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To date, the role of NODAL in normal and abnormal L-R asymmetry has been well established. In a recent paper, mutations of this gene have been reported in heterotaxy but also in transposition with D- or L-ventricular loop. The effects of NODAL and other laterality genes can be recognized separately in all three cardiac segments: for topology and septation of the atria, for ventricular looping, and for spiralization and alignment of the great arteries., (© 2024. The Author(s).)

Aims: The extracardiac conduit-Fontan (ECC) has become the preferred technique for univentricular heart palliation, but there are currently no data on the incidence of long-term arrhythmias. This study investigated the incidence of arrhythmias and relation to single ventricle morphology in the long-term follow-up (FU) in ECC., Methods and Results: All patients with ECC performed in our Centre between 1987 and 2017 were included (minimum FU 5 years). Of 353 consecutive patients, 303 [57.8% males, aging 8-50 (median 20) years at last FU] were considered and divided into two groups depending on left (194 in Group 1) or right (109 in Group 2) ventricular morphology. Eighty-five (28%) experienced ≥1 arrhythmic complications, with early and late arrhythmias in 17 (5.6%) and 73 (24.1%) patients, respectively. Notably, late bradyarrhythmias occurred after 6 years in 21 (11%) patients in Group 1, and in 15 (13.8%) in Group 2 [P = 0.48]. Late tachyarrhythmias occurred in 55 (18.2%) patients after 12 years: 33 (17%) in Group 1 and 22 (20.2%) patients in Group 2 [P  = 0.5]. Ventricular tachycardias (VT) were documented after 12.5 years in 14 (7.2%) patients of Group 1 and 15 (13.8%) of Group 2 [P = 0.06] with a higher incidence in Group 2 during the FU [P = 0.005]., Conclusion: Extracardiac conduit is related to a significant arrhythmic risk in the long-term FU, higher than previously reported. Bradyarrhythmias occur earlier but are less frequent than tachyarrhythmias. Interestingly, patients with systemic right ventricle have a significantly higher incidence of VT, especially in a very long FU., Competing Interests: Conflict of interest: none by any of the authors., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: The 22q11.2 deletion syndrome is the most common microdeletion syndrome and is frequently associated with congenital heart disease. Prenatal diagnosis of 22q11.2 deletion syndrome is increasingly offered. It is unknown whether there is a clinical benefit to prenatal detection as compared with postnatal diagnosis., Objective: This study aimed to determine differences in perinatal and infant outcomes between patients with prenatal and postnatal diagnosis of 22q11.2 deletion syndrome., Study Design: This was a retrospective cohort study across multiple international centers (30 sites, 4 continents) from 2006 to 2019. Participants were fetuses, neonates, or infants with a genetic diagnosis of 22q11.2 deletion syndrome by 1 year of age with or without congenital heart disease; those with prenatal diagnosis or suspicion (suggestive ultrasound findings and/or high-risk cell-free fetal DNA screen for 22q11.2 deletion syndrome with postnatal confirmation) were compared with those