A Pathogenic Homozygous Mutation in the Pleckstrin Homology Domain of Rasa1 Is Responsible for Familial Tricuspid Atresia in an Iranian Consanguineous Family

A Pathogenic Homozygous Mutation in the Pleckstrin Homology Domain of Rasa1 Is Responsible for Familial Tricuspid Atresia in an Iranian Consanguineous Family Publisher

Nozari A¹ ; Aghaeimoghadam E² ; Zeinaloo A² ; Alavi A¹ ; Firouzabdi SG¹ ; Minaee S² ; Hesari ME² ; Behjati F¹

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1. Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, P.O. Box: 1985713871, Tehran, Iran
2. Department of Pediatrics Cardiology, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran

Source: Cell Journal Published:2019

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. © 2019 Royan Institute (ACECR). All rights reserved.

Style	Citing Format
MLA	Nozari A, et al.. "A Pathogenic Homozygous Mutation in the Pleckstrin Homology Domain of Rasa1 Is Responsible for Familial Tricuspid Atresia in an Iranian Consanguineous Family." Cell Journal, vol. 21, no. 1, 2019, pp. 70-77.
APA	Nozari A, Aghaeimoghadam E, Zeinaloo A, Alavi A, Firouzabdi SG, Minaee S, Hesari ME, Behjati F (2019). A Pathogenic Homozygous Mutation in the Pleckstrin Homology Domain of Rasa1 Is Responsible for Familial Tricuspid Atresia in an Iranian Consanguineous Family. Cell Journal, 21(1), 70-77.
Chicago	Nozari A, Aghaeimoghadam E, Zeinaloo A, Alavi A, Firouzabdi SG, Minaee S, Hesari ME, Behjati F. "A Pathogenic Homozygous Mutation in the Pleckstrin Homology Domain of Rasa1 Is Responsible for Familial Tricuspid Atresia in an Iranian Consanguineous Family." Cell Journal 21, no. 1 (2019): 70-77.
Harvard	Nozari A et al. (2019) 'A Pathogenic Homozygous Mutation in the Pleckstrin Homology Domain of Rasa1 Is Responsible for Familial Tricuspid Atresia in an Iranian Consanguineous Family', Cell Journal, 21(1), pp. 70-77.
Vancouver	Nozari A, Aghaeimoghadam E, Zeinaloo A, Alavi A, Firouzabdi SG, Minaee S, et al.. A Pathogenic Homozygous Mutation in the Pleckstrin Homology Domain of Rasa1 Is Responsible for Familial Tricuspid Atresia in an Iranian Consanguineous Family. Cell Journal. 2019;21(1):70-77.
BibTex	@article{ author = {Nozari A and Aghaeimoghadam E and Zeinaloo A and Alavi A and Firouzabdi SG and Minaee S and Hesari ME and Behjati F}, title = {A Pathogenic Homozygous Mutation in the Pleckstrin Homology Domain of Rasa1 Is Responsible for Familial Tricuspid Atresia in an Iranian Consanguineous Family}, journal = {Cell Journal}, volume = {21}, number = {1}, pages = {70-77}, year = {2019} }
RIS	TY - JOUR AU - Nozari A AU - Aghaeimoghadam E AU - Zeinaloo A AU - Alavi A AU - Firouzabdi SG AU - Minaee S AU - Hesari ME AU - Behjati F TI - A Pathogenic Homozygous Mutation in the Pleckstrin Homology Domain of Rasa1 Is Responsible for Familial Tricuspid Atresia in an Iranian Consanguineous Family JO - Cell Journal VL - 21 IS - 1 SP - 70 EP - 77 PY - 2019 ER -

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