De novo variants in FRYL are associated with developmental delay, intellectual disability, and dysmorphic features.

FRY-like transcription coactivator (FRYL) belongs to a Furry protein family that is evolutionarily conserved from yeast to humans. The functions of FRYL in mammals are largely unknown, and variants in FRYL have not previously been associated with a Mendelian disease. Here, we report fourteen individuals with heterozygous variants in FRYL who present with developmental delay, intellectual disability, dysmorphic features, and other congenital anomalies in multiple systems. The variants are confirmed de novo in all individuals except one. Human genetic data suggest that FRYL is intolerant to loss of function (LoF). We find that the fly FRYL ortholog, furry (fry), is expressed in multiple tissues, including the central nervous system where it is present in neurons but not in glia. Homozygous fry LoF mutation is lethal at various developmental stages, and loss of fry in mutant clones causes defects in wings and compound eyes. We next modeled four out of the five missense variants found in affected individuals using fry knockin alleles. One variant behaves as a severe LoF variant, whereas two others behave as partial LoF variants. One variant does not cause any observable defect in flies, and the corresponding human variant is not confirmed to be de novo, suggesting that this is a variant of uncertain significance. In summary, our findings support that fry is required for proper development in flies and that the LoF variants in FRYL cause a dominant disorder with developmental and neurological symptoms due to haploinsufficiency.

The phenotypic and genotypic spectrum of individuals with mono- or biallelic ANK3 variants.

ANK3 encodes ankyrin-G, a protein involved in neuronal development and signaling. Alternative splicing gives rise to three ankyrin-G isoforms comprising different domains with distinct expression patterns. Mono- or biallelic ANK3 variants are associated with non-specific syndromic intellectual disability in 14 individuals (seven with monoallelic and seven with biallelic variants). In this study, we describe the clinical features of 13 additional individuals and review the data on a total of 27 individuals (16 individuals with monoallelic and 11 with biallelic ANK3 variants) and demonstrate that the phenotype for biallelic variants is more severe. The phenotypic features include language delay (92%), autism spectrum disorder (76%), intellectual disability (78%), hypotonia (65%), motor delay (68%), attention deficit disorder (ADD) or attention deficit hyperactivity disorder (ADHD) (57%), sleep disturbances (50%), aggressivity/self-injury (37.5%), and epilepsy (35%). A notable phenotypic difference was presence of ataxia in three individuals with biallelic variants, but in none of the individuals with monoallelic variants. While the majority of the monoallelic variants are predicted to result in a truncated protein, biallelic variants are almost exclusively missense. Moreover, mono- and biallelic variants appear to be localized differently across the three different ankyrin-G isoforms, suggesting isoform-specific pathological mechanisms.

Characteristics of ocular injuries associated with mortality in patients admitted with major trauma.

BACKGROUND: Few ocular trauma studies have addressed mortality outcomes. We sought to determine characteristics of mortality-related ocular trauma admissions and compared them with non-fatal injuries. METHODS: A retrospective study was conducted using de-identified data of patients admitted with major trauma from the National Trauma Data Bank (2008-2014). Patients with ocular injury were identified using ICD- 9CM codes. Demographics, intention and mechanism, types of ocular and head injuries, and injury severity were documented. Mortality was determined using post-admission disposition. Statistical analysis using student t-test, chi-square, and odds ratios (OR) calculations were performed with STATA-17 software. Significance was set at P < 0.05. RESULTS: Of 316,485 patients admitted with ocular trauma, 12,233 (3.86%) were mortality related. Expired patients were older than survivors: mean (SD) of 50.1(25.5) vs. 41.5(22.8) years. White (OR = 1.32; P < 0.001), ≥ 65years old (OR = 2.25; P < 0.001), and male (OR = 1.05; P = 0.029) patients were most likely to expire than their counterparts. Common mechanisms of injury in survivors were falls (25.3%), motor vehicle traffic-occupant, MVTO (21.8%) and struck by/against (18.1%) and for fatal injuries, falls (29.7%), MVTO (21.9%) and firearms (11.5%). Traumatic brain injury (TBI) was documented in 88.2% of mortality-related admissions. Very severe injury severity scores (ISS > 24) (OR = 19.19; P < 0.001) and severe Glasgow Coma Score (GCS < 8) (OR = 19.22; P < 0.001) were most associated with mortality than survival. Firearms were most associated with very severe ISS (OR = 3.73; P < 0.001), severe GCS (OR = 4.68; P < 0.001) and mortality (OR = 5.21; P < 0.001) than other mechanisms. Patients with cut/pierce injuries had the greatest odds of survival (OR = 13.48; P < 0.001). Optic nerve/visual pathways injuries (3.1%) had the highest association with very severe ISS (OR = 2.51; P < 0.001), severe GCS (OR = 3.64; P < 0.001) and mortality (OR = 2.58; P < 0.001) than other ocular injuries. Black patients with very severe ISS (OR = 32.14; P < 0.001) and severe GCS (OR = 31.89; P < 0.001) were more likely to expire than other race/ethnicities with similar injury severity. CONCLUSIONS: Mortality-related admissions were older, male, and mostly of White race than ocular trauma admissions of survivors. Firearms were the deadliest mechanism. TBI was commonly associated and patients with optic nerve/pathway injuries, very severe ISS and severe GCS had higher mortality rates. Characteristics and demographic variations identified in this study may be useful in developing focused measures aimed at preventing trauma-related deaths.

