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A Case Series of Familial ARID1B Variants Illustrating Variable Expression and Suggestions to Update the ACMG Criteria

ARID1B is one of the most frequently mutated genes in intellectual disability (~1%). Most variants are readily classified, since they are de novo and are predicted to lead to loss of function, and therefore classified as pathogenic according to the American College of Medical Genetics and Genomics (...

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Autores principales: van der Sluijs, Pleuntje J., Alders, Mariëlle, Dingemans, Alexander J. M., Parbhoo, Kareesma, van Bon, Bregje W., Dempsey, Jennifer C., Doherty, Dan, den Dunnen, Johan T., Gerkes, Erica H., Milller, Ilana M., Moortgat, Stephanie, Regier, Debra S., Ruivenkamp, Claudia A. L., Schmalz, Betsy, Smol, Thomas, Stuurman, Kyra E., Vincent-Delorme, Catherine, de Vries, Bert B. A., Sadikovic, Bekim, Hickey, Scott E., Rosenfeld, Jill A., Maystadt, Isabelle, Santen, Gijs W. E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8393241/
https://www.ncbi.nlm.nih.gov/pubmed/34440449
http://dx.doi.org/10.3390/genes12081275
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author van der Sluijs, Pleuntje J.
Alders, Mariëlle
Dingemans, Alexander J. M.
Parbhoo, Kareesma
van Bon, Bregje W.
Dempsey, Jennifer C.
Doherty, Dan
den Dunnen, Johan T.
Gerkes, Erica H.
Milller, Ilana M.
Moortgat, Stephanie
Regier, Debra S.
Ruivenkamp, Claudia A. L.
Schmalz, Betsy
Smol, Thomas
Stuurman, Kyra E.
Vincent-Delorme, Catherine
de Vries, Bert B. A.
Sadikovic, Bekim
Hickey, Scott E.
Rosenfeld, Jill A.
Maystadt, Isabelle
Santen, Gijs W. E.
author_facet van der Sluijs, Pleuntje J.
Alders, Mariëlle
Dingemans, Alexander J. M.
Parbhoo, Kareesma
van Bon, Bregje W.
Dempsey, Jennifer C.
Doherty, Dan
den Dunnen, Johan T.
Gerkes, Erica H.
Milller, Ilana M.
Moortgat, Stephanie
Regier, Debra S.
Ruivenkamp, Claudia A. L.
Schmalz, Betsy
Smol, Thomas
Stuurman, Kyra E.
Vincent-Delorme, Catherine
de Vries, Bert B. A.
Sadikovic, Bekim
Hickey, Scott E.
Rosenfeld, Jill A.
Maystadt, Isabelle
Santen, Gijs W. E.
author_sort van der Sluijs, Pleuntje J.
collection PubMed
description ARID1B is one of the most frequently mutated genes in intellectual disability (~1%). Most variants are readily classified, since they are de novo and are predicted to lead to loss of function, and therefore classified as pathogenic according to the American College of Medical Genetics and Genomics (ACMG) guidelines for the interpretation of sequence variants. However, familial loss-of-function variants can also occur and can be challenging to interpret. Such variants may be pathogenic with variable expression, causing only a mild phenotype in a parent. Alternatively, since some regions of the ARID1B gene seem to be lacking pathogenic variants, loss-of-function variants in those regions may not lead to ARID1B haploinsufficiency and may therefore be benign. We describe 12 families with potential loss-of-function variants, which were either familial or with unknown inheritance and were in regions where pathogenic variants have not been described or are otherwise challenging to interpret. We performed detailed clinical and DNA methylation studies, which allowed us to confidently classify most variants. In five families we observed transmission of pathogenic variants, confirming their highly variable expression. Our findings provide further evidence for an alternative translational start site and we suggest updates for the ACMG guidelines for the interpretation of sequence variants to incorporate DNA methylation studies and facial analyses.
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spelling pubmed-83932412021-08-28 A Case Series of Familial ARID1B Variants Illustrating Variable Expression and Suggestions to Update the ACMG Criteria van der Sluijs, Pleuntje J. Alders, Mariëlle Dingemans, Alexander J. M. Parbhoo, Kareesma van Bon, Bregje W. Dempsey, Jennifer C. Doherty, Dan den Dunnen, Johan T. Gerkes, Erica H. Milller, Ilana M. Moortgat, Stephanie Regier, Debra S. Ruivenkamp, Claudia A. L. Schmalz, Betsy Smol, Thomas Stuurman, Kyra E. Vincent-Delorme, Catherine de Vries, Bert B. A. Sadikovic, Bekim Hickey, Scott E. Rosenfeld, Jill A. Maystadt, Isabelle Santen, Gijs W. E. Genes (Basel) Article ARID1B is one of the most frequently mutated genes in intellectual disability (~1%). Most variants are readily classified, since they are de novo and are predicted to lead to loss of function, and therefore classified as pathogenic according to the American College of Medical Genetics and Genomics (ACMG) guidelines for the interpretation of sequence variants. However, familial loss-of-function variants can also occur and can be challenging to interpret. Such variants may be pathogenic with variable expression, causing only a mild phenotype in a parent. Alternatively, since some regions of the ARID1B gene seem to be lacking pathogenic variants, loss-of-function variants in those regions may not lead to ARID1B haploinsufficiency and may therefore be benign. We describe 12 families with potential loss-of-function variants, which were either familial or with unknown inheritance and were in regions where pathogenic variants have not been described or are otherwise challenging to interpret. We performed detailed clinical and DNA methylation studies, which allowed us to confidently classify most variants. In five families we observed transmission of pathogenic variants, confirming their highly variable expression. Our findings provide further evidence for an alternative translational start site and we suggest updates for the ACMG guidelines for the interpretation of sequence variants to incorporate DNA methylation studies and facial analyses. MDPI 2021-08-20 /pmc/articles/PMC8393241/ /pubmed/34440449 http://dx.doi.org/10.3390/genes12081275 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 Article
van der Sluijs, Pleuntje J.
Alders, Mariëlle
Dingemans, Alexander J. M.
Parbhoo, Kareesma
van Bon, Bregje W.
Dempsey, Jennifer C.
Doherty, Dan
den Dunnen, Johan T.
Gerkes, Erica H.
Milller, Ilana M.
Moortgat, Stephanie
Regier, Debra S.
Ruivenkamp, Claudia A. L.
Schmalz, Betsy
Smol, Thomas
Stuurman, Kyra E.
Vincent-Delorme, Catherine
de Vries, Bert B. A.
Sadikovic, Bekim
Hickey, Scott E.
Rosenfeld, Jill A.
Maystadt, Isabelle
Santen, Gijs W. E.
A Case Series of Familial ARID1B Variants Illustrating Variable Expression and Suggestions to Update the ACMG Criteria
title A Case Series of Familial ARID1B Variants Illustrating Variable Expression and Suggestions to Update the ACMG Criteria
title_full A Case Series of Familial ARID1B Variants Illustrating Variable Expression and Suggestions to Update the ACMG Criteria
title_fullStr A Case Series of Familial ARID1B Variants Illustrating Variable Expression and Suggestions to Update the ACMG Criteria
title_full_unstemmed A Case Series of Familial ARID1B Variants Illustrating Variable Expression and Suggestions to Update the ACMG Criteria
title_short A Case Series of Familial ARID1B Variants Illustrating Variable Expression and Suggestions to Update the ACMG Criteria
title_sort case series of familial arid1b variants illustrating variable expression and suggestions to update the acmg criteria
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8393241/
https://www.ncbi.nlm.nih.gov/pubmed/34440449
http://dx.doi.org/10.3390/genes12081275
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