BackgroundAutism spectrum disorders (ASDs) are common and have a strong genetic basis, yet the cause of ∼70–80% ASDs remains unknown. By clinical cytogenetic testing, we identified a family in which two brothers had ASD, mild intellectual disability and a chromosome 22 pericentric inversion, not detected in either parent, indicating de novo mutation with parental germinal mosaicism. We hypothesised that the rearrangement was causative of their ASD and localised the chromosome 22 breakpoints.MethodsThe rearrangement was characterised using fluorescence in situ hybridisation, Southern blotting, inverse PCR and dideoxy-sequencing. Open reading frames and intron/exon boundaries of the two physically disrupted genes identified, TCF20 and TNRC6B, were sequenced in 342 families (260 multiplex and 82 simplex) ascertained by the International Molecular Genetic Study of Autism Consortium (IMGSAC).ResultsIMGSAC family screening identified a de novo missense mutation of TCF20 in a single case and significant association of a different missense mutation of TCF20 with ASD in three further families. Through exome sequencing in another project, we independently identified a de novo frameshifting mutation of TCF20 in a woman with ASD and moderate intellectual disability. We did not identify a significant association of TNRC6B mutations with ASD.ConclusionsTCF20 encodes a transcriptional coregulator (also termed SPBP) that is structurally and functionally related to RAI1, the critical dosage-sensitive protein implicated in the behavioural phenotypes of the Smith–Magenis and Potocki–Lupski 17p11.2 deletion/duplication syndromes, in which ASD is frequently diagnosed. This study provides the first evidence that mutations in TCF20 are also associated with ASD.

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ObjectiveTo determine whether electrical activity of the diaphragm (Edi) changes with weaning nasal high-flow (HF) therapy in preterm infants according to a standardised protocol.DesignProspective observational cohort study.SettingNeonatal intensive care unit.PatientsPreterm infants born at <32 weeks gestation, receiving nasal HF as part of routine clinical care.InterventionsInfants recruited to the study had their HF weaned according to set clinical criteria. Edi was measured using a modified gastric feeding tube serially from baseline (pre-wean) to 24-hours post-wean.Main outcome measuresChange in Edi from baseline was measured at four time points up to 24 hours after weaning. Minimum Edi during expiration, maximum Edi during inspiration and amplitude of the Edi signal (Edidelta) were measured. Clinical parameters (heart rate, respiratory rate and fraction of inspired oxygen) were also recorded.ResultsForty preterm infants were recruited at a mean corrected gestational age of 31.6 (±2.7) weeks. Data from 156 weaning steps were analysed, 91% of which were successful. Edi did not change significantly from baseline during flow reduction steps, but a significant increase in diaphragm activity was observed when discontinuing HF (median increase in Edideltaimmediately post-discontinuation 1.7 µV (95% CI: 0.6 to 3.0)) and at 24 hours 1.9 µV (95% CI: 0.7 to 3.8)). No significant difference in diaphragm activity was observed between successful and unsuccessful weaning steps.ConclusionsA protocolised approach to weaning has a high probability of success. Edi does not change with reducing HF rate, but significantly increases with discontinuation of HF from 2 L/min.