Haploinsufficiency of FOXP2 causes FOXP2-related speech and language disorder. We report a 9.8 Mb deletion downstream of FOXP2 in a girl with speech and language impairment, developmental delay, and other features. We propose involvement of FOXP2 in pathogenesis of these phenotypes, likely due to positional effects on the gene.

Environmental cues are known to alter the methylation profile of genomic DNA, and thereby change the expression of some genes. A proportion of such modifications may become adaptive by adjusting expression of stress response genes but others have been shown to be highly stochastic, even under controlled conditions. The influence of environmental flux on plants adds an additional layer of complexity that has potential to confound attempts to interpret interactions between environment, methylome, and plant form. We therefore adopt a positional and longitudinal approach to study progressive changes to barley DNA methylation patterns in response to salt exposure during development under greenhouse conditions. Methylation-sensitive amplified polymorphism (MSAP) and phenotypic analyses of nine diverse barley varieties were grown in a randomized plot design, under two salt treatments (0 and 75 mM NaCl). Combining environmental, phenotypic and epigenetic data analyses, we show that at least part of the epigenetic variability, previously described as stochastic, is linked to environmental micro-variations during plant growth. Additionally, we show that differences in methylation increase with time of exposure to micro-variations in environment. We propose that subsequent epigenetic studies take into account microclimate-induced epigenetic variability.

Split hand/foot malformation (SHFM) or ectrodactyly is a rare congenital disorder affecting limb development characterized by clinical and genetic heterogeneity. SHFM is usually inherited as an autosomal dominant trait with incomplete penetrance. Isolated and syndromic forms are described. The extent of associated malformations is highly variable and multiple syndromes with clinical and genetic overlap have been described. We report here a 28 year-old man presenting with SHFM, sparse hair and widespread freckles. Array-CGH identified a 450 kb de novo 20p12.1 microdeletion encompassing three exons (exon 6 to 8) of MACROD2. Although MACROD2 mutations have not been associated with limb malformation until now, it is located next to KIF16B, which is involved in fibroblast growth factor receptor (FGFR) signaling. Additionally, the deletion encompassed a histone modification H3K27ac mark, known as a provider of quantitative readout of promoter and enhancer activity during human limb development. Altogether, these findings suggest that the 20p12.1 CNV is causative of SHFM in the present case through disturbance of regulatory elements functioning.

Splice site selection is a key step that determines the mRNA isoforms generated from a single transcript. The large diversity in splice site sequences emphasizes the plasticity of splice site recognition and selection. In this report, a cell-based reporter system using a SMN1/2 cassette exon was applied to study the roles governing the activation of a cryptic 5\'SS from the intron 4 of the CT/CGRP gene. We found that the cryptic site was activated when placed within 124nt downstream the cassette exon, and the level of activation was negatively correlated with its distance from the exon. In addition, activation was not affected by PTB but was eliminated by an insertion extending the exon length. Activated cryptic 5\'SSs in intron or exon could override the original alternative 5\'SS, obeying the U1 base-pairing rule. These results suggest that the exon length itself could represent a factor in determining the splice site selection.

The RNA-binding protein (RBP) LIN41, also known as LIN-41 or TRIM71, is a key regulator of animal development, but its physiological targets and molecular mechanism of action are largely elusive. Here we find that this RBP has two distinct mRNA-silencing activities. Using genome-wide ribosome profiling, RNA immunoprecipitation, and in vitro-binding experiments, we identify four mRNAs, each encoding a transcription factor or cofactor, as direct physiological targets of C. elegans LIN41. LIN41 silences three of these targets through their 3\' UTRs, but it achieves isoform-specific silencing of one target, lin-29A, through its unique 5\' UTR. Whereas the 3\' UTR targets mab-10, mab-3, and dmd-3 undergo transcript degradation, lin-29A experiences translational repression. Through binding site transplantation experiments, we demonstrate that it is the location of the LIN41-binding site that specifies the silencing mechanism. Such position-dependent dual activity may, when studied more systematically, emerge as a feature shared by other RBPs.