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

Renee Carroll, Marie Shaw, Maria Arvio, Alison Gardner, Raman Kumar, Bree Hodgson, Sarah Heron, Fiona McKenzie, Irma Järvelä, Jozef Gecz

Research output: Contribution to journalArticleScientificpeer-review


The 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.

Original languageEnglish
Article number104010
JournalEuropean Journal of Medical Genetics
Issue number10
Number of pages6
Publication statusPublished - Oct 2020
MoE publication typeA1 Journal article-refereed

Fields of Science

  • FMR1
  • Intragenic variants
  • Whole exome sequencing
  • WES
  • Whole genome sequencing
  • WGS
  • FMRP
  • Fragile X syndrome
  • FXS
  • No repeat expansion
  • 3111 Biomedicine
  • 1184 Genetics, developmental biology, physiology

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