Congenital heart disease in 22q11.2 deletion syndrome: a meta-analysis and systematic review of the literature

Abstract

The 22q11.2 deletion syndrome (22q11.2DS) results from a heterozygous deletion at chromosomal locus 22q11.2 and is associated with multisystem symptoms, including cardiovascular, psychiatric and palatal manifestations. Although congenital cardiovascular aberrations are frequent in patients with 22q11.DS, exact prevalence figures remain unclear. Literature was searched in August 2022 and updated in May 2024 using the databases PubMed, Web of Science and Cochrane library to retrieve studies in English and German focusing only on studies involving 22q11.2DS. Prevalence data for cardiovascular aberrations were arcsine transformed and summarised by random-effects models using Meta-XL. Evidence quality was assessed via the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach. The systematic searches identified 4338 studies, of which 7 were included for the meta-analysis of prevalence using random-effects models and sensitivity analyses. The pooled prevalence for heart defects (mean; 95% CI) was found to be elevated for tetralogy of Fallot (20%; 0.17 to 0.23), ventricular septal defect (14%; 0.12 to 0.16), pulmonary atresia with ventricular septal defect (9%; 0.06; 0.12), interrupted aortic arch (10%; 0.06 to 0.15), truncus arteriosus communis (9%; 0.07 to 0.12) and atrial septal defect (3%; 0.01 to 0.04). The risk of bias of the included studies was low to moderate. This study, to our knowledge, represents the first systematic review and meta-analysis of prevalences for congenital cardiovascular aberrations in individuals with 22q11.2DS. The high frequencies observed underline the need for cardiovascular screening in patients with 22q11.2DS and genetic screening for 22q11.2DS in congenital heart disease.

Keywords: Cardiovascular Abnormalities; Genetic Testing; Heart Defects, Congenital.

Figure 1. PRISMA (Preferred Reporting Items for Systematic reviews and Meta-analyses) flowchart showing the systematic literature search. 5300 studies were found in the systematic literature search, of which 4338 were screened for title and abstract after removal of duplicates. Of those, 4252 were excluded and 86 selected for full-text screening. Ten studies could not be retrieved because of no access; hence, 76 studies were assessed for eligibility and screened in full text. Further, 69 studies were excluded and 7 studies were included for the systematic review and meta-analysis.

Figure 2. Forest plot of the prevalences of ventricular septal defect (VSD) (A), pulmonary atresia with ventricular septal defect (PA+VSD) (B) and atrial septal defect (ASD) (C) calculated by random-effects models in MetaXL. The included studies are listed on the left side, prevalence rates of each study with 95% CIs are shown on the first column on the right side. The second column on the right side represents the weight a study represents on the meta-analytically calculated pooled prevalence. The diamond on the bottom represents the pooled prevalence. I², percentage of variation in prevalence across studies that is due to heterogeneity rather than chance; p, significance level of Q derived by χ² distribution; Q, Cochran’s Q.

Figure 3. Forest plot of the prevalences of tetralogy of Fallot (TOF) calculated by use of random-effects models in MetaXL (A) and forest plot of the prevalences of TOF calculated by sensitivity analysis by use of random-effects models in MetaXL (B). The included studies are listed on the left side, prevalence rates of each study with 95% CIs are shown on the first column on the right side. The second column on the right side represents the weight a study represents on the meta-analytically calculated pooled prevalence. The diamond on the bottom represents the pooled prevalence. I², percentage of variation in prevalence across studies that is due to heterogeneity rather than chance; p, significance level of Q derived by χ² distribution (df=2); Q, Cochran’s Q.

Figure 4. Forest plot of the prevalences of truncus arteriosus communis (TAC) calculated by random-effects models in MetaXL (A) and forest plot of the prevalences of TAC calculated by leave-one-out analysis by use of random-effects models in MetaXL (B). The included studies are listed on the left side, prevalence rates of each study with 95% CIs are shown on the first column on the right side. The second column on the right side represents the weight a study represents on the meta-analytically calculated pooled prevalence. The diamond on the bottom represents the pooled prevalence. I², percentage of variation in prevalence across studies that is due to heterogeneity rather than chance; p, significance level of Q derived by χ² distribution (df=2); Q, Cochran’s Q.

Figure 5. Forest plot of the prevalences of interrupted aortic arch (IAA) calculated by random-effects models in MetaXL (A) and forest plot of the prevalences of IAA calculated by sensitivity analysis by use of random-effects models in MetaXL (B). The included studies are listed on the left side, prevalence rates of each study with 95% CIs are shown on the first column on the right side. The second column on the right side represents the weight a study represents on the meta-analytically calculated pooled prevalence. The diamond on the bottom represents the pooled prevalence. I², percentage of variation in prevalence across studies that is due to heterogeneity rather than chance; p, significance level of Q derived by χ² distribution (df=4); Q, Cochran’s Q.