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CalDAG-GEFI Deficiency in a Family with Symptomatic Heterozygous and Homozygous Carriers of a Likely Pathogenic Variant in RASGRP2

RASGRP2 encodes the calcium and diacylglycerol (DAG)-regulated guanine nucleotide exchange factor I (CalDAG-GEFI) identified as a Rap1-activating molecule. Pathogenic variants previously identified in RASGRP2 allowed the characterization of CalDAG-GEFI deficiency as a non-syndromic, autosomal recess...

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Autores principales: Morais, Sara, Pereira, Mónica, Lau, Catarina, Gonçalves, Ana, Monteiro, Catarina, Gonçalves, Marta, Oliveira, Jorge, Moreira, Lurdes, Cruz, Eugénia, Santos, Rosário, Lima, Margarida
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8618213/
https://www.ncbi.nlm.nih.gov/pubmed/34830306
http://dx.doi.org/10.3390/ijms222212423
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author Morais, Sara
Pereira, Mónica
Lau, Catarina
Gonçalves, Ana
Monteiro, Catarina
Gonçalves, Marta
Oliveira, Jorge
Moreira, Lurdes
Cruz, Eugénia
Santos, Rosário
Lima, Margarida
author_facet Morais, Sara
Pereira, Mónica
Lau, Catarina
Gonçalves, Ana
Monteiro, Catarina
Gonçalves, Marta
Oliveira, Jorge
Moreira, Lurdes
Cruz, Eugénia
Santos, Rosário
Lima, Margarida
author_sort Morais, Sara
collection PubMed
description RASGRP2 encodes the calcium and diacylglycerol (DAG)-regulated guanine nucleotide exchange factor I (CalDAG-GEFI) identified as a Rap1-activating molecule. Pathogenic variants previously identified in RASGRP2 allowed the characterization of CalDAG-GEFI deficiency as a non-syndromic, autosomal recessive platelet function disease. We report on the clinical manifestations and laboratory features of a Portuguese family with a likely pathogenic variant in RASGRP2 (c.999G>C leading to a p.Lys333Asn change in the CDC25 catalytic domain of CalDAG-GEFI) and discuss the contribution of this variant to the disease manifestations. Based on the study of this family with one homozygous patient and five heterozygous carriers and on a critical analysis of the literature, we challenge previous knowledge that CalDAG-GEFI deficiency only manifests in homozygous patients. Our data suggest that at least for the RASGRP2 variant reported herein, there is a phenotypic expression, albeit milder, in heterozygous carriers.
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spelling pubmed-86182132021-11-27 CalDAG-GEFI Deficiency in a Family with Symptomatic Heterozygous and Homozygous Carriers of a Likely Pathogenic Variant in RASGRP2 Morais, Sara Pereira, Mónica Lau, Catarina Gonçalves, Ana Monteiro, Catarina Gonçalves, Marta Oliveira, Jorge Moreira, Lurdes Cruz, Eugénia Santos, Rosário Lima, Margarida Int J Mol Sci Case Report RASGRP2 encodes the calcium and diacylglycerol (DAG)-regulated guanine nucleotide exchange factor I (CalDAG-GEFI) identified as a Rap1-activating molecule. Pathogenic variants previously identified in RASGRP2 allowed the characterization of CalDAG-GEFI deficiency as a non-syndromic, autosomal recessive platelet function disease. We report on the clinical manifestations and laboratory features of a Portuguese family with a likely pathogenic variant in RASGRP2 (c.999G>C leading to a p.Lys333Asn change in the CDC25 catalytic domain of CalDAG-GEFI) and discuss the contribution of this variant to the disease manifestations. Based on the study of this family with one homozygous patient and five heterozygous carriers and on a critical analysis of the literature, we challenge previous knowledge that CalDAG-GEFI deficiency only manifests in homozygous patients. Our data suggest that at least for the RASGRP2 variant reported herein, there is a phenotypic expression, albeit milder, in heterozygous carriers. MDPI 2021-11-17 /pmc/articles/PMC8618213/ /pubmed/34830306 http://dx.doi.org/10.3390/ijms222212423 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Case Report
Morais, Sara
Pereira, Mónica
Lau, Catarina
Gonçalves, Ana
Monteiro, Catarina
Gonçalves, Marta
Oliveira, Jorge
Moreira, Lurdes
Cruz, Eugénia
Santos, Rosário
Lima, Margarida
CalDAG-GEFI Deficiency in a Family with Symptomatic Heterozygous and Homozygous Carriers of a Likely Pathogenic Variant in RASGRP2
title CalDAG-GEFI Deficiency in a Family with Symptomatic Heterozygous and Homozygous Carriers of a Likely Pathogenic Variant in RASGRP2
title_full CalDAG-GEFI Deficiency in a Family with Symptomatic Heterozygous and Homozygous Carriers of a Likely Pathogenic Variant in RASGRP2
title_fullStr CalDAG-GEFI Deficiency in a Family with Symptomatic Heterozygous and Homozygous Carriers of a Likely Pathogenic Variant in RASGRP2
title_full_unstemmed CalDAG-GEFI Deficiency in a Family with Symptomatic Heterozygous and Homozygous Carriers of a Likely Pathogenic Variant in RASGRP2
title_short CalDAG-GEFI Deficiency in a Family with Symptomatic Heterozygous and Homozygous Carriers of a Likely Pathogenic Variant in RASGRP2
title_sort caldag-gefi deficiency in a family with symptomatic heterozygous and homozygous carriers of a likely pathogenic variant in rasgrp2
topic Case Report
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8618213/
https://www.ncbi.nlm.nih.gov/pubmed/34830306
http://dx.doi.org/10.3390/ijms222212423
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