Cargando…
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 (...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , |
---|---|
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 |
_version_ | 1783743687757398016 |
---|---|
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. |
format | Online Article Text |
id | pubmed-8393241 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT vandersluijspleuntjej acaseseriesoffamilialarid1bvariantsillustratingvariableexpressionandsuggestionstoupdatetheacmgcriteria AT aldersmarielle acaseseriesoffamilialarid1bvariantsillustratingvariableexpressionandsuggestionstoupdatetheacmgcriteria AT dingemansalexanderjm acaseseriesoffamilialarid1bvariantsillustratingvariableexpressionandsuggestionstoupdatetheacmgcriteria AT parbhookareesma acaseseriesoffamilialarid1bvariantsillustratingvariableexpressionandsuggestionstoupdatetheacmgcriteria AT vanbonbregjew acaseseriesoffamilialarid1bvariantsillustratingvariableexpressionandsuggestionstoupdatetheacmgcriteria AT dempseyjenniferc acaseseriesoffamilialarid1bvariantsillustratingvariableexpressionandsuggestionstoupdatetheacmgcriteria AT dohertydan acaseseriesoffamilialarid1bvariantsillustratingvariableexpressionandsuggestionstoupdatetheacmgcriteria AT dendunnenjohant acaseseriesoffamilialarid1bvariantsillustratingvariableexpressionandsuggestionstoupdatetheacmgcriteria AT gerkesericah acaseseriesoffamilialarid1bvariantsillustratingvariableexpressionandsuggestionstoupdatetheacmgcriteria AT milllerilanam acaseseriesoffamilialarid1bvariantsillustratingvariableexpressionandsuggestionstoupdatetheacmgcriteria AT moortgatstephanie acaseseriesoffamilialarid1bvariantsillustratingvariableexpressionandsuggestionstoupdatetheacmgcriteria AT regierdebras acaseseriesoffamilialarid1bvariantsillustratingvariableexpressionandsuggestionstoupdatetheacmgcriteria AT ruivenkampclaudiaal acaseseriesoffamilialarid1bvariantsillustratingvariableexpressionandsuggestionstoupdatetheacmgcriteria AT schmalzbetsy acaseseriesoffamilialarid1bvariantsillustratingvariableexpressionandsuggestionstoupdatetheacmgcriteria AT smolthomas acaseseriesoffamilialarid1bvariantsillustratingvariableexpressionandsuggestionstoupdatetheacmgcriteria AT stuurmankyrae acaseseriesoffamilialarid1bvariantsillustratingvariableexpressionandsuggestionstoupdatetheacmgcriteria AT vincentdelormecatherine acaseseriesoffamilialarid1bvariantsillustratingvariableexpressionandsuggestionstoupdatetheacmgcriteria AT devriesbertba acaseseriesoffamilialarid1bvariantsillustratingvariableexpressionandsuggestionstoupdatetheacmgcriteria AT sadikovicbekim acaseseriesoffamilialarid1bvariantsillustratingvariableexpressionandsuggestionstoupdatetheacmgcriteria AT hickeyscotte acaseseriesoffamilialarid1bvariantsillustratingvariableexpressionandsuggestionstoupdatetheacmgcriteria AT rosenfeldjilla acaseseriesoffamilialarid1bvariantsillustratingvariableexpressionandsuggestionstoupdatetheacmgcriteria AT maystadtisabelle acaseseriesoffamilialarid1bvariantsillustratingvariableexpressionandsuggestionstoupdatetheacmgcriteria AT santengijswe acaseseriesoffamilialarid1bvariantsillustratingvariableexpressionandsuggestionstoupdatetheacmgcriteria AT vandersluijspleuntjej caseseriesoffamilialarid1bvariantsillustratingvariableexpressionandsuggestionstoupdatetheacmgcriteria AT aldersmarielle caseseriesoffamilialarid1bvariantsillustratingvariableexpressionandsuggestionstoupdatetheacmgcriteria AT dingemansalexanderjm caseseriesoffamilialarid1bvariantsillustratingvariableexpressionandsuggestionstoupdatetheacmgcriteria AT parbhookareesma caseseriesoffamilialarid1bvariantsillustratingvariableexpressionandsuggestionstoupdatetheacmgcriteria AT vanbonbregjew caseseriesoffamilialarid1bvariantsillustratingvariableexpressionandsuggestionstoupdatetheacmgcriteria AT dempseyjenniferc caseseriesoffamilialarid1bvariantsillustratingvariableexpressionandsuggestionstoupdatetheacmgcriteria AT dohertydan caseseriesoffamilialarid1bvariantsillustratingvariableexpressionandsuggestionstoupdatetheacmgcriteria AT dendunnenjohant caseseriesoffamilialarid1bvariantsillustratingvariableexpressionandsuggestionstoupdatetheacmgcriteria AT gerkesericah caseseriesoffamilialarid1bvariantsillustratingvariableexpressionandsuggestionstoupdatetheacmgcriteria AT milllerilanam caseseriesoffamilialarid1bvariantsillustratingvariableexpressionandsuggestionstoupdatetheacmgcriteria AT moortgatstephanie caseseriesoffamilialarid1bvariantsillustratingvariableexpressionandsuggestionstoupdatetheacmgcriteria AT regierdebras caseseriesoffamilialarid1bvariantsillustratingvariableexpressionandsuggestionstoupdatetheacmgcriteria AT ruivenkampclaudiaal caseseriesoffamilialarid1bvariantsillustratingvariableexpressionandsuggestionstoupdatetheacmgcriteria AT schmalzbetsy caseseriesoffamilialarid1bvariantsillustratingvariableexpressionandsuggestionstoupdatetheacmgcriteria AT smolthomas caseseriesoffamilialarid1bvariantsillustratingvariableexpressionandsuggestionstoupdatetheacmgcriteria AT stuurmankyrae caseseriesoffamilialarid1bvariantsillustratingvariableexpressionandsuggestionstoupdatetheacmgcriteria AT vincentdelormecatherine caseseriesoffamilialarid1bvariantsillustratingvariableexpressionandsuggestionstoupdatetheacmgcriteria AT devriesbertba caseseriesoffamilialarid1bvariantsillustratingvariableexpressionandsuggestionstoupdatetheacmgcriteria AT sadikovicbekim caseseriesoffamilialarid1bvariantsillustratingvariableexpressionandsuggestionstoupdatetheacmgcriteria AT hickeyscotte caseseriesoffamilialarid1bvariantsillustratingvariableexpressionandsuggestionstoupdatetheacmgcriteria AT rosenfeldjilla caseseriesoffamilialarid1bvariantsillustratingvariableexpressionandsuggestionstoupdatetheacmgcriteria AT maystadtisabelle caseseriesoffamilialarid1bvariantsillustratingvariableexpressionandsuggestionstoupdatetheacmgcriteria AT santengijswe caseseriesoffamilialarid1bvariantsillustratingvariableexpressionandsuggestionstoupdatetheacmgcriteria |