Small noncoding differentially methylated copy-number variants, including lncRNA genes, cause a lethal lung developmental disorder

An unanticipated and tremendous amount of the noncoding sequence of the human genome is transcribed. Long noncoding RNAs (lncRNAs) constitute a significant fraction of non-protein-coding transcripts; however, their functions remain enigmatic. We demonstrate that deletions of a small noncoding differentially methylated region at 16q24.1, including lncRNA genes, cause a lethal lung developmental disorder, alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV), with parent-of-origin effects. We identify overlapping deletions 250 kb upstream of FOXF1 in nine patients with ACD/MPV that arose de novo specifically on the maternally inherited chromosome and delete lung-specific lncRNA genes. These deletions define a distant cis-regulatory region that harbors, besides lncRNA genes, also a differentially methylated CpG island, binds GLI2 depending on the methylation status of this CpG island, and physically interacts with and up-regulates the FOXF1 promoter. We suggest that lung-transcribed 16q24.1 lncRNAs may contribute to long-range regulation of FOXF1 by GLI2 and other transcription factors. Perturbation of lncRNA-mediated chromatin interactions may, in general, be responsible for position effect phenomena and potentially cause many disorders of human development

Hydrocephalus and Cerebrospinal Fluid Analysis Following Severe Traumatic Brain Injury: Evaluation of a Prospective Cohort.

The development of hydrocephalus after severe traumatic brain injury (TBI) is an under-recognized healthcare phenomenon and can increase morbidity. The current study aims to characterize post-traumatic hydrocephalus (PTH) in a large cohort. Patients were prospectively enrolled age 16-80 years old with Glasgow Coma Scale (GCS) score ≤8. Demographics, GCS, Injury Severity Score (ISS), surgery, and cerebrospinal fluid (CSF) were analyzed. Outcomes were shunt failure and Glasgow Outcome Scale (GOS) at 6 and 12-months. Statistical significance was assessed at p < 0.05. In 402 patients, mean age was 38.0 ± 16.7 years and 315 (78.4%) were male. Forty (10.0%) patients developed PTH, with predominant injuries being subdural hemorrhage (36.4%) and diffuse axonal injury (36.4%). Decompressive hemicraniectomy (DHC) was associated with hydrocephalus (OR 3.62, 95% CI (1.62-8.07), p < 0.01). Eighteen (4.5%) patients had shunt failure and proximal obstruction was most common. Differences in baseline CSF cell count were associated with increased shunt failure. PTH was not associated with worse outcomes at 6 (p = 0.55) or 12 (p = 0.47) months. Hydrocephalus is a frequent sequela in 10.0% of patients, particularly after DHC. Shunt placement and revision procedures are common after severe TBI, within the first 4 months of injury and necessitates early recognition by the clinician

Hydrocephalus and Cerebrospinal Fluid Analysis Following Severe Traumatic Brain Injury: Evaluation of a Prospective Cohort

The development of hydrocephalus after severe traumatic brain injury (TBI) is an under-recognized healthcare phenomenon and can increase morbidity. The current study aims to characterize post-traumatic hydrocephalus (PTH) in a large cohort. Patients were prospectively enrolled age 16–80 years old with Glasgow Coma Scale (GCS) score ≤8. Demographics, GCS, Injury Severity Score (ISS), surgery, and cerebrospinal fluid (CSF) were analyzed. Outcomes were shunt failure and Glasgow Outcome Scale (GOS) at 6 and 12-months. Statistical significance was assessed at p < 0.05. In 402 patients, mean age was 38.0 ± 16.7 years and 315 (78.4%) were male. Forty (10.0%) patients developed PTH, with predominant injuries being subdural hemorrhage (36.4%) and diffuse axonal injury (36.4%). Decompressive hemicraniectomy (DHC) was associated with hydrocephalus (OR 3.62, 95% CI (1.62–8.07), p < 0.01). Eighteen (4.5%) patients had shunt failure and proximal obstruction was most common. Differences in baseline CSF cell count were associated with increased shunt failure. PTH was not associated with worse outcomes at 6 (p = 0.55) or 12 (p = 0.47) months. Hydrocephalus is a frequent sequela in 10.0% of patients, particularly after DHC. Shunt placement and revision procedures are common after severe TBI, within the first 4 months of injury and necessitates early recognition by the clinician

Small noncoding differentially methylated copy-number variants, including IncRNA genes, cause a lethal lung developmental disorder

An unanticipated and tremendous amount of the noncoding sequence of the human genome is transcribed. Long noncoding RNAs (IncRNAs) constitute a significant fraction of non-protein-coding transcripts; however, their functions remain enigmatic. We demonstrate that deletions of a small noncoding differentially methylated region at 16q24.1, including IncRNA genes, cause a lethal lung developmental disorder, alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV), with parent-of-origin effects. We identify overlapping deletions 250 kb upstream of FOXF1 in nine patients with ACD/MPV that arose de novo specifically on the maternally inherited chromosome and delete lung-specific IncRNAgenes. These deletions define a distant cis-regulatory region that harbors, besides lncRNAgenes, also a differentially methylated CpGisland, binds GLI2 depending on the methylation status of this CpG island, and physically interacts with and up-regulates the FOXF1 promoter. Wesuggest that lung-transcribed 16q24.1 IncRNAs may contribute to long-range regulation of FOXF1 by GLI2 and other transcription factors. Perturbation of IncRNA-mediated chromatin interactions may, in general, be responsible for position effect phenomena and potentially cause many disorders of human development