with postnatal diagnosis. Perinatal management, cardiac and noncardiac morbidity, and mortality by 1 year were assessed. Outcomes were adjusted for presence of critical congenital heart disease, gestational age at birth, and site., Results: A total of 625 fetuses, neonates, or infants with 22q11.2 deletion syndrome (53.4% male) were included: 259 fetuses were prenatally diagnosed (156 [60.2%] were live-born) and 122 neonates were prenatally suspected with postnatal confirmation, whereas 244 infants were postnatally diagnosed. In the live-born cohort (n=522), 1-year mortality was 5.9%, which did not differ between groups but differed by the presence of critical congenital heart disease (hazard ratio, 4.18; 95% confidence interval, 1.56-11.18; P<.001) and gestational age at birth (hazard ratio, 0.78 per week; 95% confidence interval, 0.69-0.89; P<.001). Adjusting for critical congenital heart disease and gestational age at birth, the prenatal cohort was less likely to deliver at a local community hospital (5.1% vs 38.2%; odds ratio, 0.11; 95% confidence interval, 0.06-0.23; P<.001), experience neonatal cardiac decompensation (1.3% vs 5.0%; odds ratio, 0.11; 95% confidence interval, 0.03-0.49; P=.004), or have failure to thrive by 1 year (43.4% vs 50.3%; odds ratio, 0.58; 95% confidence interval, 0.36-0.91; P=.019)., Conclusion: Prenatal detection of 22q11.2 deletion syndrome was associated with improved delivery management and less cardiac and noncardiac morbidity, but not mortality, compared with postnatal detection., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Congenital heart disease (CHD) affecting the conotruncal region of the heart, occurs in 40-50% of patients with 22q11.2 deletion syndrome (22q11.2DS). This syndrome is a rare disorder with relative genetic homogeneity that can facilitate identification of genetic modifiers. Haploinsufficiency of TBX1, encoding a T-box transcription factor, is one of the main genes responsible for the etiology of the syndrome. We suggest that genetic modifiers of conotruncal defects in patients with 22q11.2DS may be in the TBX1 gene network. To identify genetic modifiers, we analyzed rare, predicted damaging variants in whole genome sequence of 456 cases with conotruncal defects and 537 controls, with 22q11.2DS. We then performed gene set approaches and identified chromatin regulatory genes as modifiers. Chromatin genes with recurrent damaging variants include EP400, KAT6A, KMT2C, KMT2D, NSD1, CHD7 and PHF21A. In total, we identified 37 chromatin regulatory genes, that may increase risk for conotruncal heart defects in 8.5% of 22q11.2DS cases. Many of these genes were identified as risk factors for sporadic CHD in the general population. These genes are co-expressed in cardiac progenitor cells with TBX1, suggesting that they may be in the same genetic network. The genes KAT6A, KMT2C, CHD7 and EZH2, have been previously shown to genetically interact with TBX1 in mouse models. Our findings indicate that disturbance of chromatin regulatory genes impact the TBX1 gene network serving as genetic modifiers of 22q11.2DS and sporadic CHD, suggesting that there are some shared mechanisms involving the TBX1 gene network in the etiology of CHD., (© 2023. The Author(s).)

