Congenital heart disease detection in Slovenia: Improvement potential of neonatal pulse oximetry screening

Introduction: Patients with major or critical congenital heart disease (CHD) require surgical treatment or interventional cardiac catheterization during the first year or 28 days of life, respectively. Currently, the detection of CHD in Slovenia relies on the prenatal ultrasound screening and physical examination of the newborn.Aims: 1) To determine the incidence of major/critical CHD in Slovenia; 2) to determine the proportion of infants with late detection of major/critical CHD based on the existing clinical practice; and 3) to estimate the improvement in CHD detection with a nation-wide neonatal pulse oximetry screening programme.Methods: We reviewed the documentation of all patients with major/critical CHD born in Slovenia in years 2007–2012. We determined whether the heart condition was detected: 1) on time – prenatally or prior to discharge from maternity ward; or 2) late – after discharge or at autopsy.Results: Among 128,839 live-born babies, 293 were diagnosed with a major CHD (2.27/1000 live births, 95 % confidence interval (CI): 2.0–2.5/1000) and of those 150 with a critical CHD (1.16/1000 live births, 95 % CI: 1.0–1.4/1000). Late detection occurred in 17.7 % of patients with major and 10.9 % patients with critical CHD. Out of 15 late-detected patients with critical CHD, 14 had an obstructive left heart lesion. In 2 patients CHD was diagnosed after death.Conclusions: Detection of CHD in Slovenia is satisfactory. However, in the observed period, 10.9 % of newborns with a critical CHD were discharged undiagnosed. A nation-wide pulse oximetry screening programme could improve pre-discharge CHD detection. </p

Biallelic variants of ATP13A3 cause dose-dependent childhood-onset pulmonary arterial hypertension characterized by extreme morbidity and mortality

Background: The molecular genetic basis of pulmonary arterial hypertension (PAH) is heterogeneous, with at least 26 genes displaying putative evidence for disease causality. Heterozygous variants in the ATP13A3 gene were recently identified as a new cause of adult-onset PAH. However, the contribution of ATP13A3 risk alleles to child-onset PAH remains largely unexplored. Methods and results: We report three families with a novel, autosomal recessive form of childhood-onset PAH due to biallelic ATP13A3 variants. Disease onset ranged from birth to 2.5 years and was characterised by high mortality. Using genome sequencing of parent-offspring trios, we identified a homozygous missense variant in one case, which was subsequently confirmed to cosegregate with disease in an affected sibling. Independently, compound heterozygous variants in ATP13A3 were identified in two affected siblings and in an unrelated third family. The variants included three loss of function variants (two frameshift, one nonsense) and two highly conserved missense substitutions located in the catalytic phosphorylation domain. The children were largely refractory to treatment and four died in early childhood. All parents were heterozygous for the variants and asymptomatic. Conclusion: Our findings support biallelic predicted deleterious ATP13A3 variants in autosomal recessive, childhood-onset PAH, indicating likely semidominant dose-dependent inheritance for this gene

A lethal course of hypertrophic cardiomyopathy in Noonan syndrome due to a novel germline mutation in the KRAS gene: case study

Abstract Noonan syndrome is a relatively common and heterogeneous genetic disorder, including congenital heart defect in more than half of the cases. If the defect is not large, life expectancy is normal. Here we report on a case of an infant with Noonan syndrome and rapidly progressive hypertrophic cardiomyopathy with lethal outcome, in whom we identified a novel mutation in the KRAS gene. This heterozygous unclassified missense variant in exon 3: c.179G>T (p.Gly60Val) might be associated with a lethal form of Noonan syndrome. The malignant clinical course of the disease and the lethal outcome in an infant only a few months old might be connected to RAS-mitogen- activated protein kinase pathway hyperactivation, consequently promoting cell growth and proliferation, leading to rapidly progressive hypertrophic cardiomyopathy. Further biochemical and functional studies are needed to confirm this hypothesis

Paediatric and adult congenital cardiology education and training in Europe

Publisher Copyright: © The Author(s), 2022. Published by Cambridge University Press.Background: Limited data exist on training of European paediatric and adult congenital cardiologists. Methods: A structured and approved questionnaire was circulated to national delegates of Association for European Paediatric and Congenital Cardiology in 33 European countries. Results: Delegates from 30 countries (91%) responded. Paediatric cardiology was not recognised as a distinct speciality by the respective ministry of Health in seven countries (23%). Twenty countries (67%) have formally accredited paediatric cardiology training programmes, seven (23%) have substantial informal (not accredited or certified) training, and three (10%) have very limited or no programme. Twenty-two countries have a curriculum. Twelve countries have a national training director. There was one paediatric cardiology centre per 2.66 million population (range 0.87-9.64 million), one cardiac surgical centre per 4.73 million population (range 1.63-10.72 million), and one training centre per 4.29 million population (range 1.63-10.72 million population). The median number of paediatric cardiology fellows per training programme was 4 (range 1-17), and duration of training was 3 years (range 2-5 years). An exit examination in paediatric cardiology was conducted in 16 countries (53%) and certification provided by 20 countries (67%). Paediatric cardiologist number is affected by gross domestic product (R2 = 0.41). Conclusion: Training varies markedly across European countries. Although formal fellowship programmes exist in many countries, several countries have informal training or no training. Only a minority of countries provide both exit examination and certification. Harmonisation of training and standardisation of exit examination and certification could reduce variation in training thereby promoting high-quality care by European congenital cardiologists.Peer reviewe