While next-generation sequencing has accelerated the discovery of human disease genes, progress has been largely limited to the “low hanging fruit” of mutations with obvious exonic coding or canonical splice site impact. In contrast, the lack of high-throughput, unbiased approaches for functional assessment of most noncoding variants has bottlenecked gene discovery. We report the integration of transcriptome sequencing (RNA-seq), which surveys all mRNAs to reveal functional impacts of variants at the transcription level, into the gene discovery framework for a unique human disease, microcephaly-micromelia syndrome (MMS). MMS is an autosomal recessive condition described thus far in only a single First Nations population and causes intrauterine growth restriction, severe microcephaly, craniofacial anomalies, skeletal dysplasia, and neonatal lethality. Linkage analysis of affected families, including a very large pedigree, identified a single locus on Chromosome 21 linked to the disease (LOD > 9). Comprehensive genome sequencing did not reveal any pathogenic coding or canonical splicing mutations within the linkage region but identified several nonconserved noncoding variants. RNA-seq analysis detected aberrant splicing in DONSON due to one of these noncoding variants, showing a causative role for DONSON disruption in MMS. We show that DONSON is expressed in progenitor cells of embryonic human brain and other proliferating tissues, is co-expressed with components of the DNA replication machinery, and that Donson is essential for early embryonic development in mice as well, suggesting an essential conserved role for DONSON in the cell cycle. Our results demonstrate the utility of integrating transcriptomics into the study of human genetic disease when DNA sequencing alone is not sufficient to reveal the underlying pathogenic mutation.

Experimental increase of CpG dinucleotides in an RNA virus genome impairs infection providing a promising approach for vaccine development. While CpG recoding is an emerging and promising vaccine approach, little is known about infection phenotypes caused by recoded viruses in vivo. For example, infection phenotypes, immunogenicity, and protective efficacy induced by CpG-recoded viruses in different age groups were not studied yet. This is important, because attenuation of infection phenotypes caused by recoded viruses may depend on the population-based expression of cellular components targeting viral CpG dinucleotides. In the present study, we generated several Zika virus (ZIKV) variants with the increasing CpG content and compared infection in neonatal and adult mice. Increasing the CpG content caused host-age-dependent attenuation of infection with considerable attenuation in neonates and high attenuation in adults. Expression of the zinc-finger antiviral protein (ZAP)-the host protein targeting viral CpG dinucleotides-was also age-dependent. Similar to the wild-type virus, ZIKV variants with the increased CpG content evoked robust cellular and humoral immune responses and protection against lethal challenge. Collectively, the host age should be accounted for in future studies on mechanisms targeting viral CpG dinucleotides, development of safe dinucleotide recoding strategies, and applications of CpG-recoded vaccines.

This document reflects emerging clinical and scientific advances on the date issued, and is subject to change. The information should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate amendments to these opinions. They should be well documented if modified at the local level. None of these contents may be reproduced in any form without prior written permission of the SOGC. AbstractObjective: To provide guidelines for the use of antenatal magnesium sulphate (MgSO 4 ) for fetal neuroprotection of the preterm infant .Options: Antenatal MgSO 4 administration should be considered for fetal neuroprotection when women present at ≤ 31+6 weeks with imminent preterm birth, defined as a high likelihood of birth because of active labour with cervical dilatation ≥ 4 cm, with or without preterm pre-labour rupture of membranes, and/or planned preterm birth for fetal or maternal indications .There are no other known fetal neuroprotective agents .Outcomes: The outcomes measured are the incidence of cerebral palsy (CP) and neonatal death . Values: The quality of evidence was rated using the criteria described in the Report of the Canadian Task Force on Preventive Health Care (Table 1) .Benefits, harms, and costs: Antenatal magnesium sulphate for fetal neuroprotection reduces the risk of "death or CP" (RR 0 .85; 95% CI 0 .74 to 0 .98; 4 trials, 4446 infants), "death or moderatesevere CP" (RR 0 .85; 95% CI 0 .73 to 0 .99; 3 trials, 4250 infants), "any CP" (RR 0 .71; 95% CI 0 .55 to 0 .91; 4, trials, 4446 infants), "moderate-to-severe CP" (RR 0 .60; 95% CI 0 .43 to 0 .84; 3 trials, 4250 infants), and "substantial gross motor dysfunction" (inability to walk without assistance) (RR 0 .60; 95% CI 0 .43 to 0 .83; 3 trials, 4287 women) at 2 years of age . Results were consistent between trials and across the meta-analyses . There is no anticipated significant increase in health care-related costs, because women eligible to receive antenatal MgSO 4 will be judged to have imminent preterm birth .

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