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Beyond Trinucleotide Repeat Expansion in Fragile X Syndrome: Rare Coding and Noncoding Variants in FMR1 and Associated Phenotypes

FMR1 (FMRP translational regulator 1) variants other than repeat expansion are known to cause disease phenotypes but can be overlooked if they are not accounted for in genetic testing strategies. We collected and reanalyzed the evidence for pathogenicity of FMR1 coding, noncoding, and copy number va...

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Autores principales: Tekendo-Ngongang, Cedrik, Grochowsky, Angela, Solomon, Benjamin D., Yano, Sho T.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8623550/
https://www.ncbi.nlm.nih.gov/pubmed/34828275
http://dx.doi.org/10.3390/genes12111669
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author Tekendo-Ngongang, Cedrik
Grochowsky, Angela
Solomon, Benjamin D.
Yano, Sho T.
author_facet Tekendo-Ngongang, Cedrik
Grochowsky, Angela
Solomon, Benjamin D.
Yano, Sho T.
author_sort Tekendo-Ngongang, Cedrik
collection PubMed
description FMR1 (FMRP translational regulator 1) variants other than repeat expansion are known to cause disease phenotypes but can be overlooked if they are not accounted for in genetic testing strategies. We collected and reanalyzed the evidence for pathogenicity of FMR1 coding, noncoding, and copy number variants published to date. There is a spectrum of disease-causing FMR1 variation, with clinical and functional evidence supporting pathogenicity of five splicing, five missense, one in-frame deletion, one nonsense, and four frameshift variants. In addition, FMR1 deletions occur in both mosaic full mutation patients and as constitutional pathogenic alleles. De novo deletions arise not only from full mutation alleles but also alleles with normal-sized CGG repeats in several patients, suggesting that the CGG repeat region may be prone to genomic instability even in the absence of repeat expansion. We conclude that clinical tests for potentially FMR1-related indications such as intellectual disability should include methods capable of detecting small coding, noncoding, and copy number variants.
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spelling pubmed-86235502021-11-27 Beyond Trinucleotide Repeat Expansion in Fragile X Syndrome: Rare Coding and Noncoding Variants in FMR1 and Associated Phenotypes Tekendo-Ngongang, Cedrik Grochowsky, Angela Solomon, Benjamin D. Yano, Sho T. Genes (Basel) Article FMR1 (FMRP translational regulator 1) variants other than repeat expansion are known to cause disease phenotypes but can be overlooked if they are not accounted for in genetic testing strategies. We collected and reanalyzed the evidence for pathogenicity of FMR1 coding, noncoding, and copy number variants published to date. There is a spectrum of disease-causing FMR1 variation, with clinical and functional evidence supporting pathogenicity of five splicing, five missense, one in-frame deletion, one nonsense, and four frameshift variants. In addition, FMR1 deletions occur in both mosaic full mutation patients and as constitutional pathogenic alleles. De novo deletions arise not only from full mutation alleles but also alleles with normal-sized CGG repeats in several patients, suggesting that the CGG repeat region may be prone to genomic instability even in the absence of repeat expansion. We conclude that clinical tests for potentially FMR1-related indications such as intellectual disability should include methods capable of detecting small coding, noncoding, and copy number variants. MDPI 2021-10-22 /pmc/articles/PMC8623550/ /pubmed/34828275 http://dx.doi.org/10.3390/genes12111669 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
Tekendo-Ngongang, Cedrik
Grochowsky, Angela
Solomon, Benjamin D.
Yano, Sho T.
Beyond Trinucleotide Repeat Expansion in Fragile X Syndrome: Rare Coding and Noncoding Variants in FMR1 and Associated Phenotypes
title Beyond Trinucleotide Repeat Expansion in Fragile X Syndrome: Rare Coding and Noncoding Variants in FMR1 and Associated Phenotypes
title_full Beyond Trinucleotide Repeat Expansion in Fragile X Syndrome: Rare Coding and Noncoding Variants in FMR1 and Associated Phenotypes
title_fullStr Beyond Trinucleotide Repeat Expansion in Fragile X Syndrome: Rare Coding and Noncoding Variants in FMR1 and Associated Phenotypes
title_full_unstemmed Beyond Trinucleotide Repeat Expansion in Fragile X Syndrome: Rare Coding and Noncoding Variants in FMR1 and Associated Phenotypes
title_short Beyond Trinucleotide Repeat Expansion in Fragile X Syndrome: Rare Coding and Noncoding Variants in FMR1 and Associated Phenotypes
title_sort beyond trinucleotide repeat expansion in fragile x syndrome: rare coding and noncoding variants in fmr1 and associated phenotypes
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8623550/
https://www.ncbi.nlm.nih.gov/pubmed/34828275
http://dx.doi.org/10.3390/genes12111669
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