Aug 2026· iScience· Vol 29, pp. 117178· 0 citations· 63 references
Medicine
TL;DR
It is demonstrated that gap10 deletion disrupts body axis extension, left-right organizer (LRO) formation, and ciliogenesis, leading to severe cardiac looping defects that closely mirror human CHD phenotypes in Xenopus.
Abstract
Summary Congenital heart disease (CHD) remains a major cause of pediatric morbidity and mortality, yet many patients lack a genetic diagnosis. Two studies identified rare deletions in ARHGAP10 (GAP10), a Rho GTPase-activating protein at 4q31.2 in individuals with heterotaxy and atrial septal defects, highlighting GAP10 as a new candidate CHD gene; however, the function of GAP10 has not been investigated. We demonstrate that gap10 deletion disrupts body axis extension, left-right organizer (LRO) formation, and ciliogenesis, leading to severe cardiac looping defects that closely mirror human CHD phenotypes in Xenopus. Gap10 localizes to basal bodies of motile cilia in multiciliated cells, where it regulates basal body and apical F-actin organization by recruiting focal adhesion kinase (FAK) to specialized ciliary-adhesion complexes. Our findings implicate GAP10 as a clinically relevant, genetically supported, and functionally validated regulator of CHD and ciliogenesis, underscoring the power of functional genomics for discovering rare disease genes.
TrioMix-UPD, an integrated short- and long-read sequencing framework for UPD detection and classification, is developed and established UPD as an underrecognized contributor to CHD.
Nahyun Kong, Javier Abello, Christopher J. Yoon et al.· Research Square· 0 citations
Plasma proteomic analysis of patients with CILD40 identified significant enrichment of pathways related to platelet activation, complement and coagulation cascades and differential signatures in CILD40, highlighting the potential of plasma proteomics for understanding distinct pathogenic mechanisms across PCD subtypes.
Siming Kong, Mingshuo Wang, Xuedong Wang et al.· Phenomics· 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
It is concluded that PC2C331S may perturb protein stability and/or polycystin complex formation prior to ciliary/EV trafficking and a C. elegans pipeline for mechanistic classification of conserved ADPKD-associated missense variants is established.
Juan Wang, Carlos Nava Cruz, Jonathon D. Walsh et al.· Genetics· 0 citations
Congenital heart diseases (CHDs) encompass a broad spectrum of structural anomalies with substantial clinical and genetic heterogeneity. They are the most common birth defects in humans, and a leading cause of paediatric morbidity and mortality. Yet, its genetic substrate remains difficult to interpret at the bedside: despite advances in cytogenetics and next-generation sequencing, a definitive or candidate genetic cause is identified in fewer than half of cases, and even when a variant is recovered, mapping it onto the developmental program that produces a specific malformation is rarely straightforward for the practising clinician. This narrative review revisits normal cardiogenesis as a single, coordinated developmental program, integrating embryological events with progenitor populations, transcription factor networks, and signalling pathways. We then highlight how perturbation of these developmental modules may result in syndromic and non-syndromic CHD. By aligning embryological events with their regulatory logic, the review offers a developmental framework intended to help clinicians situate molecular findings within the biology of heart formation, sharpen genotype–phenotype interpretation, support more precise diagnostic and prognostic reasoning, and inform emerging regenerative strategies for the malformed and injured heart.
Aline Saliba, J. Afiune, Aline Pic-Taylor et al.· Frontiers in Genetics· 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
We use cookies to run the site and, with your consent, for analytics and to show ads.
See our Cookie Policy.
