Human gene copy number spectra analysis in congenital heart malformations

The clinical significance of copy number variants (CNVs) in congenital heart disease (CHD) continues to be a challenge. Although CNVs including genes can confer disease risk, relationships between gene dosage and phenotype are still being defined. Our goal was to perform a quantitative analysis of CNVs involving 100 well-defined CHD risk genes identified through previously published human association studies in subjects with anatomically defined cardiac malformations. A novel analytical approach permitting CNV gene frequency “spectra” to be computed over prespecified regions to determine phenotype-gene dosage relationships was employed. CNVs in subjects with CHD (n = 945), subphenotyped into 40 groups and verified in accordance with the European Paediatric Cardiac Code, were compared with two control groups, a disease-free cohort (n = 2,026) and a population with coronary artery disease (n = 880). Gains (≥200 kb) and losses (≥100 kb) were determined over 100 CHD risk genes and compared using a Barnard exact test. Six subphenotypes showed significant enrichment (P ≤ 0.05), including aortic stenosis (valvar), atrioventricular canal (partial), atrioventricular septal defect with tetralogy of Fallot, subaortic stenosis, tetralogy of Fallot, and truncus arteriosus. Furthermore, CNV gene frequency spectra were enriched (P ≤ 0.05) for losses at: FKBP6, ELN, GTF2IRD1, GATA4, CRKL, TBX1, ATRX, GPC3, BCOR, ZIC3, FLNA and MID1; and gains at: PRKAB2, FMO5, CHD1L, BCL9, ACP6, GJA5, HRAS, GATA6 and RUNX1. Of CHD subjects, 14% had causal chromosomal abnormalities, and 4.3% had likely causal (significantly enriched), large, rare CNVs. CNV frequency spectra combined with precision phenotyping may lead to increased molecular understanding of etiologic pathways

Impact of \u3cem\u3eMYH6\u3c/em\u3e Variants in Hypoplastic Left Heart Syndrome

Hypoplastic left heart syndrome (HLHS) is a clinically and anatomically severe form of congenital heart disease (CHD). Although prior studies suggest that HLHS has a complex genetic inheritance, its etiology remains largely unknown. The goal of this study was to characterize a risk gene in HLHS and its effect on HLHS etiology and outcome. We performed next-generation sequencing on a multigenerational family with a high prevalence of CHD/HLHS, identifying a rare variant in the α-myosin heavy chain (MYH6) gene. A case-control study of 190 unrelated HLHS subjects was then performed and compared with the 1000 Genomes Project. Damaging MYH6 variants, including novel, missense, in-frame deletion, premature stop, de novo, and compound heterozygous variants, were significantly enriched in HLHS cases (P \u3c 1 × 10−5). Clinical outcomes analysis showed reduced transplant-free survival in HLHS subjects with damaging MYH6 variants (P \u3c 1 × 10−2). Transcriptome and protein expression analyses with cardiac tissue revealed differential expression of cardiac contractility genes, notably upregulation of the β-myosin heavy chain (MYH7) gene in subjects with MYH6 variants (P \u3c 1 × 10−3). We subsequently used patient-specific induced pluripotent stem cells (iPSCs) to model HLHS in vitro. Early stages of in vitro cardiomyogenesis in iPSCs derived from two unrelated HLHS families mimicked the increased expression of MYH7 observed in vivo (P \u3c 1 × 10−2), while revealing defective cardiomyogenic differentiation. Rare, damaging variants in MYH6 are enriched in HLHS, affect molecular expression of contractility genes, and are predictive of poor outcome. These findings indicate that the etiology of MYH6-associated HLHS can be informed using iPSCs and suggest utility in future clinical applications

Aortic valve replacement in neonates and infants: An analysis of the Society of Thoracic Surgeons Congenital Heart Surgery Database

