Linkage analysis identifies an isolated strabismus locus at 14q12 overlapping with FOXG1 syndrome region.

Strabismus is a common condition, affecting 1%-4% of individuals. Isolated strabismus has been studied in families with Mendelian inheritance patterns. Despite the identification of multiple loci via linkage analyses, no specific genes have been identified from these studies. The current study is based on a seven-generation family with isolated strabismus inherited in an autosomal dominant manner. A total of 13 individuals from a common ancestor have been included for linkage analysis. Among these, nine are affected and four are unaffected. A single linkage signal has been identified at an 8.5 Mb region of chromosome 14q12 with a multipoint LOD (logarithm of the odds) score of 4.69. Disruption of this locus is known to cause FOXG1 syndrome (or congenital Rett syndrome; OMIM #613454 and *164874), in which 84% of affected individuals present with strabismus. With the incorporation of next-generation sequencing and in-depth bioinformatic analyses, a 4 bp non-coding deletion was prioritised as the top candidate for the observed strabismus phenotype. The deletion is predicted to disrupt regulation of FOXG1, which encodes a transcription factor of the Forkhead family. Suggestive of an autoregulation effect, the disrupted sequence matches the consensus FOXG1 and Forkhead family transcription factor binding site and has been observed in previous ChIP-seq studies to be bound by Foxg1 in early mouse brain development. Future study of this specific deletion may shed light on the regulation of FOXG1 expression and may enhance our understanding of the mechanisms contributing to strabismus and FOXG1 syndrome.

A cross-sectional study of the relationship between CYP2D6 and CYP2C19 variations and depression symptoms, for women taking SSRIs during pregnancy.

Depression during pregnancy affects 10-15% of women, and 5% of women take antidepressants during pregnancy. Clinical guidelines provide recommendations for selective serotonin reuptake inhibitor (SSRI) drug choice and dose based on CYP2D6 and CYP2C19 genotype; however, they are based on evidence from non-pregnant cohorts. This study aimed to test the hypothesis that women with function-altering variants (increased, decreased, or no function) in these pharmacogenes, taking SSRIs prenatally, would have more depression symptoms than women whose pharmacogenetic variants are associated with normal SSRI metabolism. Comprehensive CYP2D6 and CYP2C19 genotyping using a range of methods, including gene copy number analysis, was performed as secondary analyses on two longitudinal cohorts of pregnant women (N = 83) taking the SSRIs paroxetine, citalopram, escitalopram, or sertraline. The Kruskal-Wallis test compared mean depression scores across four predicted metabolizer groups: poor (n = 5), intermediate (n = 10), normal (n = 53), and ultrarapid (n = 15). There were no significant differences between mean depression scores across the four metabolizer groups (H(3) = .73, p = .87, eta-squared = .029, epsilon-squared = .0089). This is the first study of the relationship in pregnancy between CYP2C19 pharmacogenetic variations and depression symptoms in the context of SSRI use. Findings from this initial study do not support the clinical use of pharmacogenetic testing for SSRI use during the second or third trimesters of pregnancy, but these findings should be confirmed in larger cohorts. There is an urgent need for further research to clarify the utility of pharmacogenetic testing for pregnant women, especially as companies offering direct-to-consumer genetic testing expand their marketing efforts.

Differentiation of vascular smooth muscle cells from local precursors during embryonic and adult arteriogenesis requires Notch signaling.

Vascular smooth muscle cells (VSMC) have been suggested to arise from various developmental sources during embryogenesis, depending on the vascular bed. However, evidence also points to a common subpopulation of vascular progenitor cells predisposed to VSMC fate in the embryo. In the present study, we use binary transgenic reporter mice to identify a Tie1(+)CD31(dim)vascular endothelial (VE)-cadherin(-)CD45(-) precursor that gives rise to VSMC in vivo in all vascular beds examined. This precursor does not represent a mature endothelial cell, because a VE-cadherin promoter-driven reporter shows no expression in VSMC during murine development. Blockade of Notch signaling in the Tie1(+) precursor cell, but not the VE-cadherin(+) endothelial cell, decreases VSMC investment of developing arteries, leading to localized hemorrhage in the embryo at the time of vascular maturation. However, Notch signaling is not required in the Tie1(+) precursor after establishment of a stable artery. Thus, Notch activity is required in the differentiation of a Tie1(+) local precursor to VSMC in a spatiotemporal fashion across all vascular beds.

A pharmacogenomic investigation of the cardiac safety profile of ondansetron in children and pregnant women.

BACKGROUND: Ondansetron is a highly effective antiemetic for the treatment of nausea and vomiting. However, this medication has also been associated with QT prolongation. Pharmacogenomic information on therapeutic response to ondansetron exists, but no investigation has been performed on genetic factors that influence the cardiac safety of this medication. METHODS: Three patient groups receiving ondansetron were recruited and followed prospectively (pediatric post-surgical patients n = 101; pediatric oncology patients n = 98; pregnant women n = 62). Electrocardiograms were conducted at baseline, and 5- and 30-min post-ondansetron administration, to determine the effect of ondansetron treatment on QT interval. Pharmacogenomic associations were assessed via analyses of comprehensive CYP2D6 genotyping and genome-wide association study data. RESULTS: In the entire cohort, 62 patients (24.1%) met the criteria for prolonged QT, with 1.2% of the cohort exhibiting unsafe QT prolongation. The most significant shift from baseline occurred at five minutes post-ondansetron administration (P = 9.8 × 10-4). CYP2D6 activity score was not associated with prolonged QT. Genome-wide analyses identified novel associations with a missense variant in TLR3 (rs3775291; P = 2.00 × 10-7) and a variant linked to the expression of SLC36A1 (rs34124313; P = 1.97 × 10-7). CONCLUSIONS: This study has provided insight into the genomic basis of ondansetron-induced cardiac changes and has emphasized the importance of genes that have been implicated in serotonin-related traits. These biologically-relevant findings represent the first step towards understanding this adverse event with the overall goal to improve the safety of this commonly used antiemetic medication.