This study expands the understanding of the genetic landscape underlying congenital heart anomalies and emphasises the need for larger, deeply phenotyped cohorts to translate preliminary insights into clinically applicable predictors.
Abstract
Introduction Congenital heart defects (CHD) constitute a prevalent group of structural birth anomalies, characterised by substantial genetic heterogeneity and diverse clinical phenotypes. Methods To investigate the underlying genetic architecture, we performed whole-genome sequencing (WGS) in a cohort of 50 patients with echocardiographically confirmed CHD, followed by systematic variant identification and functional annotation. Results Our analysis reveals the limited discriminatory capacity of current genomic annotation databases and underscores the necessity of stratifying genetic risk assessments by specific CHD subtypes. By integrating clinical classifications, genomic data, and tissue-specific expression profiles, we identified novel coding and non-coding variants alongside putative regulatory signals that may contribute to CHD pathogenesis. Within cardiac-specific genes, we identified CHD subtype-specific genetic associations, including JARID2 with PDA, GOSR2/TBX18 with VSD, PCDHA9 with ASD, and a multi-gene signature (CREBBP, ZFPM2, SLC27A6, ADAM17, ETS1) with atrioventricular septal defects. Among coding variants in non-CHD-associated genes, we identified COL11A2 and PCOLCE2 as plausible collagen-related candidates for CHD pathogenesis. Discussion These findings reinforce the polygenic architecture of CHD and highlight the value of context-aware, phenotype-driven interpretation of genetic variants. Collectively, this study expands the understanding of the genetic landscape underlying congenital heart anomalies and emphasises the need for larger, deeply phenotyped cohorts to translate these preliminary insights into clinically applicable predictors.
Background Congenital heart disease (CHD) is the most common major congenital anomaly and a leading cause of infant morbidity and mortality. The rapid expansion of genomic technologies has accelerated the discovery of rare genetic variants implicated in CHD pathogenesis. However, most individuals with CHD still lack an identifiable molecular etiology. The purpose of this scoping review is to systematically characterize genes reported in the recent literature as candidate CHD-associated genes and contextualize these findings within the stages of cardiac morphogenesis. Methods PubMed was searched using predefined terms related to CHD and genetic variants, supplemented by a prospectively maintained internal database. We included human studies published between January 2023 and December 2025 that identified pathogenic, likely pathogenic, or uncertain monogenic variants in at least one patient with CHD. Animal-only studies, chromosomal abnormalities, copy number variants, multigenic associations, transcriptomic/proteomic analyses, reviews, and maternal-only genetic studies were excluded. Gene–disease validity classifications were assigned using the Clinical Genome Resource (ClinGen) CHD Gene Curation Expert Panel framework. Results Of 2,834 screened articles, 391 studies met inclusion criteria, identifying 912 unique genes reported as candidate CHD-associated genes. Frequently reported genes included PTPN11, NOTCH1, GATA4, JAG1, MYH6, GATA6, and LZTR1. Identified genes spanned all major stages of cardiogenesis, including developmental priming, cardiac progenitor specification, left-right axis formation, neural crest migration, outflow tract development, septation, and postnatal structural remodeling. Studies increasingly implicated ciliary dysfunction, transcriptional regulation, ribosomal biology, and multigenic inheritance in CHD pathogenesis. Emerging methodologies included stem cell-derived cardiac models, machine learning-based gene prioritization, and epigenetic analyses. Conclusions Recent literature substantially expands the catalog of candidate genes that may be associated with CHD and highlights the biologic complexity underlying cardiac morphogenesis. Integration of genomic, developmental, and functional approaches will be essential to improve mechanistic understanding, refine genetic counseling, and support future precision medicine strategies for CHD.
Shani Israel, S. Morton· Translational Pediatrics· 0 citations
Recent medical advances have significantly improved the life expectancy of individuals with congenital heart disease (CHD); however, these children remain at increased risk of co‐occurring neurodevelopmental disorders (NDD), such as attention‐deficit/hyperactivity disorder and autism spectrum disorder. Although prenatal environmental factors, including placental dysfunction and altered oxygen levels in utero, as well as postnatal events such as cardiac surgery, may contribute to this increased risk, shared genetic factors may also underlie both conditions. Therefore, this study is aimed at investigating genomic, transcriptomic and epigenomic findings in patients with NDD and/or CHD using an integrative multiomic approach. A cohort of 14 trios and one duo was recruited: Two probands had both NDD and CHD, two had CHD only and 11 had NDD only. Blood samples were analysed using whole‐genome sequencing, RNA sequencing and DNA methylation profiling. We identified one large deletion (~2.5 Mb) and seven likely pathogenic/pathogenic (LP/P) variants, including two in autosomal dominant genes relevant to the patients′ phenotypes and five in autosomal recessive genes consistent with carrier status. This included a likely pathogenic de novo splice‐disrupting variant in the chromatin remodelling gene ARID1B, validated by RNA sequencing. DNA methylation analysis revealed epigenetic differences between CHD and NDD patients, with CHD patients showing elevated biological age acceleration. Comparison with a reference cohort of 178 controls identified four probands with extreme methylation dysregulation, including the individual with the ARID1B variant. Overall, these findings highlight the diagnostic and mechanistic value of integrative multiomic profiling in paediatric developmental disease cohorts.
