De novo and rare inherited mutations implicate the transcriptional coregulator TCF20/SPBP in autism spectrum disorder.

BACKGROUND: Autism 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. METHODS: The 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). RESULTS: IMGSAC 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. CONCLUSIONS: TCF20 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.

Diaphragm electrical activity during weaning of nasal high-flow therapy in preterm infants.

OBJECTIVE: To determine whether electrical activity of the diaphragm (Edi) changes with weaning nasal high-flow (HF) therapy in preterm infants according to a standardised protocol. DESIGN: Prospective observational cohort study. SETTING: Neonatal intensive care unit. PATIENTS: Preterm infants born at <32 weeks gestation, receiving nasal HF as part of routine clinical care. INTERVENTIONS: Infants 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 MEASURES: Change 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. RESULTS: Forty 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 Edidelta immediately 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. CONCLUSIONS: A 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.

Life-threatening bronchopulmonary dysplasia: a British Paediatric Surveillance Unit Study.

OBJECTIVES: To assess the minimum incidence of life-threatening bronchopulmonary dysplasia (BPD), defined as need for positive pressure respiratory support or pulmonary vasodilators at 38 weeks corrected gestational age (CGA), in infants born <32 weeks gestation in the UK and Ireland; and to describe patient characteristics, management and outcomes to 1 year. METHODS: Prospective national surveillance study performed via the British Paediatric Surveillance Unit from June 2017 to July 2018. Data were collected in a series of three questionnaires from notification to 1 year of age. RESULTS: 153 notifications met the case definition, giving a minimum incidence of 13.9 (95% CI: 11.8 to 16.3) per 1000 live births <32 weeks' gestation. Median gestation was 26.1 (IQR 24.6-28) weeks, and birth weight 730 g (IQR 620-910 g). More affected infants were male (95 of 153, 62%; p<0.05). Detailed management and outcome data were provided for 94 infants. Fifteen died at median age 159 days (IQR 105-182) or 49.6 weeks CGA (IQR 43-53). Median age last receiving invasive ventilation was 50 days (IQR 22-98) and total duration of pressure support for surviving infants 103 (IQR 87-134) days. Fifty-seven (60.6%) received postnatal steroids and 22 (23.4%) pulmonary vasodilators. Death (16%) and/or major neurodevelopmental impairment (37.3%) or long-term ventilation (23.4%) were significantly associated with need for invasive ventilation near term and pulmonary hypertension. CONCLUSIONS: This definition of life-threatening BPD identified an extremely high-risk subgroup, associated with serious morbidity and mortality. Wide variability in management was demonstrated, and future prospective study, particularly in key areas of postnatal steroid use and pulmonary hypertension management, is required.