Congenital heart disease (CHD) is the most common congenital anomaly. Almost 90% of isolated cases have an unexplained genetic etiology after clinical testing. Non-canonical splice variants that disrupt mRNA splicing through the loss or creation of exon boundaries are not routinely captured and/or evaluated by standard clinical genetic tests. Recent computational algorithms such as SpliceAI have shown an ability to predict such variants, but are not specific to cardiac-expressed genes and transcriptional isoforms.
Introduction: Motile ciliary dysfunction plays a central role in the pathogenesis of respiratory abnormalities and congenital heart disease (CHD). The role of ciliary gene variants in the non-heterotaxic CHD population is not well characterised. Methods: This single-centre retrospective cohort study aimed to determine the prevalence of Primary Ciliary Dyskinesia (PCD) gene variants in children with isolated Transposition of the Great Arteries (TGA) and Tetralogy of Fallot (TOF). Patients with whole genome sequencing between 2008-2018 were included. We identified pathogenic (P) or likely pathogenic (LP) single-nucleotide variants (SNVs) and short insertion/deletions (indels) in coding regions of 45 genes known to cause PCD. Patient characteristics and associated respiratory outcomes were evaluated from chart reviews. Results: PCD gene variants were found in 2.9% (5/172) TGA and 3.8% (10/264) TOF patients. Thirteen probands were heterozygous for P/LP SNVs/ indels; CCDC40 N=6, DNAH11 N=2, SPAG1 N=2 and one each of DNAH8/DNAAF1/ARMC4. Two were compound heterozygotes for variants in DNAH11 and DNAH8. At last follow-up, mean age was 14.5 years (SD 6.8, 57.9% male) and 7 deaths had occurred. Asthma was diagnosed in 10.5% TGAs and 8.1% TOFs with 3.9% and 7.3% respectively requiring hospitalisation for primary respiratory illness. In the variant positive subgroup, 5/15 had respiratory abnormalities - bronchiectasis (N = 1), asthma (N = 2), neonatal cough (N = 1), ventilator-associated pneumonia (N = 2). Additional cardiac anomalies occurred in 53% (8/15) - abnormal systemic veins (N = 3), situs inversus, dextrocardia (N = 1), right arch (N = 5), hypoplastic right ventricle (N = 1). An abnormal coronary pattern was seen in 4/5 TGAs. Vaginal and renal agenesis each occurred in 1 patient. Conclusions: Our findings suggest a high prevalence and potential association of ciliary gene variants with respiratory outcomes and situs anomalies in non-heterotaxy CHD.
ABSTRACT Congenital heart disease (CHD) is the most common congenital anomaly. Non-canonical splice-disrupting variants are not routinely evaluated by clinical tests. Algorithms including SpliceAI predict such variants, but are not specific to cardiac-expressed genes. Whole genome (WGS) (n=1083) and myocardial RNA-Sequencing (RNA-Seq) (n=114) of CHD cases was used to identify splice-disrupting variants. Using features of variants confirmed to affect splicing in myocardial RNA, we trained a machine learning model that outperformed SpliceAI for predicting cardiac-specific splice-disrupting variants (AUC 0.92 vs 0.66), and was independently validated in 43 cardiomyopathy probands (AUC 0.88 vs 0.64). Application of this model to 971 CHD WGS samples identified 9% patients with splice-disrupting variants in CHD genes. Forty-one% of predicted splice-disrupting variants were deeply intronic. The burden of variants in CHD genes was higher in cases compared with 2,570 controls. Our model improved genetic yield by identifying splice-disrupting variants that are not evaluated by routine tests.
Elastin insufficiency causes recurrent vascular stenoses. Hemizygous deletion of the elastin gene (ELN) causes Williams-Beuren syndrome (WBS), while single nucleotide variants in ELN cause nonsyndromic supravalvar aortic stenosis (SVAS). Our objective was to compare cardiovascular disease outcomes in patients with WBS and nonsyndromic SVAS.Patients (81 WBS, 42 nonsyndromic SVAS) with cardiovascular disease were included in this retrospective single center study. Freedom from surgical and catheter interventions and reinterventions was compared. Vascular tissue from 8 patients and 6 controls was analyzed for arterial wall architecture.Patients with nonsyndromic SVAS presented at a younger age (median 0.3 [0.4-0.7] years) compared with patients with WBS (1.3 [0.2-3.0] years) and had lower freedom from surgical/catheter interventions compared with patients with WBS, with median event-free survival 1.1 (0.3-5.9) versus 4.7 (2.4-13.3) years, respectively (hazard ratio, 1.62 [95% CI, 1.02-2.56]; P=0.04). Patients with nonsyndromic SVAS also had a lower freedom from reinterventions (P=0.054 by log-rank test). This was related in part to a higher frequency of primary and reinterventions for concomitant valvar aortic stenosis. Histology revealed abnormal intimal and medial thickening, disorganized and fragmented elastic fibers, reduced smooth muscle calponin expression, and increased macrophage marker, CD68, expression in the arterial walls in patients with WBS and nonsyndromic SVAS compared with controls.Patients with nonsyndromic SVAS require early and more frequent vascular and valvular interventions and reinterventions, in particular for concomitant valvar aortic stenosis compared with patients with WBS. This provides important prognostic information to guide counseling of affected families with cardiovascular disease and may guide primary intervention strategies based on predicted risk of restenosis.
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