ObjectiveWe sought to describe early outcomes of aortic valve replacement in neonates and infants across a large multicenter cohort.MethodsNeonates and infants in the Society of Thoracic Surgeons Congenital Heart Surgery Database undergoing nontruncal aortic valve replacement with the Ross-Konno procedure, Ross procedure, or homograft replacement from 2000 to 2009 were included. Preoperative characteristics, operative data, and early outcomes are described.ResultsA total of 160 patients (43 neonates, 117 infants) from 47 centers were included. Society of Thoracic Surgeons–defined preoperative risk factors were present in 76 patients (48%) and were most prevalent in neonates (67%) and patients undergoing homograft aortic valve replacement (93%). Concomitant arch repair or mitral valve surgery was performed in 30 patients (19%) and 19 patients (12%), respectively. Postoperative mechanical circulatory support was used in 17 patients (11%). Overall in-hospital mortality was 18% and was highest for neonates (28%) and patients undergoing homograft aortic valve replacement (40%). Concomitant arch repair was associated with higher in-hospital mortality (33% vs 15%, P = .02), whereas concurrent mitral valve surgery was not (21% vs 18%, P = .73). Postoperative mechanical circulatory support was also associated with increased in-hospital mortality (65% vs 13%, P < .0001).ConclusionsNeonates and infants undergoing aortic valve replacement are a high-risk group, with hospital mortality comparable with some of the highest risk procedures in this age group. The requirement for arch repair or postoperative mechanical circulatory support was associated with an increased risk of death in this cohort

Hypoplastic Left Heart Syndrome Current Considerations and Expectations

In the recent era, no congenital heart defect has undergone a more dramatic change in diagnostic approach, management, and outcomes than hypoplastic left heart syndrome (HLHS). During this time, survival to the age of 5 years (including Fontan) has ranged from 50% to 69%, but current expectations are that 70% of newborns born today with HLHS may reach adulthood. Although the 3-stage treatment approach to HLHS is now well founded, there is significant variation among centers. In this white paper, we present the current state of the art in our understanding and treatment of HLHS during the stages of care: 1) pre-Stage I: fetal and neonatal assessment and management; 2) Stage I: perioperative care, interstage monitoring, and management strategies; 3) Stage II: surgeries; 4) Stage III: Fontan surgery; and 5) long-term follow-up. Issues surrounding the genetics of HLHS, developmental outcomes, and quality of life are addressed in addition to the many other considerations for caring for this group of complex patients

Tratamiento quir\ufargico para la muerte cardiaca s\ufabita en ni\uf1os

La muerte cardiaca s\ufabita (SCD) en ni\uf1os es resultado de m\ufaltiples causas y el tratamiento (profilaxia) se ajusta en consecuencia de manera espec\uedfica. En ni\uf1os sin cardiopat\ueda cong\ue9nita, el tratamiento quir\ufargico de la SCD consta por lo general de la iniplaniaci\uf3n de un desfibrilador interno, con atenci\uf3n espec\uedfica.a la talla peque\uf1a del paciente. En ni\uf1os con cardiopat\ueda cong\ue9nita no reparada, el tratamiento de la SCD es sobre todo la reparaci\uf3n de la anomal\ueda cong\ue9nita. En ni\uf1os o adultos j\uf3venes a quienes ya se realiz\uf3 cirug\ueda parar cadiopat\uedn cong\ue9nita. el tratamiento consta de reparaci\uf3n de cualquier defecto estrucral residual o adquirido. a menudo en combinaci\uf3n con cirug\ueda para antiarritmia o la implataci\uf3n de un desfibrilador

Intervenci\uf3n quir\ufargica cardiaca en reci\ue9n nacidos: expectativas y resultados razonables

En este art\uedculo se comenta la necesidad de est\ue1ndares para expectativas y resultados razonables para el tratamiento neonatal de cardiopat\ueda cong\ue9nita y las bases de datos que permiten que esos est\ue1ndares se midan y se comparen entre centros de tratamiento