Left ventricular (LV) pacing in newborns and infants. Echo assessment of LV systolic function and synchrony at 5-year follow-up

Background: Small retrospective studies reported that left ventricular (LV) pacing is likely to preserve LV function in children with isolated congenital complete atrioventricular block (CCAVB). The aim of this study was to prospectively evaluate LV contractility and synchrony in a cohort of neonates/infants at pacemaker implantation and follow-up. Methods: Patients with CCAVB who underwent LV pacing were evaluated with electrocardiogram and echocardiogram in a single-center, prospective study. Data were collected at implantation, at 1-month and every year of follow-up, up to 5 years. LV ventricular dimensions (diameters and volumes), systolic function (ejection fraction [EF] and global longitudinal strain [GLS]), and synchrony were evaluated. Data are reported as median (25th-75th centiles). Results: Twenty consecutive patients with CCAVB underwent pacemaker implantation (12 single-chamber pacemaker [VVIR] and eight dual-chamber pacemaker [DDD]) with epicardial leads: 17 on the LV apex and three on the free wall. Age at implantation was 0.3 months (1 day-4.5 months). Patients showed good clinical status, normal LV dimensions, preserved systolic function, and synchrony at 60 (30-60) months follow-up. EF increased to normal values in patients with preimplantation EF <50%. Presence of antibodies and pacing mode (DDD vs VVIR) had no impact on the outcome. Conclusions: LV pacing preserved LV systolic function and synchrony in neonates and infants with CCAVB at 5-year follow-up. LV EF improved in patients with low preimplantation EF. Pacing mode or the presence of autoantibodies did not demonstrated an impact on LV contractility and synchrony

22q11.2 Deletion Syndrome. Impact of Genetics in the Treatment of Conotruncal Heart Defects

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

Nested inversion polymorphisms predispose chromosome 22q11.2 to meiotic rearrangements [RETRACTED]

Inversion polymorphisms between low-copy repeats (LCRs) might predispose chromosomes to meiotic non-allelic homologous recombination (NAHR) events and thus lead to genomic disorders. However, for the 22q11.2 deletion syndrome (22q11.2DS), the most common genomic disorder, no such inversions have been uncovered as of yet. Using fiber-FISH, we demonstrate that parents transmitting the de novo 3 Mb LCR22A–D 22q11.2 deletion, the reciprocal duplication, and the smaller 1.5 Mb LCR22A–B 22q11.2 deletion carry inversions of LCR22B–D or LCR22C–D. Hence, the inversions predispose chromosome 22q11.2 to meiotic rearrangements and increase the individual risk for transmitting rearrangements. Interestingly, the inversions are nested or flanking rather than coinciding with the deletion or duplication sizes. This finding raises the possibility that inversions are a prerequisite not only for 22q11.2 rearrangements but also for all NAHR-mediated genomic disorders

Atypical cardiac defects in patients with RASopathies: Updated data on CARNET study

Background: RASopathies are a set of relatively common autosomal dominant clinically and genetically heterogeneous disorders. Cardiac outcomes in terms of mortality and morbidity for common heart defects (such as pulmonary valve stenosis and hypertrophic cardiomyopathy) have been reported. Nevertheless, also Atypical Cardiac Defects (ACDs) are described. The aim of the present study was to report both prevalence and cardiac outcome of ACDs in patients with RASopathies. Methods: A retrospective, multicentric observational study (CArdiac Rasopathy NETwork—CARNET study) was carried out. Clinical, surgical, and genetic data of the patients who were followed until December 2019 were collected. Results: Forty‐five patients out of 440 followed in CARNET centers had ACDs. Noonan Syndrome (NS), NS Multiple Lentigines (NSML) and CardioFacioCutaneous Syndrome (CFCS) were present in 36, 5 and 4 patients, respectively. Median age at last follow‐up was 20.1 years (range 6.9–47 years). Different ACDs were reported, including mitral and aortic valve dysfunction, ascending and descending aortic arch anomalies, coronary arteries dilation, enlargement of left atrial appendage and isolated pulmonary branches diseases. Five patients (11%) underwent cardiac surgery and one of them underwent a second intervention for mitral valve replacement and severe pericardial effusion. No patients died in our cohort until December 2019. Conclusions: Patients with RASopathies present a distinct CHD spectrum. Present data suggest that also ACDs must be carefully investigated for their possible impact on the clinical outcome. A careful longitudinal follow up until the individuals reach an adult age is recommended

Genetic contributors to risk of schizophrenia in the presence of a 22q11.2 deletion

Schizophrenia occurs in about one in four individuals with 22q11.2 deletion syndrome (22q11.2DS). The aim of this International Brain and Behavior 22q11.2DS Consortium (IBBC) study was to identify genetic factors that contribute to schizophrenia, in addition to the ~20-fold increased risk conveyed by the 22q11.2 deletion. Using whole-genome sequencing data from 519 unrelated individuals with 22q11.2DS, we conducted genome-wide comparisons of common and rare variants between those with schizophrenia and those with no psychotic disorder at age ≥25 years. Available microarray data enabled direct comparison of polygenic risk for schizophrenia between 22q11.2DS and independent population samples with no 22q11.2 deletion, with and without schizophrenia (total n = 35,182). Polygenic risk for schizophrenia within 22q11.2DS was significantly greater for those with schizophrenia (padj = 6.73 × 10−6). Novel reciprocal case–control comparisons between the 22q11.2DS and population-based cohorts showed that polygenic risk score was significantly greater in individuals with psychotic illness, regardless of the presence of the 22q11.2 deletion. Within the 22q11.2DS cohort, results of gene-set analyses showed some support for rare variants affecting synaptic genes. No common or rare variants within the 22q11.2 deletion region were significantly associated with schizophrenia. These findings suggest that in addition to the deletion conferring a greatly increased risk to schizophrenia, the risk is higher when the 22q11.2 deletion and common polygenic risk factors that contribute to schizophrenia in the general population are both present

