, we used whole exome sequencing (WES) followed by serial bioinformatics filtering steps for two siblings with TA and early onset CM. Their parents were consanguineous which had a history of recurrent abortions. Patients were carefully assessed to exclude extra-cardiac anomalies.

Results

We identified a homozygous RASA1 germline mutation, c.1583A>G (p.Tyr528Cys) in the family. This mutation lies in the pleckstrin homology (PH) domain of the gene. The parents who were heterozygous for this variant displayed CM.

Conclusion

This is the first study reporting an adverse phenotypic outcome of a RASA1 homozygous mutation. Here, we propose that the phenotypic consequence of the homozygous RASA1 p.Tyr528Cys mutation is more serious than the heterozygous type. This could be responsible for the TA pathogenesis in our patients. We strongly suggest that parents with CM/AVM should be investigated for RASA1 heterozygous mutations. Prenatal diagnosis and fetal echocardiography should also be carried out in the event of pregnancy in heterozygous parents.