J Med Genet

was previously implicated in periventricular nodular heterotopia (PVNH) in only five individuals and systematic clinical characterisation was not available. The aim of this study is to provide a comprehensive description of the phenotypic and genotypic spectrum of -related neurodevelopmental disorder. We collected detailed phenotypes of an international cohort of individuals (n=17) with variants assembled through the GeneMatcher platform. Missense variants were structurally modelled, and the impact of several were functionally validated. De novo variants (10 missense, 1 frameshift, 1 splice altering resulting in 9 residues insertion) in were identified among 17 unrelated individuals. Detailed phenotypes included intellectual disability (ID), microcephaly, seizures and PVNH. No specific facial characteristics were consistent across all cases, however microretrognathia was common. Various hearing and visual defects were recurrent, and interestingly, some inflammatory features were reported. MRI of the brain frequently showed abnormalities consistent with a neuronal migration disorder. We confirm the role of in an autosomal dominant syndrome with a phenotypic spectrum including severe ID, microcephaly, seizures and PVNH due to impaired neuronal migration

2,3,7,8-tetrachlorodibenzo-p-dioxin slows the progression of experimental cutaneous Leishmaniasis in susceptible BALB/c and SCID mice.

In a model of experimental cutaneous leishmaniasis, pre-exposure of Leishmania major-resistant mice to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), an aryl hydrocarbon receptor agonist, causes suppression of the protective anti-parasite T helper 1 response while paradoxically also reducing parasite burdens in those animals. In this study, we examined if TCDD exposure could also reduce parasite burdens in L. major-susceptible BALB/c mice. In the highest dose group (160 µg/Kg), TCDD treatment caused a significant reduction of parasite burdens by 10-fold after three weeks while also causing a significant lymphoid atrophy indicating suppression of the non-protective T helper 2 response. A dose-dependent delay of foot lesion progression was also observed such that lesion size in the highest dose group was less than half that of controls after 35 days of infection. Importantly, although TCDD exposure initially reduced disease severity and prolonged the course of disease by as much as three fold in some animals, this effect was transitory and TCDD did not induce resistance to L. major infection. Because TCDD exposure reduced L. major burdens in both resistant and susceptible mice, we hypothesized that TCDD reduces L. major burdens in mice by a mechanism that does not involve adaptive immunity. To test this, severe combined immunodeficient (SCID) mice were used. In mice infected with a moderate number of L. major (10,000), TCDD treatment caused a time- and dose-dependent decrease of parasite burdens by nearly 100-fold after six weeks in the highest dose group (200 µg/Kg). A significant and dose-dependent delay of foot lesion progression was also observed in these animals. These results indicate that TCDD exposure can reduce the severity of leishmanial disease in mice independent of adaptive immunity

TCDD reduces parasite burdens and slows the progression of cutaneous leishmaniasis in SCID mice.

<p>Female SCID mice were treated with peanut oil (vehicle) or TCDD (160 µg/Kg body weight) per os one day prior to infection with one million stationary phase L. major promastigotes in one rear footpad. <b>(A)</b> Lesion size is shown as mean ± SEM for five mice per group. *Indicates a statistically significant difference from vehicle-treated mice on that day (p < 0.05). The results are representative of four separate experiments. <b>(B)</b> Parasite burdens in individual infected feet were analyzed at four weeks post infection (six mice per treatment group; data represent mean ± SEM). Parasite burdens in individual spleens were analyzed at four weeks post infection (three mice per treatment group; data represent mean ± SEM). *Indicates a statistically significant difference from vehicle-treated mice on that day (p < 0.05). The results are representative of 2-3 separate experiments.</p

TCDD reduces parasite burdens and slows the progression of cutaneous leishmaniasis in BALB/c mice.

<p>Female BALB/c mice were treated with peanut oil (vehicle) or TCDD at various doses (per os) one day prior to infection with one million stationary phase L. major promastigotes in one rear footpad. Data are shown for 3-5 mice per treatment group on days 2-35 and are representative of three independent experiments. Data for two mice from one experiment are shown after day 35. <b>(A)</b> Lesion size is shown as mean ± SEM. Symbols with internal plus marks (+) indicate a statistically significant difference from vehicle-treated mice on that day (p < 0.05). <b>(B)</b> Parasite burdens in infected feet are shown (mean ± SEM) for mice euthanized on the days indicated: three mice per group up to day 35; after day 35, two mice were pooled (n = 1) . *Indicates a statistically significant difference from vehicle-treated mice on that day (p < 0.02).</p

Effects of TCDD in SCID mice after low dose infection.

<p>Female SCID mice were treated with peanut oil (vehicle) or TCDD at various doses (per os) one day prior to infection with ten thousand stationary phase <i>L. major</i> promastigotes in one rear footpad. (<b>A</b>) Lesion size is shown as mean ± SEM for 3-5 mice per time point. Symbols with internal plus marks (+) indicate a statistically significant difference from vehicle mice on that day (<i>p</i> < 0.05). All animals within a treatment group were euthanized following the last indicated measurement. (<b>B</b>) Mice were euthanized on the days indicated, and the infected feet of 2-3 mice per group were analyzed as a pool (n=1) for parasite burdens. (<b>C</b>) Percent body weight change is shown as mean ± SEM for 5 mice per time point. Data shown on day 35 reflects body weight change of animals measured either on day 35 or day 37.</p

Whole-exome sequencing reveals novel USP9X variant in female fetus with isolated agenesis of the corpus callosum.

Whole-exome sequencing in a female fetus detected a USP9X variant. This X-linked gene was recently associated with intellectual disability and distinct pattern of malformation in females. Isolated agenesis of the corpus callosum has not been reported in association with USP9X. Identifying this variant impacted management of the subsequent pregnancy

A Randomized, Controlled Trial of the Analytic and Diagnostic Performance of Singleton and Trio, Rapid Genome and Exome Sequencing in Ill Infants

The second Newborn Sequencing in Genomic Medicine and Public Health study was a randomized, controlled trial of the effectiveness of rapid whole-genome or -exome sequencing (rWGS or rWES, respectively) in seriously ill infants with diseases of unknown etiology. Here we report comparisons of analytic and diagnostic performance. Of 1,248 ill inpatient infants, 578 (46%) had diseases of unknown etiology. 213 infants (37% of those eligible) were enrolled within 96&nbsp;h of admission. 24 infants (11%) were very ill and received ultra-rapid whole-genome sequencing (urWGS). The remaining infants were randomized, 95 to rWES and 94 to rWGS. The analytic performance of rWGS was superior to rWES, including variants likely to affect protein function, and ClinVar pathogenic/likely pathogenic variants (p &lt; 0.0001). The diagnostic performance of rWGS and rWES were similar (18 diagnoses in 94 infants [19%] versus 19 diagnoses in 95 infants [20%], respectively), as was time to result (median 11.0 versus 11.2&nbsp;days, respectively). However, the proportion diagnosed by urWGS (11 of 24 [46%]) was higher than rWES/rWGS (p = 0.004) and time to result was less (median 4.6&nbsp;days, p &lt; 0.0001). The incremental diagnostic yield of reflexing to trio after negative proband analysis was 0.7% (1 of 147). In conclusion, rapid genomic sequencing can be performed as a first-tier diagnostic test in inpatient infants. urWGS had the shortest time to result, which was important in unstable infants, and those in whom a genetic diagnosis was likely to impact immediate management. Further comparison of urWGS and rWES is warranted because genomic technologies and knowledge of variant pathogenicity are evolving rapidly