Congenital heart disease (CHD) affects ~1% of live births, yet the genetic basis of many cases remains unresolved. Uniparental disomy (UPD), the inheritance of both homologous chromosomes from one parent, is often overlooked. We developed TrioMix-UPD, an integrated short- and long-read sequencing framework for UPD detection and classification. Applying it to 3,740 CHD trios, we identified 12 UPD events, representing a 6.57-fold enrichment relative to the general population. Both advanced maternal age and enrichment of rare inherited variants in synaptonemal complex genes implicated meiotic chromosome segregation defects in UPD risk. Within UPD regions, we identified pathogenic homozygous variants in PIEZO1 and GLYR1 and nominate MESD as a novel CHD candidate gene. Functional studies in zebrafish and human cells recapitulated patient-specific cardiac phenotypes. Differential methylation analyses implicated imprinting dysregulation, including at the Prader-Willi critical region. Collectively, these findings establish UPD as an underrecognized contributor to CHD.
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
This work proposes FAM222B as a novel candidate gene for cardiovascular laterality defects, described as a substrate of Nemo-like kinase (NLK), associated with left–right body axis determination in zebrafish homologues, fam222ba/bb, and fam222aa.
Nina Reitz, J. Lambertz, Öznur Yilmaz et al.· Scientific Reports· 0 citations
BACKGROUND
Congenital heart disease (CHD) is one of the most common birth defects in infants and significantly impacts life expectancy. Nonsyndromic CHDs are more severe than syndromic clinical phenotypes, with life expectancy often limited to days or weeks. It is imperative to evaluate genes associated with CHD or developmental defects at the population level to ascertain their severity and inform appropriate therapeutic interventions. This study aimed to evaluate GATA4 gene variants in sporadic congenital heart defects in children in the rural Vidarbha region.
MATERIALS AND METHODS
We collected blood samples from 40 clinically proven nonsyndromic CHD for genotyping the GATA4 gene. All the children had normal cytogenetic profiles. We performed specific genotyping of exon 4 of the GATA4 gene using Sanger sequencing. In silico analyses, including Mutation Taster, PolyPhen2, Missense3D, HOPE, and SwissModel, were performed to evaluate the disease-causing effects of detected variants in exon 4 of GATA4 gene.
RESULTS
Our analysis identified three novel missense exonic nucleotide variants, E287K (c. 859G > A, p. Glu287Lys), G296A (c. 887G > C, p. Gly296Ala), and K300R (c. 899A > G, p. Lys300Arg), which were potentially deleterious according to in silico analysis. The present analysis indicates that the variants identified in this study are likely to be associated with CHD in children.
CONCLUSION
Notably, we report for the first time these three novel variants in exon 4, which may represent potential risk factors for CHD development.
J. Waghmare, P. Ambulkar, Tejas Tajne et al.· Annals of African medicine· 0 citations
Congenital heart disease (CHD), which represents the most common type of human birth defect affecting approximately 1% of all live births globally, is a leading cause of substantial infant mortality and morbidity worldwide. Although aggregating evidence has convincingly suggested a strong genetic basis underpinning CHD, the inherited components underlying CHD in most cases remain indefinite. Hence, the current investigation aimed to identify and characterize novel genetic variations underlying CHD. A five-generation pedigree with patent ductus arteriosus (PDA) and another group of 174 index patients with CHD were enrolled. In addition, 218 unrelated non-CHD people were employed as controls. Clinical assessments, along with exome-sequencing and Sanger-sequencing examinations, were performed in the study participants. The functional effects of the detected variations in the SMAD5 gene, which encodes a transcription factor required for proper cardiovascular morphogenesis, were measured by dual-luciferase reporter assays. Two new SMAD5 variants, NM_005903.7: c.244 A > T; p.(Lys82*) and NM_005903.7: c.209G > T; p.(Arg70Ile), were detected in a heterozygous status in the PDA pedigree and one PDA case out of the 174 index patients affected with CHD, respectively. Neither of the two SMAD5 variations was observed in the 436 control chromosomes. Quantitative biochemical assays using dual-reporter genes revealed that the Lys82*- or Arg70Ile-mutant SMAD5 possessed diminished transactivation of NKX2.5, an established CHD-causative gene. Furthermore, the Lys82* or Arg70Ile variation nullified or significantly reduced the synergistic transactivation of ID2 between SMAD5 and BMP4, and both ID2 and BMP4 had been causally implicated in the pathogenesis underpinning CHD. The present findings indicate that SMAD5 haplo-insufficient variants contribute to PDA in humans, which sheds more light on the genetic architecture of PDA and implies a potential target for genetic counseling and individualized medicine of PDA in a subgroup of patients.
Hong Zhang, Xiao-Qing Hu, Yan-Jie Li et al.· Scientific Reports· 0 citations
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.
A. Korobeinikova, E. Petriaikina, D. Tychinin et al.· Frontiers in Cardiovascular...· 0 citations
Pathogenic CHD8 variants cause autosomal dominant 'Intellectual developmental disorder with autism and macrocephaly' (IDDAM) and are amongst the most common monogenic causes of autism. The clinical significance of CHD8 missense variants (MVs) frequently remains uncertain. Systematically applying ACGS/ACMG guidelines to 36 CHD8 MVs in 39 affected patients, only two variants were classified likely pathogenic (LP), with the remaining 34 classified variants of uncertain significance (VUS). We subclassified the variants according to posterior probability of pathogenicity (PPP), with 14 being at least tepid VUS (PPP ≥ 50%). Comprehensive phenotypic analysis revealed no discernible clinical differences between individuals carrying at least tepid VUS and others, offering no additional insight for variant classification. EpiSign™ testing revealed a CHD8-IDDAM episignature, as previously detected in patients with truncating/null variants, in 11 cases, allowing reclassification of 8 VUS (all previously classified at least tepid) as LP. Molecular modelling indicated that disease-causing (LP/P) CHD8 MVs are concentrated in structured and/or functional protein domains. Compared to truncating/null variants, disease-causing MVs were less often associated with attention issues and macrocephaly, but clinical features were otherwise similar. Additionally, three disease-causing MVs were inherited from unaffected/mildly affected parents. Overall, we show that determining the clinical significance of CHD8 MVs is challenging, even with detailed clinical information, but that incorporating episignature analysis increases diagnostic yield. Further, our results indicate that CHD8 MVs are likely to act via a loss-of-or reduced function mechanism. These findings reveal the importance and complexity of interpreting CHD8 MVs 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
