Two novel intragenic variants in the FMR1 gene in patients with suspect clinical diagnosis of Fragile X syndrome and no CGG repeat expansion

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dc.contributor.authorCarroll, R.
dc.contributor.authorShaw, M.
dc.contributor.authorArvio, M.
dc.contributor.authorGardner, A.
dc.contributor.authorKumar, R.
dc.contributor.authorHodgson, B.
dc.contributor.authorHeron, S.
dc.contributor.authorMcKenzie, F.
dc.contributor.authorJärvelä, I.
dc.contributor.authorGecz, J.
dc.date.issued2020
dc.description.abstractThe major and most well-studied genetic cause of Fragile-X syndrome (FXS) is expansion of a CGG repeat in the 5'-UTR of the FMR1 gene. Routine testing for this expansion is performed globally. Overall, there is a paucity of intragenic variants explaining FXS, a fact which is being addressed by a more systematic application of whole exome (WES) and whole genome (WGS) sequencing, even in the diagnostic setting. Here we report two families comprising probands with a clinical suspicion of FXS and no CGG repeat expansions. Using WES/WGS we identified deleterious variants within the coding region of FMR1 in both families. In a family from Finland we identified a complex indel c.1021-1028delinsTATTGG in exon 11 of FMR1 which gives rise to a frameshift and a premature termination codon (PTC), p.Asn341Tyrfs*7. Follow-up mRNA and protein studies on a cell line from the proband revealed that although the mRNA levels of FMR1 were not altered, Fragile X Mental Retardation 1 Protein (FMRP) was undetectable. Additionally, we identified a variant, c.881-1G > T, affecting the canonical acceptor splice site of exon 10 of FMR1 in an Australian family. Our findings reinforce the importance of intragenic FMR1 variant testing, particularly in cases with clinical features of FXS and no CGG repeat expansions identified.
dc.description.statementofresponsibilityRenee Carroll, Marie Shaw, Maria Arvio, Alison Gardner, Raman Kumar, Bree Hodgson ... ET AL.
dc.identifier.citationEuropean Journal of Medical Genetics, 2020; 63(10):1-6
dc.identifier.doi10.1016/j.ejmg.2020.104010
dc.identifier.issn1769-7212
dc.identifier.issn1878-0849
dc.identifier.orcidCarroll, R. [0000-0002-6979-3710]
dc.identifier.orcidShaw, M. [0000-0002-5060-190X]
dc.identifier.orcidGardner, A. [0009-0009-7321-1697]
dc.identifier.orcidKumar, R. [0000-0001-7976-8386]
dc.identifier.orcidHeron, S. [0000-0001-8759-6748]
dc.identifier.orcidGecz, J. [0000-0002-7884-6861]
dc.identifier.urihttp://hdl.handle.net/2440/128714
dc.language.isoen
dc.publisherElsevier
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1155224
dc.rights© 2020 Elsevier Masson SAS. All rights reserved.
dc.source.urihttps://doi.org/10.1016/j.ejmg.2020.104010
dc.subjectFMR1
dc.subjectFMRP
dc.subjectFRAXA
dc.subjectFXS
dc.subjectFragile X syndrome
dc.subjectIntragenic variants
dc.subjectNo repeat expansion
dc.subjectWES
dc.subjectWGS
dc.subjectWhole exome sequencing
dc.subjectWhole genome sequencing
dc.titleTwo novel intragenic variants in the FMR1 gene in patients with suspect clinical diagnosis of Fragile X syndrome and no CGG repeat expansion
dc.typeJournal article
pubs.publication-statusPublished

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