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. 2022 May 11:13:884424.
doi: 10.3389/fgene.2022.884424. eCollection 2022.

De Novo Large Deletion Leading to Fragile X Syndrome

Poonnada Jiraanont  1 , Esther Manor  2   3 , Nazi Tabatadze  4 , Marwa Zafarullah  5 , Guadalupe Mendoza  5 , Gia Melikishvili  4 , Flora Tassone  5   6
Affiliations

De Novo Large Deletion Leading to Fragile X Syndrome

Poonnada Jiraanont et al. Front Genet. .

Abstract

Fragile X syndrome (FXS) is the most frequent cause of X-linked inherited intellectual disabilities (ID) and the most frequent monogenic form of autism spectrum disorders. It is caused by an expansion of a CGG trinucleotide repeat located in the 5'UTR of the FMR1 gene, resulting in the absence of the fragile X mental retardation protein, FMRP. Other mechanisms such as deletions or point mutations of the FMR1 gene have been described and account for approximately 1% of individuals with FXS. Here, we report a 7-year-old boy with FXS with a de novo deletion of approximately 1.1 Mb encompassing several genes, including the FMR1 and the ASFMR1 genes, and several miRNAs, whose lack of function could result in the observed proband phenotypes. In addition, we also demonstrate that FMR4 completely overlaps with ASFMR1, and there are no sequencing differences between both transcripts (i.e., ASFMR1/FMR4 throughout the article).

Keywords: ASFMR1/FMR4 gene; FMR1 gene; fragile X syndrome; large deletion; miRNA.

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Conflict of interest statement

FT received funds from Azrieli Foundation and Zynerba for studies on Fragile X syndrome. The remaining authors declared that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Diagram illustrating the main molecular mechanisms leading to fragile X syndrome and FMR1-associated disorders. (A) Schematic of molecular causes of fragile X syndrome and FMR1-associated disorders. (B) Diagram of the deleted region detected in the proband. (C) Majority of the fragile X syndrome cases are due to an expansion of the CGG repeat in the 5′UTR of the FMR1 gene. However, several mutations, including missense, nonsense, and deletion (as demonstrated in the proband) have been reported. A list can be found in the Human Gene Mutation Database for FXS (http://www.hgmd.cf.ac.uk/ac/gene.php?gene=FMR1).
FIGURE 2
FIGURE 2
Family pedigree. His family history demonstrates two healthy 16- and 14-year-old sisters. The maternal uncle (II-3) displayed mild to moderate intellectual disability, and the maternal aunt (II-4) displayed psychiatric problems (depressive disorder) and ovarian cysts, unrelated to a mutation in the FMR1 gene.
FIGURE 3
FIGURE 3
FMR4 overlaps with ASFMR1. The figure shows a visualization of sequence alignment in Integrative Genomic Viewer (IGV) at 3487 base-pair resolution on chromosome X in human genome assembly GRCh38 (hg38). (A) ASFMR1 and FMR1 genes from the human genome assembly are shown (the top of the three tracks are highlighted in blue). The middle track is the ASFMR1 transcript reported by (Ladd et al., 2007) overlapping with the FMR1 gene (going in the opposite direction). For the FMR1 gene, only exon 1 (containing the CGG repeat) and intron 1 (thin blue line) are shown. The bottom track (highlighted in red) shows the sequence of the FMR4 reported by (Khalil et al., 2008). The location of the CGG repeat in the FMR1 is indicated (CCG in the antisense direction). (B) Diagram shows the overlap between the two transcripts ASFMR1 (highlighted in blue) and FMR4 (highlighted in red) on a zoom image of the 6-kb ASFMR1 identified transcripts. The overlap demonstrates the sequencing identity of the two transcripts. The location of the CGG repeat in the FMR1 is indicated (CCG in the antisense direction).
See this image and copyright information in PMC

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