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

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 < 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 × 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

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

Some Isolated Cardiac Malformations Can Be Related to Laterality Defects

Human beings are characterized by a left⁻right asymmetric arrangement of their internal organs, and the heart is the first organ to break symmetry in the developing embryo. Aberrations in normal left⁻right axis determination during embryogenesis lead to a wide spectrum of abnormal internal laterality phenotypes, including situs inversus and heterotaxy. In more than 90% of instances, the latter condition is accompanied by complex and severe cardiovascular malformations. Atrioventricular canal defect and transposition of the great arteries—which are particularly frequent in the setting of heterotaxy—are commonly found in situs solitus with or without genetic syndromes. Here, we review current data on morphogenesis of the heart in human beings and animal models, familial recurrence, and upstream genetic pathways of left⁻right determination in order to highlight how some isolated congenital heart diseases, very common in heterotaxy, even in the setting of situs solitus, may actually be considered in the pathogenetic field of laterality defects

Impact of genetic studies on comprehension and treatment of congenital heart disease

The great impact of genetic factors in the field of congenital heart disease (CHD) was highlighted about 30 years ago by the Baltimore-Washington Infant Study. Moreover, recent genetic studies have shown their importance not only in detecting the cause of some heart malformations, but also in improving their treatment and prognosis. Three fields may be recognized in which genetic studies have enhanced our knowledge and ability to care for children with CHD: • Reverse medicine includes genotype-phenotype correlations and the new diagnostic criteria to classify CHD. • Predictive medicine regards genotype-prognosis correlations to detect risk factors and to establish specific protocols and treatment. • Preventive medicine can help to prevent the defect or to reduce its severity and complications. This approach proved to be useful in CHD associated with genetic syndromes but it is also promising in isolated non-syndromic CHD

Congenital heart disease and genetic syndromes: new insights into molecular mechanisms

Introduction: Advances in genetics allowed a better definition of the role of specific genetic background in the etiology of syndromic congenital heart defects (CHDs). The identification of a number of disease genes responsible for different syndromes have led to the identification of several transcriptional regulators and signaling transducers and modulators that are critical for heart morphogenesis. Understanding the genetic background of syndromic CHDs allowed a better characterization of the genetic basis of non-syndromic CHDs. In this sense, the well-known association of typical CHDs in Down syndrome, 22q11.2 microdeletion and Noonan syndrome represent paradigms as chromosomal aneuploidy, chromosomal microdeletion and intragenic mutation, respectively. Area covered: For each syndrome the anatomical features, distinctive cardiac phenotype and molecular mechanisms are discussed. Moreover, the authors include recent genetic findings that may shed light on some aspects of still unclear molecular mechanisms of these syndromes. Expert commentary: Further investigations are needed to enhance the translational approach in the field of genetics of CHDs. When there is a well-established definition of genotype-phenotype (reverse medicine) and genotype-prognosis (predictive and personalized medicine) correlations, hopefully preventive medicine will make its way in this field. Subsequently a reduction will be achieved in the morbidity and mortality of children with CHDs

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

Clinical Risk Factors for Aortic Root Dilation in Patients with 22q11.2 Deletion Syndrome: A Longitudinal Single-Center Study

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