Jamie-Lee M. Thompson, Yun-Kai Gao, Eri Iwasawa et al.· Human Mutation· 0 citations
Congenital heart disease (CHD) combined with anomalies of the kidney and urinary tract (CAKUT) belongs to severe clinical conditions that represent isolated cases or can be part of complex inherited syndromes. To date, knowledge of the genetic basis of cardio-renal birth defects is very limited. Using chromosomal microarray analysis and exome sequencing, we investigated the spectrum of copy number variations (CNVs) and point genetic variants in a pediatric cohort of 30 patients presenting with combined CHD and CAKUT. Two patients possessed a pathogenic deletion in the 22q11.2 genomic region, well-known as the DiGeorge/velocardiofacial syndrome locus. Four other patients harbored rare copy number gains, which included one of the dosage-sensitive genes:
DHFR
(5q14.1),
NPHP1
(2q13),
NNT
(5p12), and
MCTP2
(15q26.2). In six children, novel or previously described causative variants were detected in the genes associated with orphan monogenic disorders such as Kabuki (
KMT2D)
, Noonan (
PTPN11
), Adams-Oliver (
NOTCH1
), and Alagille (
JAG1
) syndromes, as well as
SALL4
- and
MED13
-related syndromes. Furthermore, potentially disease-contributing variants were identified in the genes that primarily code for cardiac transcription factors, chromatin remodeling proteins, Notch- or
BMP-
signaling molecules, and components of cilia. Notably, two children had loss-of-function variants in
ROBO1
, encoding one of the receptors of the SLIT/ROBO signaling pathway.
In vitro
studies on cardiac mesenchymal cells demonstrated a dramatically diminished expression level of ROBO1 in a patient with novel compound heterozygous variants c.541_542del (p.Val181CysfsTer18) and c.657+4A>G and a moderately reduced ROBO1 expression in a patient with a heterozygous stop-gain variant c.2758C>T (p.Arg920Ter), which suggests a haploinsufficiency mechanism. Together, our findings underlined the utility of early cytogenetic screening for the 22q11.2 deletion among children with cardio-renal malformations and confirmed the importance of rare single-nucleotide variants in the genes involved in cardiogenesis and kidney development. In particular,
ROBO1
can be regarded as a candidate gene associated with combined heart and kidney structural defects and should be included in appropriate diagnostic gene-sequencing panels. The results support the usefulness of WES and array-based comparative genomic hybridization (array-CGH) analysis for new candidate gene identification, more accurate diagnosis, and family genetic counseling.
A. Zlotina, Sergei Zhuk, I. Kozyrev et al.· Frontiers in Cell and Develo...· 0 citations
It is shown that determining the clinical significance of CHD8 MVs is challenging, even with detailed clinical information, but that incorporating episignature analysis increases diagnostic yield and will improve the diagnosis and understanding of CHD8-related disorders.
Molly Godfrey, Michael A. Levy, Christopher Campbell et al.· European Journal of Human Ge...· 0 citations
Background/Objectives: Dilated cardiomyopathy (DCM) is a genetically heterogeneous myocardial disorder. Emerging evidence suggests that some genes implicated in DCM may also be associated with neurological disorders, supporting the concept of genetic pleiotropy. This study explored the intersection between cardiac and neurological genetics, with the aim of identifying candidate genes that may contribute to shared pathogenic pathways linking these clinically distinct conditions. Methods: We performed exome sequencing in 149 patients with echocardiographically confirmed DCM and subsequently applied an in silico filter to a predefined list of 211 genes associated with inherited cardiomyopathies. Variants were classified according to the American College of Medical Genetics and Genomics (ACMG) criteria. Genes with validated evidence for DCM according to the Clinical Genome Resource (ClinGen) were further investigated through the Human Gene Mutation Database (HGMD) and a focused literature review to identify reported associations with neurological disorders. Results: Genetic variants in DCM-associated genes were identified in 105 patients. Overall, 137 variants were detected, including pathogenic variants and variants of uncertain significance. The most frequently involved genes were TTN, FLNC, and MYH6. Several DCM-associated genes also showed reported associations with neurological disorders, including autism spectrum disorder, Alzheimer’s disease, Parkinson’s disease, epilepsy, and schizophrenia. Among them, TTN, FLNC, RYR2, and SCN5A displayed the broadest overlap between cardiac and neurological phenotypes. Conclusions: These descriptive findings show that variants were most frequently observed in TTN, FLNC, and MYH6 and that several genes included in the ClinGen DCM curation framework have also been independently reported in neurological disorders. Because most identified variants were VUS and no control group or systematic neurological phenotyping was available, the findings indicate gene-level co-annotation only and do not establish variant enrichment, shared pathogenic mechanisms, or clinical overlap.
M. G. Salluzzo, F. Schillaci, Elisa Zago et al.· Diagnostics· 0 citations
Increased CNV burden, in both number and cumulative genomic size, co-occurred more frequently in individuals with severe phenotypes, including ASD with intellectual disability, epilepsy, and broader NDDs, reflecting a real-world clinical setting rather than a prospectively recruited research cohort.
M. R. Di Iorio, Ilaria La Monica, Antonio Imperatore et al.· International Journal of Mol...· 0 citations
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