This review aimed to update the clinical practice guidelines for managing children and adolescents with 22q11.2 deletion syndrome (22q11.2DS). The 22q11.2 Society, the international scientific organization studying chromosome 22q11.2 differences and related conditions, recruited expert clinicians worldwide to revise the original 2011 pediatric clinical practice guidelines in a stepwise process: (1) a systematic literature search (1992-2021), (2) study selection and data extraction by clinical experts from 9 different countries, covering 24 subspecialties, and (3) creation of a draft consensus document based on the literature and expert opinion, which was further shaped by survey results from family support organizations regarding perceived needs. Of 2441 22q11.2DS-relevant publications initially identified, 2344 received full-text reviews, including 1545 meeting criteria for potential relevance to clinical care of children and adolescents. Informed by the available literature, recommendations were formulated. Given evidence base limitations, multidisciplinary recommendations represent consensus statements of good practice for this evolving field. These recommendations provide contemporary guidance for evaluation, surveillance, and management of the many 22q11.2DS-associated physical, cognitive, behavioral, and psychiatric morbidities while addressing important genetic counseling and psychosocial issues., Competing Interests: Conflict of Interest The authors declare no conflicts of interest., (Copyright © 2022 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)

Background: Diagnosis and treatment of 22q11.2 deletion syndrome (22q11.2DS) have led to improved life expectancy and achievement of adulthood. Limited data on long-term outcomes reported an increased risk of premature death for cardiovascular causes, even without congenital heart disease (CHD). The aim of this study was to assess the cardiac function in adolescents and young adults with 22q11.2DS without CHDs., Methods: A total of 32 patients (20M, 12F; mean age 26.00 ± 8.08 years) and a healthy control group underwent transthoracic echocardiography, including Tissue Doppler Imaging (TDI) and 2-dimensional Speckle Tracking Echocardiography (2D-STE)., Results: Compared to controls, 22q11.2DS patients showed a significant increase of the left ventricle (LV) diastolic and systolic diameters (p = 0.029 and p = 0.035 respectively), interventricular septum thickness (p = 0.005), LV mass index (p < 0.001) and aortic root size (p < 0.001). 2D-STE analysis revealed a significant reduction of LV global longitudinal strain (p < 0.001) in 22q11.2DS than controls. Moreover, several LV diastolic parameters were significantly different between groups., Conclusions: Our results suggest that an echocardiographic follow-up in 22q11.2DS patients without CHDs can help to identify subclinical impairment of the LV and evaluate a potential progression of aortic root dilation over time, improving outcomes, reducing long-term complications and allowing for a better prognosis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

Interruption of the aortic arch (IAA) is a rare but life-threatening congenital heart defect if not corrected in the neonatal period. IAA type B is highly correlated with 22q11.2 deletion syndrome (22q11.2DS); approximately 50% of patients with IAA type B also have 22q11.2DS (Peyvandi et al.; Goldmuntz et al.). Early identification and repair of IAA can prevent severe morbidity and death. However, IAA is challenging to identify prenatally, or even in the neonatal period. In this study, we examined infants with IAA, diagnosed during pregnancy and prior to discharge (PPTD) from the birth hospital vs. those diagnosed following discharge (FD) from the newborn nursery. Our goals were to determine: (1) if early diagnosis improved outcomes; and (2) if patients with IAA and without 22q11.2DS had similar outcomes. In total, 135 patients with a diagnosis of 22q11.2DS and IAA were ascertained through the 22q and You Center at the Children's Hospital of Philadelphia (CHOP). The examined outcomes included: timing of diagnosis; age at diagnosis (days); hospital length of stay (LOS); duration of intensive care unit (ICU) stay; mechanical ventilation (days); duration of inotrope administration (days); year of surgical intervention; birth hospital trauma level; and overall morbidity. These outcomes were then compared with 40 CHOP patients with IAA but without 22q11.2DS. The results revealed that the PPTD neonates had fewer days of intubation, inotrope administration, and hospital LOS when compared to the FD group. The outcomes between deleted and non-deleted individuals with IAA differed significantly, in terms of the LOS (40 vs. 39 days) and time in ICU (28 vs. 24 days), respectively. These results support the early detection of 22q11.2DS via prenatal screening/diagnostics/newborn screening, as IAA can evade routine prenatal ultrasound and postnatal pulse oximetry. However, as previously reported in patients with 22q11.2DS and congenital heart disease (CHD), patients with 22q11.2DS tend to fare poorer compared to non-deleted neonates with IAA.

Background: Aortic root dilation (ARD) has been described in 22q11.2DS, even without congenital heart disease (CHD). However, the clinical implications and longitudinal course are unclear. In this study, we evaluated aortic root (AR) dimensions in 22q112.DS adolescents/adults without major intracardiac CHDs, analyzed the progression over time and investigated correlations with extracardiac comorbidities., Methods: AR dimensions were evaluated in 74 patients, measuring the sinus of Valsalva (VS) and proximal ascending aorta (AA), using Z-score to define mild, moderate and severe degrees. Changes in AR dimensions during longitudinal echocardiographic follow-up were investigated. Phenotypic characteristics have been collected., Results: Twenty-four patients (32.4%) showed ARD in terms of VS Z-score (2.43; IQR 2.08-3.01), eight (33.3%) of a moderate/severe degree. Thirteen (54.2%) had concomitant AAD (Z-score 2.34; IQR 1.60-2.85). The risk of ARD was significantly directly related to skeletal/connective tissue disorders (OR 12.82, 95% CI 1.43-115.31; p = 0.023) and inversely related to BMI (OR 0.86, 95% CI 0.77-0.97; p = 0.011). A significant increase in AR diameter's absolute value ( p = 0.001) over time has been detected., Conclusion: Isolated ARD is common in 22q11.2DS. Although some clinical risk factors have been identified, pathogenetic mechanisms and risk of complications are undefined. Regular cardiac evaluations should be part of the 22q11.2DS follow-up, and also in non-CHDs patients, to improve long-term outcome.

