Language impairment in a case of a complex chromosomal rearrangement with a breakpoint downstream of FOXP2

Abstract

BackgroundWe report on a young female, who presents with a severe speech and language disorder and a balanced de novo complex chromosomal rearrangement, likely to have resulted from a chromosome 7 pericentromeric inversion, followed by a chromosome 7 and 11 translocation.ResultsUsing molecular cytogenetics, we mapped the four breakpoints to 7p21.1-15.3 (chromosome position: 20,954,043-21,001,537, hg19), 7q31 (chromosome position: 114,528,369-114,556,605, hg19), 7q21.3 (chromosome position: 93,884,065-93,933,453, hg19) and 11p12 (chromosome position: 38,601,145-38,621,572, hg19). These regions contain only non-coding transcripts (ENSG00000232790 on 7p21.1 and TCONS_00013886, TCONS_00013887, TCONS_00014353, TCONS_00013888 on 7q21) indicating that no coding sequences are directly disrupted. The breakpoint on 7q31 mapped 200 kb downstream of FOXP2, a well-known language gene. No splice site or non-synonymous coding variants were found in the FOXP2 coding sequence. We were unable to detect any changes in the expression level of FOXP2 in fibroblast cells derived from the proband, although this may be the result of the low expression level of FOXP2 in these cells.ConclusionsWe conclude that the phenotype observed in this patient either arises from a subtle change in FOXP2 regulation due to the disruption of a downstream element controlling its expression, or from the direct disruption of non-coding RNAs.Electronic supplementary materialThe online version of this article (doi:10.1186/s13039-015-0148-1) contains supplementary material, which is available to authorized users.

Functional genetic characterization by CRISPR-Cas9 of two enhancers ofFOXP2in a child with speech and language impairment

“…Our findings in a neuronal cell line give support to the view that the breakpoint in our proband which separated these two functional enhancers may have altered the expression levels of both FOXP2 and MDFIC contributing to the observed speech and language deficits (Moralli et al 2015). Accordingly, we expect the expression of FOXP2 to be downregulated and the expression of MDFIC to be upregulated because of the displacement of both enhancers with respect to both genes (whereas FOXP2-E distal and MDFIC remained in chromosome 7, FOXP2-E proximal and FOXP2 were rearranged to chromosome 11).…”

“…Our findings in a human neuronal cell line give support to the view that the breakpoint in our proband, which separated each of these two intergenic enhancers from each other and consequently from one of the two genes they regulate, may have altered the expression levels of both FOXP2 and MDFIC contributing to the observed speech and language deficits (Moralli et al 2015). Whereas MDFIC remained in chromosome 7q with, predictably, FOXP2-E distal , FOXP2 was rearranged to chromosome 11p with, predictably, FOXP2-E proximal .…”

“…Apart from gene mutations, microdeletions involving FOXP2 and/or MDFIC, the adjacent gene downstream FOXP2, and the region between these two genes have been found in subjects with speech delay and cognitive impairment (DECIPHER patients 262086, 292652, and 301696). We have recently reported on a young female harbouring a genomic complex rearrangement involving chromosomes 7 and 11, who presents with severe expressive and receptive speech and language impairment in both Castilian Spanish and Valencian (Moralli et al 2015). Although the FOXP2 coding region is intact, the breakpoint in 7q31.1 is located 205.5 kb downstream the 3' end of FOXP2 and 22.8 kb upstream the 5' region of MDFIC.…”

“…In our proband this element was hypothesized to be in derivative chromosome 7q separated from FOXP2. While FOXP2 was shown to have been rearranged to derivative chromosome 11p, MDFIC had been located in derivative chromosome 7q, based on the FISH results from the RP11-243D16 BAC (Moralli et al 2015). A more robust approach, aimed at looking for changes in the expression levels of the gene seems desirable in order to know if this enhancer regulates FOXP2 expression.…”

The Long Non-Coding RNA LncRNA8975-1 is Upregulated in Hypertrophic Scar Fibroblasts and Controls Collagen Expression

“…A recent study reported that lncRNA8975-1 (TCONS_00013888) was disrupted in severe speech and language disorders [20]. Our group previously showed that lncRNA8975-1 was overexpressed in regressive scars compared to mature scar tissue [12].…”