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...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Royan Institute (ACECR), Tehran
2018-12-01
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| Series: | Cell Journal |
| Subjects: | |
| Online Access: | https://celljournal.org/journal/article/abstract/5734 |
| _version_ | 1811194625217527808 |
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| author | Ahoura Nozari Ehsan Aghaei-Moghadam Aliakbar Zeinaloo Afagh Alavi Saghar Ghasemi Firouzabad Shohre Minaee Marzeieh Eskandari Hesari Farkhondeh Behjati |
| author_facet | Ahoura Nozari Ehsan Aghaei-Moghadam Aliakbar Zeinaloo Afagh Alavi Saghar Ghasemi Firouzabad Shohre Minaee Marzeieh Eskandari Hesari Farkhondeh Behjati |
| author_sort | Ahoura Nozari |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-04-12T00:29:52Z |
| format | Article |
| id | doaj.art-59cff7a96e2a4fb2ae234452f9a18e1d |
| institution | Directory Open Access Journal |
| issn | 2228-5806 2228-5814 |
| language | English |
| last_indexed | 2024-04-12T00:29:52Z |
| publishDate | 2018-12-01 |
| publisher | Royan Institute (ACECR), Tehran |
| record_format | Article |
| series | Cell Journal |
| spelling | doaj.art-59cff7a96e2a4fb2ae234452f9a18e1d2022-12-22T03:55:23ZengRoyan Institute (ACECR), TehranCell Journal2228-58062228-58142018-12-012117077A Pathogenic Homozygous Mutation In The Pleckstrin Homology Domain Of RASA1 Is Responsible For Familial Tricuspid Atresia In An Iranian Consanguineous Family Ahoura Nozari0Ehsan Aghaei-Moghadam1Aliakbar Zeinaloo2 Afagh Alavi3Saghar Ghasemi Firouzabad4Shohre Minaee5Marzeieh Eskandari Hesari6Farkhondeh Behjati7Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, IranDepartment of Pediatrics Cardiology, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, IranDepartment of Pediatrics Cardiology, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, IranGenetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, IranGenetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, IranDepartment of Pediatrics Cardiology, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, IranDepartment of Pediatrics Cardiology, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, IranGenetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, IranObjective 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.https://celljournal.org/journal/article/abstract/5734Pleckstrin Homology DomainRASA1Tricuspid AtresiaWhole Exome Sequencing |
| spellingShingle | Ahoura Nozari Ehsan Aghaei-Moghadam Aliakbar Zeinaloo Afagh Alavi Saghar Ghasemi Firouzabad Shohre Minaee Marzeieh Eskandari Hesari Farkhondeh Behjati A Pathogenic Homozygous Mutation In The Pleckstrin Homology Domain Of RASA1 Is Responsible For Familial Tricuspid Atresia In An Iranian Consanguineous Family Cell Journal Pleckstrin Homology Domain RASA1 Tricuspid Atresia Whole Exome Sequencing |
| 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 | Pleckstrin Homology Domain RASA1 Tricuspid Atresia Whole Exome Sequencing |
| url | https://celljournal.org/journal/article/abstract/5734 |
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