Crossed pulmonary arteries (CPAs) represent an uncommon anatomic variant, usually associated with some specific syndromes and conotruncal defects. This finding has been described in 22q11.2 Deletion Syndrome (22q11.2DS). We evaluated the correlation between CPAs and genetic diseases, in order to better define the characteristics of this variant, considered a rare anatomic pattern. An in-depth analysis of CPAs genotype-phenotype correlations was performed via a literature review. We detected 74 CPAs patients through echocardiography. Of these 74 patients, 35.1% of patients showed additional intracardiac malformations, while 29.7% showed extracardiac vascular anomalies, of which 16.2% were associated with intracardiac defects and 13.5% were not. In all, 62.2% of patients were diagnosed with genetic diseases and 52.2% of them were 22q11.2DS patients. In conclusions, CPAs represent a cardiovascular variant, which is detectable in nonsyndromic individuals, but especially in various genetic syndromes and in particular in 22q11.2DS patients. Data on the real prevalence of this morphology is lacking in literature. Knowledge of this anatomic variant is useful to interpret the unusual course of the pulmonary branches and is helpful information before cardiovascular surgical correction. Moreover, due to the strong association of CPAs with some genetic syndromes, the identification of this anatomic pattern can indicate the utility of a genetic assessment of these patients., (© 2022 Wiley Periodicals LLC.)

Congenital heart diseases represent one of the hallmarks of 22q11.2 deletion syndrome. In particular, conotruncal heart defects are the most frequent cardiac malformations and are often associated with other specific additional cardiovascular anomalies. These findings, together with extracardiac manifestations, may affect perioperative management and influence clinical and surgical outcome. Over the past decades, advances in genetic and clinical diagnosis and surgical treatment have led to increased survival of these patients and to progressive improvements in postoperative outcome. Several studies have investigated long-term follow-up and results of cardiac surgery in this syndrome. The aim of our review is to examine the current literature data regarding cardiac outcome and surgical prognosis of patients with 22q11.2 deletion syndrome. We thoroughly evaluate the most frequent conotruncal heart defects associated with this syndrome, such as tetralogy of Fallot, pulmonary atresia with major aortopulmonary collateral arteries, aortic arch interruption, and truncus arteriosus, highlighting the impact of genetic aspects, comorbidities, and anatomical features on cardiac surgical treatment.

Congenital heart defects (CHDs) are known to occur in 9%-25% of patients with KBG syndrome. In this study we analyzed the prevalence and anatomic types of CHDs in 46 personal patients with KBG syndrome, carrying pathogenetic variants in ANKRD11 or 16q24.3 deletion, and reviewed CHDs in patients with molecular diagnosis of KBG syndrome from the literature. CHD was diagnosed in 15/40 (38%) patients with ANKRD11 variant, and in one patient with 16q24.3 deletion. Left ventricular outflow tract obstructions have been diagnosed in 9/15 (60%), subaortic or muscular ventricular septal defect in 5/15 (33%), dextrocardia in 1/15 (8%). The single patient with 16q24.3 deletion and CHD had complete atrioventricular septal defect (AVSD) with aortic coarctation. Review of KBG patients from the literature and present series showed that septal defects have been diagnosed in 44% (27/61) of the cases, left ventricular tract obstructions in 31% (19/61), AVSD in 18% (11/61). Septal defects have been diagnosed in 78% of total patients with 16q24.3 deletion. Valvar anomalies are frequently diagnosed, prevalently involving the left side of the heart. A distinctive association with AVSD is identifiable and could represent a marker to suggest the diagnosis in younger patients. In conclusion, after precise molecular diagnosis and systematic cardiological screening the prevalence of CHD in KBG syndrome seems to be higher than previously reported in clinical articles. In addition to septal defects, left-sided anomalies and AVSD should be considered. Clinical management of KBG syndrome should include accurate and detailed echocardiogram at time of diagnosis., (© 2021 Wiley Periodicals LLC.)