Prenatal vs postnatal diagnosis of 22q11.2 deletion syndrome: cardiac and noncardiac outcomes through 1 year of age

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

Complete sequence of the 22q11.2 allele in 1,053 subjects with 22q11.2 deletion syndrome reveals modifiers of conotruncal heart defects

The 22q11.2 deletion syndrome (22q11.2DS) results from non-allelic homologous recombination between low-copy repeats termed LCR22. About 60%-70% of individuals with the typical 3 megabase (Mb) deletion from LCR22A-D have congenital heart disease, mostly of the conotruncal type (CTD), whereas others have normal cardiac anatomy. In this study, we tested whether variants in the hemizygous LCR22A-D region are associated with risk for CTDs on the basis of the sequence of the 22q11.2 region from 1,053 22q11.2DS individuals. We found a significant association (FDR p &lt; 0.05) of the CTD subset with 62 common variants in a single linkage disequilibrium (LD) block in a 350 kb interval harboring CRKL. A total of 45 of the 62 variants were associated with increased risk for CTDs (odds ratio [OR) ranges: 1.64-4.75). Associations of four variants were replicated in a meta-analysis of three genome-wide association studies of CTDs in affected individuals without 22q11.2DS. One of the replicated variants, rs178252, is located in an open chromatin region and resides in the double-elite enhancer, GH22J020947, that is predicted to regulate CRKL (CRK-like proto-oncogene, cytoplasmic adaptor) expression. Approximately 23% of patients with nested LCR22C-D deletions have CTDs, and inactivation of Crkl in mice causes CTDs, thus implicating this gene as a modifier. Rs178252 and rs6004160 are expression quantitative trait loci (eQTLs) of CRKL. Furthermore, set-based tests identified an enhancer that is predicted to target CRKL and is significantly associated with CTD risk (GH22J020946, sequence kernal association test (SKAT) p = 7.21&nbsp;× 10-5) in the 22q11.2DS cohort. These findings suggest that variance in CTD penetrance in the 22q11.2DS population can be explained in part by variants affecting CRKL expression

Updated clinical practice recommendations for managing children with 22q11.2 deletion syndrome

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

Genetic contributors to risk of schizophrenia in the presence of a 22q11.2 deletion

Schizophrenia occurs in about one in four individuals with 22q11.2 deletion syndrome (22q11.2DS). The aim of this International Brain and Behavior 22q11.2DS Consortium (IBBC) study was to identify genetic factors that contribute to schizophrenia, in addition to the similar to 20-fold increased risk conveyed by the 22q11.2 deletion. Using whole-genome sequencing data from 519 unrelated individuals with 22q11.2DS, we conducted genome-wide comparisons of common and rare variants between those with schizophrenia and those with no psychotic disorder at age >= 25 years. Available microarray data enabled direct comparison of polygenic risk for schizophrenia between 22q11.2DS and independent population samples with no 22q11.2 deletion, with and without schizophrenia (total n = 35,182). Polygenic risk for schizophrenia within 22q11.2DS was significantly greater for those with schizophrenia (p(adj) = 6.73 x 10(-6)). Novel reciprocal case-control comparisons between the 22q11.2DS and population-based cohorts showed that polygenic risk score was significantly greater in individuals with psychotic illness, regardless of the presence of the 22q11.2 deletion. Within the 22q11.2DS cohort, results of gene-set analyses showed some support for rare variants affecting synaptic genes. No common or rare variants within the 22q11.2 deletion region were significantly associated with schizophrenia. These findings suggest that in addition to the deletion conferring a greatly increased risk to schizophrenia, the risk is higher when the 22q11.2 deletion and common polygenic risk factors that contribute to schizophrenia in the general population are both present.United States Department of Health & Human Services National Institutes of Health (NIH) - USA NIH National Institute of Mental Health (NIMH) U01MH101719 U01MH0101720 U01MH0101723 U01MH101722 U01MH101724 MH064824 R01 MH085953 R01-MH-107235 Brain and Behavior Foundation Young Researcher grant 21278 Comision Nacional de Investigacion Cientifica y Tecnologica (CONICYT) CONICYT FONDECYT 1171014 FWO G.0E11.17N MRC Centre grant MR/L010305/1 Welsh Government 514032 NARSAD United States Department of Health & Human Services National Institutes of Health (NIH) - USA R01GM117946 U54NS091859 R01MH100917 U54 EB020403 United States Department of Health & Human Services National Institutes of Health (NIH) - USA NIH National Institute of Mental Health (NIMH) U01MH101724 R01 MH085953 K01 MH112774 P01HD070454 P50MH09689 R01-MH-1072351 P50MH096891 Canadian Institutes of Health Research (CIHR) MOP-74631 MOP-79518 MOP-89066 MOP-97800 MOP-111238 Swiss National Science Foundation (SNSF) 324730_144260 Swiss National Science Foundation (SNSF) 51NF40-185897 US-Israel Binational Science Foundation 2017370 Van de Werf fund for cardiovascular research Institute for the Promotion of Innovation by Science and Technology in Flanders (IWT) 131625 Wellcome Trust 102428/Z/13/Z McLaughlin Centre Accelerator grant Canada Research Chairs Dalglish Chair Max Appeal 22Crew Unique T32 MH019112 U01 MH087626 U54HD090260 UO1-MH191719 R01 MH087636-01A