Heterozygous loss-of-function SMC3 variants are associated with variable growth and developmental features.

Heterozygous missense variants and in-frame indels in SMC3 are a cause of Cornelia de Lange syndrome (CdLS), marked by intellectual disability, growth deficiency, and dysmorphism, via an apparent dominant-negative mechanism. However, the spectrum of manifestations associated with SMC3 loss-of-function variants has not been reported, leading to hypotheses of alternative phenotypes or even developmental lethality. We used matchmaking servers, patient registries, and other resources to identify individuals with heterozygous, predicted loss-of-function (pLoF) variants in SMC3, and analyzed population databases to characterize mutational intolerance in this gene. Here, we show that SMC3 behaves as an archetypal haploinsufficient gene: it is highly constrained against pLoF variants, strongly depleted for missense variants, and pLoF variants are associated with a range of developmental phenotypes. Among 14 individuals with SMC3 pLoF variants, phenotypes were variable but coalesced on low growth parameters, developmental delay/intellectual disability, and dysmorphism, reminiscent of atypical CdLS. Comparisons to individuals with SMC3 missense/in-frame indel variants demonstrated an overall milder presentation in pLoF carriers. Furthermore, several individuals harboring pLoF variants in SMC3 were nonpenetrant for growth, developmental, and/or dysmorphic features, and some had alternative symptomatologies with rational biological links to SMC3. Analyses of tumor and model system transcriptomic data and epigenetic data in a subset of cases suggest that SMC3 pLoF variants reduce SMC3 expression but do not strongly support clustering with functional genomic signatures of typical CdLS. Our finding of substantial population-scale LoF intolerance in concert with variable growth and developmental features in subjects with SMC3 pLoF variants expands the scope of cohesinopathies, informs on their allelic architecture, and suggests the existence of additional clearly LoF-constrained genes whose disease links will be confirmed only by multilayered genomic data paired with careful phenotyping.

Heterozygous loss-of-function SMC3 variants are associated with variable and incompletely penetrant growth and developmental features.

Heterozygous missense variants and in-frame indels in SMC3 are a cause of Cornelia de Lange syndrome (CdLS), marked by intellectual disability, growth deficiency, and dysmorphism, via an apparent dominant-negative mechanism. However, the spectrum of manifestations associated with SMC3 loss-of-function variants has not been reported, leading to hypotheses of alternative phenotypes or even developmental lethality. We used matchmaking servers, patient registries, and other resources to identify individuals with heterozygous, predicted loss-of-function (pLoF) variants in SMC3, and analyzed population databases to characterize mutational intolerance in this gene. Here, we show that SMC3 behaves as an archetypal haploinsufficient gene: it is highly constrained against pLoF variants, strongly depleted for missense variants, and pLoF variants are associated with a range of developmental phenotypes. Among 13 individuals with SMC3 pLoF variants, phenotypes were variable but coalesced on low growth parameters, developmental delay/intellectual disability, and dysmorphism reminiscent of atypical CdLS. Comparisons to individuals with SMC3 missense/in-frame indel variants demonstrated a milder presentation in pLoF carriers. Furthermore, several individuals harboring pLoF variants in SMC3 were nonpenetrant for growth, developmental, and/or dysmorphic features, some instead having intriguing symptomatologies with rational biological links to SMC3 including bone marrow failure, acute myeloid leukemia, and Coats retinal vasculopathy. Analyses of transcriptomic and epigenetic data suggest that SMC3 pLoF variants reduce SMC3 expression but do not result in a blood DNA methylation signature clustering with that of CdLS, and that the global transcriptional signature of SMC3 loss is model-dependent. Our finding of substantial population-scale LoF intolerance in concert with variable penetrance in subjects with SMC3 pLoF variants expands the scope of cohesinopathies, informs on their allelic architecture, and suggests the existence of additional clearly LoF-constrained genes whose disease links will be confirmed only by multi-layered genomic data paired with careful phenotyping.

Incidence of Hospital-Acquired Conditions During Pediatric Clinical Research Inpatient Hospitalizations: A Matched Cohort Study.

