RESUMEN
Numerous genetic studies have established a role for rare genomic variants in Congenital Heart Disease (CHD) at the copy number variation (CNV) and de novo variant (DNV) level. To identify novel haploinsufficient CHD disease genes, we performed an integrative analysis of CNVs and DNVs identified in probands with CHD including cases with sporadic thoracic aortic aneurysm. We assembled CNV data from 7,958 cases and 14,082 controls and performed a gene-wise analysis of the burden of rare genomic deletions in cases versus controls. In addition, we performed variation rate testing for DNVs identified in 2,489 parent-offspring trios. Our analysis revealed 21 genes which were significantly affected by rare CNVs and/or DNVs in probands. Fourteen of these genes have previously been associated with CHD while the remaining genes (FEZ1, MYO16, ARID1B, NALCN, WAC, KDM5B and WHSC1) have only been associated in small cases series or show new associations with CHD. In addition, a systems level analysis revealed affected protein-protein interaction networks involved in Notch signaling pathway, heart morphogenesis, DNA repair and cilia/centrosome function. Taken together, this approach highlights the importance of re-analyzing existing datasets to strengthen disease association and identify novel disease genes and pathways.
Asunto(s)
Variaciones en el Número de Copia de ADN/genética , Haploinsuficiencia/genética , Cardiopatías Congénitas/genética , Bases de Datos Genéticas , Expresión Génica/genética , Perfilación de la Expresión Génica/métodos , Predisposición Genética a la Enfermedad/genética , Genómica/métodos , Humanos , Canales Iónicos/genética , Proteínas de la Membrana/genética , Polimorfismo de Nucleótido Simple/genética , Transcriptoma/genéticaRESUMEN
[This corrects the article DOI: 10.1371/journal.pgen.1009679.].
RESUMEN
BACKGROUND: COVID-19 has caused significant worldwide morbidity and mortality. Congenital heart disease (CHD) is likely to increase vulnerability and understanding the predictors of adverse outcomes is key to optimising care. OBJECTIVE: Ascertain the impact of COVID-19 on people with CHD and define risk factors for adverse outcomes. METHODS: Multicentre UK study undertaken 1 March 2020-30 June 2021 during the COVID-19 pandemic. Data were collected on CHD diagnoses, clinical presentation and outcomes. Multivariable logistic regression with multiple imputation was performed to explore predictors of death and hospitalisation. RESULTS: There were 405 reported cases (127 paediatric/278 adult). In children (age <16 years), there were 5 (3.9%) deaths. Adjusted ORs (AORs) for hospitalisation in children were significantly lower with each ascending year of age (OR 0.85, 95% CI 0.75 to 0.96 (p<0.01)). In adults, there were 24 (8.6%) deaths (19 with comorbidities) and 74 (26.6%) hospital admissions. AORs for death in adults were significantly increased with each year of age (OR 1.05, 95% CI 1.01 to 1.10 (p<0.01)) and with pulmonary arterial hypertension (PAH; OR 5.99, 95% CI 1.34 to 26.91 (p=0.02)). AORs for hospitalisation in adults were significantly higher with each additional year of age (OR 1.03, 95% CI 1.00 to 1.05 (p=0.04)), additional comorbidities (OR 3.23, 95% CI 1.31 to 7.97 (p=0.01)) and genetic disease (OR 2.87, 95% CI 1.04 to 7.94 (p=0.04)). CONCLUSIONS: Children were at low risk of death and hospitalisation secondary to COVID-19 even with severe CHD, but hospital admission rates were higher in younger children, independent of comorbidity. In adults, higher likelihood of death was associated with increasing age and PAH, and of hospitalisation with age, comorbidities and genetic disease. An individualised approach, based on age and comorbidities, should be taken to COVID-19 management in patients with CHD.
Asunto(s)
COVID-19 , Cardiopatías Congénitas , Hipertensión Arterial Pulmonar , Adulto , Humanos , Niño , Adolescente , COVID-19/terapia , COVID-19/complicaciones , Pandemias , Hospitalización , Cardiopatías Congénitas/diagnóstico , Cardiopatías Congénitas/epidemiología , Cardiopatías Congénitas/terapia , Hipertensión Pulmonar Primaria FamiliarRESUMEN
OBJECTIVES: To report the numbers of consultant congenital cardiac surgeons and cardiologists who have joined and left UK practice over the last 10 years and explore the reasons for leaving. METHODS: Retrospective observational questionnaire study completed between 11 June 2019 and 1 July 2020 by UK level 1 congenital cardiac centres of 10-year consultant staff movement and reasons suggested for leaving UK practice. RESULTS: At survey completion there were 218 (202 whole time equivalent (WTE)) consultant cardiologists and surgeons working within level 1 centres made up of 39 (38 WTE) surgeons, 137 (128.5 WTE) paediatric cardiologists, 42 (35.5 WTE) adult congenital heart disease (ACHD) cardiologists. 161 (74%) consultants joined in the last 10 years of whom 103 (64%) were UK trained. There were 91 leavers giving a staff turnover rate 42% (surgeons 56%, paediatric cardiologists 42%, ACHD cardiologists 29%). Of those, leaving 43% moved to work abroad (surgeons 55%, paediatric cardiologists 40%, ACHD cardiologists 67%). Among the 65 reported reasons for leaving 16 were financial, 9 for work life balance, 6 to working conditions within the National Health Service (NHS) and 12 related to the profession in the UK including six specifically highlighting the national review process. CONCLUSIONS: There has been a high turnover rate of consultant staff within UK congenital cardiac services over the last 10 years with almost half of those leaving moving to work overseas. Financial reasons and pressures relating to working in the NHS or the specialty in the UK were commonly reported themes for leaving. This has major implications for future planning and staff retention within this specialised service.