Integrated genome and transcriptome sequencing identifies a noncoding mutation in the genome replication factor DONSON as the cause of microcephaly-micromelia syndrome.

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.

Cardiovascular risk reduction via telehealth: a feasibility study.

BACKGROUND: Successful cardiovascular risk reduction (CVRR) requires ongoing care, which can be difficult for patients living outside urban areas. The authors tested the feasibility of CVRR using telehealth. METHODS: Telehealth care (T group, n=9) was offered at three- to six-month intervals to patients referred from La Ronge, Saskatchewan (385 km northeast of Saskatoon, Saskatchewan). All patients who were referred to the project accepted. For the initial visit, the clinic travelled to La Ronge; all other visits were performed using telehealth (CommunityNet). Body measurements, blood pressure readings, fasting laboratory tests and food and exercise logs were completed in La Ronge. During the telehealth session, patients met with a nurse, a dietician, a fitness consultant and a physician. Changes in medication were faxed or telephoned to the local pharmacy. The T group's outcomes were compared with a control group (C group, n=15), which was offered usual care from La Ronge and had been referred to the clinic previously. Change in Framingham risk score, as well as patient and provider satisfaction, was assessed. RESULTS: The groups were similar in age (T: 44.3+/-12.8 years, C: 48.3+/-14.3 years) and initial Framingham risk score (T: 12.0+/-13.0%, C: 11.1+/-10.0%). All nine T group patients completed two or more visits, while only eight of 15 patients the C group did so. Both groups achieved a small reduction in Framingham risk score (T: -1.9+/-5.0%, C: -2.0+/-6.1%). Those with the highest initial Framingham risk scores tended to show the greatest reduction. The T group's patient and health care provider comments were generally positive. CONCLUSIONS: CVRR via telehealth is feasible and compares favourably with usual care. In particular, more complete follow-up occurs.