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...

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Autores principales:	Cedrik Tekendo-Ngongang, Angela Grochowsky, Benjamin D. Solomon, Sho T. Yano
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	<i>FMR1</i> FMRP fragile X variant classification copy number variants Genetics QH426-470
Acceso en línea:	https://doaj.org/article/6e7e7d6aa7194e14893eff7ca6a5b2b3
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spelling	oai:doaj.org-article:6e7e7d6aa7194e14893eff7ca6a5b2b32021-11-25T17:40:33ZBeyond Trinucleotide Repeat Expansion in Fragile X Syndrome: Rare Coding and Noncoding Variants in <i>FMR1</i> and Associated Phenotypes10.3390/genes121116692073-4425https://doaj.org/article/6e7e7d6aa7194e14893eff7ca6a5b2b32021-10-01T00:00:00Zhttps://www.mdpi.com/2073-4425/12/11/1669https://doaj.org/toc/2073-4425<i>FMR1</i> (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 <i>FMR1</i> coding, noncoding, and copy number variants published to date. There is a spectrum of disease-causing <i>FMR1</i> 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, <i>FMR1</i> 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 <i>FMR1</i>-related indications such as intellectual disability should include methods capable of detecting small coding, noncoding, and copy number variants.Cedrik Tekendo-NgongangAngela GrochowskyBenjamin D. SolomonSho T. YanoMDPI AGarticle<i>FMR1</i>FMRPfragile Xvariant classificationcopy number variantsGeneticsQH426-470ENGenes, Vol 12, Iss 1669, p 1669 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	<i>FMR1</i> FMRP fragile X variant classification copy number variants Genetics QH426-470
spellingShingle	<i>FMR1</i> FMRP fragile X variant classification copy number variants Genetics QH426-470 Cedrik Tekendo-Ngongang Angela Grochowsky Benjamin D. Solomon Sho T. Yano Beyond Trinucleotide Repeat Expansion in Fragile X Syndrome: Rare Coding and Noncoding Variants in <i>FMR1</i> and Associated Phenotypes
description	<i>FMR1</i> (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 <i>FMR1</i> coding, noncoding, and copy number variants published to date. There is a spectrum of disease-causing <i>FMR1</i> 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, <i>FMR1</i> 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 <i>FMR1</i>-related indications such as intellectual disability should include methods capable of detecting small coding, noncoding, and copy number variants.
format	article
author	Cedrik Tekendo-Ngongang Angela Grochowsky Benjamin D. Solomon Sho T. Yano
author_facet	Cedrik Tekendo-Ngongang Angela Grochowsky Benjamin D. Solomon Sho T. Yano
author_sort	Cedrik Tekendo-Ngongang
title	Beyond Trinucleotide Repeat Expansion in Fragile X Syndrome: Rare Coding and Noncoding Variants in <i>FMR1</i> and Associated Phenotypes
title_short	Beyond Trinucleotide Repeat Expansion in Fragile X Syndrome: Rare Coding and Noncoding Variants in <i>FMR1</i> and Associated Phenotypes
title_full	Beyond Trinucleotide Repeat Expansion in Fragile X Syndrome: Rare Coding and Noncoding Variants in <i>FMR1</i> and Associated Phenotypes
title_fullStr	Beyond Trinucleotide Repeat Expansion in Fragile X Syndrome: Rare Coding and Noncoding Variants in <i>FMR1</i> and Associated Phenotypes
title_full_unstemmed	Beyond Trinucleotide Repeat Expansion in Fragile X Syndrome: Rare Coding and Noncoding Variants in <i>FMR1</i> and Associated Phenotypes
title_sort	beyond trinucleotide repeat expansion in fragile x syndrome: rare coding and noncoding variants in <i>fmr1</i> and associated phenotypes
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/6e7e7d6aa7194e14893eff7ca6a5b2b3
work_keys_str_mv	AT cedriktekendongongang beyondtrinucleotiderepeatexpansioninfragilexsyndromerarecodingandnoncodingvariantsinifmr1iandassociatedphenotypes AT angelagrochowsky beyondtrinucleotiderepeatexpansioninfragilexsyndromerarecodingandnoncodingvariantsinifmr1iandassociatedphenotypes AT benjamindsolomon beyondtrinucleotiderepeatexpansioninfragilexsyndromerarecodingandnoncodingvariantsinifmr1iandassociatedphenotypes AT shotyano beyondtrinucleotiderepeatexpansioninfragilexsyndromerarecodingandnoncodingvariantsinifmr1iandassociatedphenotypes
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Beyond Trinucleotide Repeat Expansion in Fragile X Syndrome: Rare Coding and Noncoding Variants in <i>FMR1</i> and Associated Phenotypes

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