Integrated multi-omics for rapid rare disease diagnosis on a national scale.

Critically ill infants and children with rare diseases need equitable access to rapid and accurate diagnosis to direct clinical management. Over 2 years, the Acute Care Genomics program provided whole-genome sequencing to 290 families whose critically ill infants and children were admitted to hospitals throughout Australia with suspected genetic conditions. The average time to result was 2.9 d and diagnostic yield was 47%. We performed additional bioinformatic analyses and transcriptome sequencing in all patients who remained undiagnosed. Long-read sequencing and functional assays, ranging from clinically accredited enzyme analysis to bespoke quantitative proteomics, were deployed in selected cases. This resulted in an additional 19 diagnoses and an overall diagnostic yield of 54%. Diagnostic variants ranged from structural chromosomal abnormalities through to an intronic retrotransposon, disrupting splicing. Critical care management changed in 120 diagnosed patients (77%). This included major impacts, such as informing precision treatments, surgical and transplant decisions and palliation, in 94 patients (60%). Our results provide preliminary evidence of the clinical utility of integrating multi-omic approaches into mainstream diagnostic practice to fully realize the potential of rare disease genomic testing in a timely manner.

Maternal vitamin D deficiency during rat gestation elicits a milder phenotype compared to the mouse model: Implications for the placental glucocorticoid barrier.

Maternal vitamin D deficiency disturbs fetal development and programmes neurodevelopmental complications in offspring, possibly through increased fetal glucocorticoid exposure. We aimed to determine whether prenatal exposure to excess glucocorticoids underlies our rat model of early-life vitamin D deficiency, leading to altered adult behaviours. Vitamin D deficiency reduced the expression of the glucocorticoid-inactivating enzyme Hsd11b2 in the female placenta, but did not alter maternal glucocorticoid levels, feto-placental weights, or placental expression of other glucocorticoid-related genes at mid-gestation. This differs to the phenotype previously observed in vitamin D deficient mice, and highlights important modelling considerations.

Note: computer controlled rotation mount for large diameter optics.

We describe the construction of a motorized optical rotation mount with a 40 mm clear aperture. The device is used to remotely control the power of large diameter laser beams for a magneto-optical trap. A piezo-electric ultrasonic motor on a printed circuit board provides rotation with a precision better than 0.03° and allows for a very compact design. The rotation unit is controlled from a computer via serial communication, making integration into most software control platforms straightforward.