OBJECTIVES: In this matched cohort study using data from pediatric hospitals, we compared the incidence of hospital-acquired conditions (HACs) during clinical research hospitalizations to nonresearch hospitalizations. METHODS: Using Pediatric Health Information System data for inpatient discharges January 2017-June 2022, we matched research hospitalizations (identified by International Classification of Diseases, Tenth Revision, diagnosis code) to nonresearch hospitalizations within hospital on age (±3 y), sex, discharge year (±2), and All Patients Refined Diagnosis Related Groups classification, severity of illness (±1), and risk of mortality (±1). We calculated the incidence (per 1000 discharges) and incidence rate (per 10,000 patient days) of HAC identified by International Classification of Diseases, Tenth Revision, codes and compare research versus nonresearch using logistic and Poisson regression, accounting for matching using generalized estimating equations and adjusting for sociodemographic factors and hospital utilization. RESULTS: We matched 7000 research hospitalizations to 26,447 nonresearch from 28 hospitals. Median age was 6.0 years (interquartile range, 10.6 y). Median length of stay was 4.0 days (interquartile range, 11.0 days) with longer stays among research hospitalizations ( P < 0.001). Incidence of HAC among research hospitalizations was 13.1 versus 7.2 per 1000 for nonresearch ( P < 0.001) and incidence rate 6.7 versus 4.5 per 10,000 patient days. Adjusting for sociodemographic and clinical factors, research stays had 1.65 times the odds of any HAC (95% confidence interval, 1.27-2.16; P < 0.001) and 1.38 times the incidence rate (95% confidence interval, 1.09-1.75; P = 0.009). CONCLUSIONS: Our findings indicate that pediatric research hospitalizations are more likely to experience HACs compared with nonresearch hospitalizations. These findings have important safety implications for pediatric inpatient clinical research that warrant further study.

A Pilot Study of Inspiratory Muscle Training to Improve Exercise Capacity in Patients with Fontan Physiology.

While the Fontan procedure has improved life expectancy, patients with single ventricle physiology have impaired exercise capacity due to limited increase in pulmonary blood flow during activity. Enhancing the "thoracic pump" using inspiratory muscle training (IMT) may ameliorate this impairment. Adult nonsmokers with Fontan physiology were recruited through Boston Children's Hospital's outpatient clinic. Participants underwent cardiopulmonary exercise testing and pulmonary function testing, followed by 12 weeks of IMT and then repeat testing. The primary endpoint was change in % predicted peak oxygen consumption (VO2). Secondary endpoints were changes in other exercise metrics. Eleven patients (6 male) were enrolled. Median ages at time of enrollment and Fontan completion were 28.8 years (25.7, 45.5) and 7.8 years (3.9, 16.5), respectively. Average baseline maximal inspiratory pressure (MIP) was normal; only 2 patients had MIP <70% predicted. Peak work rate improved significantly from baseline after 12 weeks of IMT (116.5 ± 45.0 to 126.8 ± 47.0 W, P = 0.019). Peak VO2 tended to improve (baseline 68.1 ± 14.3, change + 5.3 ± 9.6% predicted, P = 0.12), as did VE/VCO2 slope (34.1 ± 6.7 to 31.4 ± 3.6, P = 0.12). There was no change in peak tidal volume or MIP. In a small cohort of Fontan patients with mostly normal MIP, IMT was associated with significant improvement in peak work rate and a trend toward higher peak VO2 and improved ventilatory efficiency. Larger studies are needed to determine if this reflects true lack of effect or whether this pilot study was underpowered for effect size, and whether IMT is more narrowly useful for patients with impaired MIP.

Using high-dose omega-3 fatty acid supplements to lower triglyceride levels in 10- to 19-year-olds.

BACKGROUND: Omega-3 fatty acids supplements lower triglyceride (TG) levels in adults; little pediatric information is available. We evaluated their effect in hypertriglyceridemic adolescents. METHODS: Twenty-five patients aged 10 to 19 years with TG levels 150 to 1000 mg/dL were randomized to 6 months double-blind trial of Lovaza (~3360 mg docosahexaenoic acid + eicosapentaenoic acid per day) versus placebo. RESULTS: Baseline mean TG levels were 227 mg/dL (standard deviation = 49). TG levels declined at 3 months in the Lovaza group by 54 ± 27 mg/dL (mean ± standard error; P = .02) and by 34 ± 26 mg/dL (P = .16) in the placebo group. The difference in TG lowering between groups was not significant (P = .52). There were no between-group differences in endothelial function, blood pressure, body mass index, C-reactive protein, or side effects. CONCLUSIONS: High-dose omega-3 fatty acid supplements are well tolerated in adolescents. However, declines in TG levels did not differ significantly from Placebo in this small study.