A genome sequencing system for universal newborn screening, diagnosis, and precision medicine for severe genetic diseases.

Newborn screening (NBS) dramatically improves outcomes in severe childhood disorders by treatment before symptom onset. In many genetic diseases, however, outcomes remain poor because NBS has lagged behind drug development. Rapid whole-genome sequencing (rWGS) is attractive for comprehensive NBS because it concomitantly examines almost all genetic diseases and is gaining acceptance for genetic disease diagnosis in ill newborns. We describe prototypic methods for scalable, parentally consented, feedback-informed NBS and diagnosis of genetic diseases by rWGS and virtual, acute management guidance (NBS-rWGS). Using established criteria and the Delphi method, we reviewed 457 genetic diseases for NBS-rWGS, retaining 388 (85%) with effective treatments. Simulated NBS-rWGS in 454,707 UK Biobank subjects with 29,865 pathogenic or likely pathogenic variants associated with 388 disorders had a true negative rate (specificity) of 99.7% following root cause analysis. In 2,208 critically ill children with suspected genetic disorders and 2,168 of their parents, simulated NBS-rWGS for 388 disorders identified 104 (87%) of 119 diagnoses previously made by rWGS and 15 findings not previously reported (NBS-rWGS negative predictive value 99.6%, true positive rate [sensitivity] 88.8%). Retrospective NBS-rWGS diagnosed 15 children with disorders that had been undetected by conventional NBS. In 43 of the 104 children, had NBS-rWGS-based interventions been started on day of life 5, the Delphi consensus was that symptoms could have been avoided completely in seven critically ill children, mostly in 21, and partially in 13. We invite groups worldwide to refine these NBS-rWGS conditions and join us to prospectively examine clinical utility and cost effectiveness.

Control of reflex reversal in stick insect walking: effects of intersegmental signals, changes in direction, and optomotor-induced turning.

In many animals, the effects of sensory feedback on motor output change during locomotion. These changes can occur as reflex reversals in which sense organs that activate muscles to counter perturbations in posture control instead reinforce movements in walking. The mechanisms underlying these changes are only partially understood. As such, it is unclear whether reflex reversals are modulated when locomotion is adapted, such as during changes in walking direction or in turning movements. We investigated these questions in the stick insect Carausius morosus, where sensory signals from the femoral chordotonal organ are known to produce resistance reflexes at rest but assistive movements during walking. We studied how intersegmental signals from neighboring legs affect the generation of reflex reversals in a semi-intact preparation that allows free leg movement during walking. We found that reflex reversal was enhanced by stepping activity of the ipsilateral neighboring rostral leg, whereas stepping of contralateral legs had no effect. Furthermore, we found that the occurrence of reflex reversals was task-specific: in the front legs of animals with five legs walking, reflex reversal was generated only during forward and not backward walking. Similarly, during optomotor-induced curved walking, reflex reversal occurred only in the middle leg on the inside of the turn and not in the contralateral leg on the outside of the turn. Thus our results show for the first time that the nervous system modulates reflexes in individual legs in the adaptation of walking to specific tasks.

A pair of motion-sensitive neurons in the locust encode approaches of a looming object.

Neurons in the locust visual system encode approaches of looming stimuli and are implicated in production of escape behaviours. The lobula giant movement detector (LGMD) and its postsynaptic partner, the descending contralateral movement detector (DCMD) compute characteristics of expanding edges across the locust eye during a loom and DCMD synapses onto motor elements associated with behaviour. We identified another descending interneuron within the locust ventral nerve cord. We named this neuron the late DCMD (LDCMD) as it responds later during an approach, with the firing rate peaking at about the time of collision. LDCMD produced lower amplitude, broader action potentials that were associated with an afterhyperpolarization, whereas DCMD action potentials showed a brief afterhyperpolarization often followed by an afterdepolarization. Within the mesothoracic ganglion, the primary LDCMD axon located adjacent to the DCMD axon, was thinner and lacked collateral projections to the lateral region of the neuropil. When compared with DCMD, LDCMD fired with fewer spikes during a loom and showed weaker habituation to repeated approaches. Coincidence of LDCMD and DCMD firing increased during object approach. Our findings indicate the presence of an additional motion-sensitive descending neuron in the locust that encodes temporally distinct properties of an approaching object.