A Case Series of Familial ARID1B Variants Illustrating Variable Expression and Suggestions to Update the ACMG Criteria
| Autor: | Claudia A. L. Ruivenkamp, Isabelle Maystadt, Scott E. Hickey, Bert B.A. de Vries, Marielle Alders, Stéphanie Moortgat, Bregje W.M. van Bon, Jill A. Rosenfeld, Kareesma Parbhoo, Catherine Vincent-Delorme, Johan T. den Dunnen, Thomas Smol, Debra S. Regier, Pleuntje J. van der Sluijs, Gijs W. E. Santen, Alexander J. M. Dingemans, Betsy Schmalz, Erica H. Gerkes, Bekim Sadikovic, Kyra E. Stuurman, Dan Doherty, Jennifer C. Dempsey, Ilana M. Milller |
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| Přispěvatelé: | Human Genetics, ACS - Pulmonary hypertension & thrombosis, ARD - Amsterdam Reproduction and Development, Clinical Genetics |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Male
Inherited Coffin–Siris syndrome Intellectual disability QH426-470 PHENOTYPE Variable Expression Familial non-pathogenic ARID1B Loss of Function Mutation Child Genetics (clinical) Genetics RISK familial Middle Aged ACMG guidelines DNA-Binding Proteins intellectual disability DNA methylation Medical genetics Female Haploinsufficiency Hand Deformities Congenital Adult medicine.medical_specialty GENES Adolescent Genomics Biology Non-pathogenic Article Young Adult All institutes and research themes of the Radboud University Medical Center medicine Humans Abnormalities Multiple Genetic Predisposition to Disease AUTISM Gene Loss function Sequence (medicine) COMPLEX Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7] DISABILITY COFFIN-SIRIS SYNDROME Variable expression DNA Methylation inherited variable expression Gene Expression Regulation Face Transcription Factors |
| Zdroj: | Genes Volume 12 Issue 8 Paediatrics Publications Genes, 12 Genes, 12, 8 Genes, 12(8):1275. Multidisciplinary Digital Publishing Institute (MDPI) Genes, 12(8) GENES Genes, Vol 12, Iss 1275, p 1275 (2021) Genes, 12(8):1275. MDPI AG |
| ISSN: | 2073-4425 |
| DOI: | 10.3390/genes12081275 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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