A de novo ACTB gene pathogenic variant in identical twins with phenotypic variation for hydrops and jejunal atresia.

The beta-actin gene (ACTB) encodes a ubiquitous cytoskeletal protein, essential for embryonic development in humans. De novo heterozygous missense variants in the ACTB are implicated in causing Baraitser-Winter cerebrofrontofacial syndrome (BWCFFS; MIM#243310). ACTB pathogenic variants are rarely associated with intestinal malformations. We report on a rare case of monozygotic twins presenting with proximal small bowel atresia and hydrops in one, and apple-peel bowel atresia and laryngeal dysgenesis in the other. The twin with hydrops could not be resuscitated. Intensive and surgical care was provided to the surviving twin. Rapid trio genome sequencing identified a de novo missense variant in ACTB (NM_00101.3:c.1043C>T; p.(Ser348Leu)) that guided the care plan. The identical variant subsequently was identified in the demised twin. To characterize the functional effect, the variant was recreated as a pseudoheterozygote in a haploid wild-type S. cerevisiae strain. There was an obvious growth defect of the yACT1S348L/WT pseudoheterozygote compared to a yACT1WT/WT strain when grown at 22°C but not when grown at 30°C, consistent with the yACT1 S348L variant having a functional defect that is dominant over the wild-type allele. The functional results provide supporting evidence that the Ser348Leu variant is likely to be a pathogenic variant, including being associated with intestinal malformations in BWCFFS, and can demonstrate variable expressivity within monozygotic twins.

Therapeutic hypothermia for neonatal encephalopathy with sepsis: a retrospective cohort study.

OBJECTIVE: Neonatal encephalopathy remains a major cause of infant mortality and neurodevelopmental impairment. Infection may exacerbate brain injury and mitigate the effect of therapeutic hypothermia (TH). Additionally, infants with sepsis treated with TH may be at increased risk of adverse effects. This study aimed to review the clinical characteristics and outcomes for infants with sepsis treated with TH. DESIGN AND SETTING: Retrospective cohort study of infants treated with TH within Australia and New Zealand. PATIENTS: 1522 infants treated with TH, including 38 with culture-positive sepsis from 2014 to 2018. INTERVENTION: Anonymised retrospective review of data from Australian and New Zealand Neonatal Network. Infants with culture-positive sepsis within 48 hours were compared with those without sepsis. MAIN OUTCOME MEASURES: Key outcomes include in-hospital mortality, intensive care support requirements and length of stay. RESULTS: Overall the rate of mortality was similar between the groups (13% vs 13%). Infants with sepsis received a higher rate of mechanical ventilation (89% vs 70%, p=0.01), high-frequency oscillatory ventilation (32% vs 13%, p=0.003) and inhaled nitric oxide for persistent pulmonary hypertension (38% vs 16%, p<0.001). Additionally, the sepsis group had a longer length of stay (20 vs 11 days, p<0.001). CONCLUSION: Infants with sepsis treated with TH required significantly more respiratory support and had a longer length of stay. Although this may suggest a more severe illness the rate of mortality was similar. Further research is warranted to review the neurodevelopmental outcomes for these infants.