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

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...

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Autores principales: Nozari, Ahoura, Aghaei-Moghadam, Ehsan, Zeinaloo, Aliakbar, Alavi, Afagh, Ghasemi Firouzabdi, Saghar, Minaee, Shohre, Eskandari Hesari, Marzieh, Behjati, Farkhondeh
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Royan Institute 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6275424/
https://www.ncbi.nlm.nih.gov/pubmed/30507091
http://dx.doi.org/10.22074/cellj.2019.5734
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author Nozari, Ahoura
Aghaei-Moghadam, Ehsan
Zeinaloo, Aliakbar
Alavi, Afagh
Ghasemi Firouzabdi, Saghar
Minaee, Shohre
Eskandari Hesari, Marzieh
Behjati, Farkhondeh
author_facet Nozari, Ahoura
Aghaei-Moghadam, Ehsan
Zeinaloo, Aliakbar
Alavi, Afagh
Ghasemi Firouzabdi, Saghar
Minaee, Shohre
Eskandari Hesari, Marzieh
Behjati, Farkhondeh
author_sort Nozari, Ahoura
collection PubMed
description 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.
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spelling pubmed-62754242019-04-01 A Pathogenic Homozygous Mutation in The Pleckstrin Homology Domain of RASA1 Is Responsible for Familial Tricuspid Atresia in An Iranian Consanguineous Family Nozari, Ahoura Aghaei-Moghadam, Ehsan Zeinaloo, Aliakbar Alavi, Afagh Ghasemi Firouzabdi, Saghar Minaee, Shohre Eskandari Hesari, Marzieh Behjati, Farkhondeh Cell J Original Article 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. Royan Institute 2019 2018-11-18 /pmc/articles/PMC6275424/ /pubmed/30507091 http://dx.doi.org/10.22074/cellj.2019.5734 Text en Any use, distribution, reproduction or abstract of this publication in any medium, with the exception of commercial purposes, is permitted provided the original work is properly cited http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Article
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
title A Pathogenic Homozygous Mutation in The Pleckstrin Homology Domain of RASA1 Is Responsible for Familial Tricuspid Atresia in An Iranian Consanguineous Family
title_full A Pathogenic Homozygous Mutation in The Pleckstrin Homology Domain of RASA1 Is Responsible for Familial Tricuspid Atresia in An Iranian Consanguineous Family
title_fullStr A Pathogenic Homozygous Mutation in The Pleckstrin Homology Domain of RASA1 Is Responsible for Familial Tricuspid Atresia in An Iranian Consanguineous Family
title_full_unstemmed A Pathogenic Homozygous Mutation in The Pleckstrin Homology Domain of RASA1 Is Responsible for Familial Tricuspid Atresia in An Iranian Consanguineous Family
title_short A Pathogenic Homozygous Mutation in The Pleckstrin Homology Domain of RASA1 Is Responsible for Familial Tricuspid Atresia in An Iranian Consanguineous Family
title_sort pathogenic homozygous mutation in the pleckstrin homology domain of rasa1 is responsible for familial tricuspid atresia in an iranian consanguineous family
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6275424/
https://www.ncbi.nlm.nih.gov/pubmed/30507091
http://dx.doi.org/10.22074/cellj.2019.5734
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