Aug 2026· Scientific Reports· Vol 16· 0 citations· 32 references
Medicine
TL;DR
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.
Abstract
Cardiovascular laterality defects occur with an estimated birth prevalence of 1.1/10,000 live births, associated with congenital heart defects (CHD) and situs abnormalities. Known disease genes explain about 20% of all cases often correlated with primary ciliary dyskinesia (PCD). We aimed to identify disease genes beyond PCD-related aetiologies using exome sequencing in 16 case-parent trios followed by exome survey in 2,109 individuals with situs inversus totalis, heterotaxy, or isolated CHD. We identified six different variants in FAM222B, previously discussed as a candidate gene for cerebral cavernous malformations. The variant c.899G > A (p.300Arg > His) was found de novo in two unrelated families. FAM222B has been described as a substrate of Nemo-like kinase (NLK), associated with left–right body axis determination. Structural modelling suggests a function of FAM222B Arg300 in NLK recognition. We investigated whole-mount in situ hybridization (WISH) expression pattern and genomic context of the zebrafish (zf) FAM222B homologues, fam222ba/bb, and fam222aa. Using a double-knockout (dd-KO) fam222ba/bb zf line, we identified aberrant cardiac looping in these larvae and enlarged atrium and ventricle in adult zf. We further tested the c.899G > A variant using human mRNA injections in Tg(kdrl:EGFP) wildtype (wt) reporter-zf, which led to perturbed cardiogenesis. Together, we propose FAM222B as a novel candidate gene for cardiovascular laterality defects.
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
The first prenatal case from a non-consanguineous Chinese family presenting with isolated right pelvicalyceal and ureteral dilation at 24 weeks of gestation is reported, highlighting the utility of prenatal exome sequencing in atypical cases and contributing to the understanding of the expanding genetic and phenotypic landscape of ciliopathies.
Jinyu Liu, Yi Wu, Shixuan Xu et al.· Intractable & Rare Diseases...· 0 citations
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.
Nahyun Kong, Javier Abello, Christopher J. Yoon et al.· Research Square· 0 citations
This study identifies novel loss-of-function RSPH4A variants causing PCD through distinct molecular mechanisms, expanding the mutational spectrum of radial spoke head protein-related ciliopathies.
Yuting Lu, Hui-Yan Tang, Kai Chen et al.· Frontiers in Genetics· 0 citations
Background: Laterality defects are rare congenital malformations that encompass congenital heart defects (CHDs) together with abnormalities of visceral organ arrangement (situs inversus or situs ambiguous). These defects may be isolated or part of a syndromic presentation with multisystem involvement. While over 50 genes have been implicated in laterality disorders, across multiple modes of inheritance, many cases remain molecularly undiagnosed. We sought to elucidate the molecular basis of dextrocardia, CHDs and visceral heterotaxy in two unrelated individuals of Arab-Muslim descent. Methods: Detailed clinical phenotyping and exome sequencing (ES) were performed for each of the probands, followed by familial segregation analysis. Results: ES revealed a shared homozygous variant in the Dan Domain Family Member 5 (DAND5) gene (NM_152654.3): c.396_397dup, p.(Tyr133SerfsTer11). DAND5 encodes a member of the Cerberus-related DAN protein family, which is involved in the establishment of left body asymmetry. This frameshift variant introduces a premature stop codon within the final exon, which is predicted to escape nonsense-mediated decay (NMD), resulting in a truncated protein lacking the functional DAN domain. Conclusions: DAND5 has recently been suggested as a candidate gene in heterotaxy and CHDs. Our findings further support biallelic loss of function variants in DAND5 autosomal recessive laterality defects.
O. Chorin, Yoav Bolkier, U. Katz et al.· Genes· 0 citations
Heterotaxy (HTX) is a rare condition characterized by complex congenital heart defects and a wide spectrum of extracardiac abnormalities that significantly impact survival. While molecular diagnosis is essential for clinical management, next-generation sequencing (NGS) currently identifies disease-causing variants in only 20%-30% of HTX cases. To address this diagnostic gap, we collected cases of HTX investigated by trio-based whole-exome (WES) and whole-genome sequencing (WGS) and performed detailed clinical and molecular characterization in seven children and fetuses from France and Vietnam. In parallel, we conducted a systematic review of 108 published cases to refine genotype-phenotype correlations. We identified seven variants in four key genes: DNAH9, PKD1L1, MMP21, and GDF1. The findings revealed significant phenotypic heterogeneity while highlighting strong genotype-phenotype correlations, such as the association of MMP21 and GDF1 variants with severe conotruncal malformations. Two unreported variants were identified, further expanding the mutational spectrum of laterality defects. By integrating fetopathological data with advanced genomic analyses, we further delineate the phenotypic spectrum of these conditions. Ultimately, this work underscores the high diagnostic value of NGS in prenatal and neonatal cardiology, enabling earlier diagnosis and more personalized clinical management.
Thi Bich Tuyen Ho, Alicia Coudert, Thi Thuy Hang Do et al.· Clinical Genetics· 0 citations