Rare coronary artery variants are associated with increased mortality and reinterventions following the arterial switch operation.

OBJECTIVE: To determine the influence of coronary anatomy on long-term outcomes of the arterial switch operation (ASO). METHODS: We retrospectively reviewed patients with transposition of the great arteries or Taussig-Bing anomaly who underwent ASO at our institution between 1992 and 2022. The primary endpoint was freedom from a composite of death, transplantation, and coronary reintervention. RESULTS: A total of 632 patients (median age, 5.0 days; interquartile range [IQR], 4.0-7.0 days) underwent ASO. Coronary anatomy included the following categories: usual (n = 411; 65%), circumflex (Cx) from sinus 2 (n = 89; 14%), inverted (n = 55; 9%), single sinus (n = 46; 7%), and intramural (n = 31; 5%). Overall operative mortality was 3% (n = 16) and highest in patients with intramural cardiac anatomy (n = 3; 10%), although it dropped to 0% in this group in the most recent decade. The median duration of follow-up was 14.5 years (IQR, 6.0-20.3 years). Twenty-year freedom from the primary endpoint was 95 ± 1% for usual anatomy, 99 ± 1% for Cx from sinus 2, 90 ± 4% for inverted, 91 ± 4% for single sinus, and 80 ± 9% for intramural (P < .001). Intramurals had the highest 20-year incidence of coronary reintervention (11 ± 8%). Cox modeling identified intraoperative coronary revision (hazard ratio [HR], 20.1; 95% confidence interval [CI], 9.4-53.9; P < .001), Taussig-Bing anomaly (HR, 4.9; 95% CI, 2.2-10.9; P < .001), and an intramural coronary artery (HR, 2.9; 95% CI, 1.0-8.2; P = .04) to be risk factors for the composite endpoint. CONCLUSIONS: Rare coronary artery variants-particularly intramural-are associated with increased mortality and coronary reinterventions after ASO. A low threshold for unroofing intramurals is likely associated with declining mortality and improved outcomes. Additional investigations are needed to determine the long-term fate of the coronary arteries after ASO.

Neurodevelopment of children exposed to prolonged anesthesia in infancy: GABA study interim analysis of resting-state brain networks at 2, 4, and 10-months old.

BACKGROUND: Previous studies have raised concerns regarding neurodevelopmental impacts of early exposures to general anesthesia and surgery. Electroencephalography (EEG) can be used to study ontogeny of brain networks during infancy. As a substudy of an ongoing study, we examined measures of functional connectivity in awake infants with prior early and prolonged anesthetic exposures and in control infants. METHODS: EEG functional connectivity was assessed using debiased weighted phase lag index at source and sensor levels and graph theoretical measures for resting state activity in awake infants in the early anesthesia (n = 26 at 10 month visit, median duration of anesthesia = 4 [2, 7 h]) and control (n = 38 at 10 month visit) groups at ages approximately 2, 4 and 10 months. Theta and low alpha frequency bands were of primary interest. Linear mixed models incorporated impact of age and cumulative hours of general anesthesia exposure. RESULTS: Models showed no significant impact of cumulative hours of general anesthesia exposure on debiased weighted phase lag index, characteristic path length, clustering coefficient or small-worldness (conditional R2 0.05-0.34). An effect of age was apparent in many of these measures. CONCLUSIONS: We could not demonstrate significant impact of general anesthesia in the first months of life on early development of resting state brain networks over the first postnatal year. Future studies will explore these networks as these infants grow older.