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6 recordsLinked to original sources
PubMed2026

Dual Aberrant Splicing Caused by an Apparently Missense CHD7 Variant, c.5273A>G (p.Asp1758Gly), in CHARGE Syndrome.

CHARGE syndrome is a rare congenital disorder primarily attributed to heterozygous pathogenic variants of the CHD7 gene. Most pathogenic CHD7 variants are loss-of-function (LoF) variants, whereas the interpretation of missense variants remains challenging in the absence of functional evidence for their pathogenicity. We report a female infant presenting with clinical features characteristic of CHARGE syndrome. Targeted sequencing identified a heterozygous CHD7 variant (NM_017780.4:c.5273A>G), initially annotated as a missense substitution p.Asp1758Gly. This variant has been previously reported and registered with conflicting pathogenicity classifications; however, its transcript-level consequences remain unclear. Long-PCR-based RNA sequencing of total RNA from peripheral blood mononuclear cells revealed two aberrant splicing patterns associated with the variant: a predominant transcript carrying a 28-bp deletion due to cryptic donor splice-site activation, and a minor transcript with partial intron 24 retention. Both transcripts were predicted to result in premature termination codons. These findings demonstrate that c.5273A>G functions as a LoF variant through dual aberrant splicing rather than a simple missense substitution. This case underscores the importance of RNA-level splicing analysis for the accurate interpretation and classification of CHD7 missense variants.

CHD7↗
PubMed2026

ATRX Condensates as Candidate Organizers of Enhancer-Centered Nuclear Microenvironments in Neural Progenitors: A Hypothesis for Enhancer-Associated ATRX Function in Neural Progenitors.

Neural progenitor cells (NPCs) must preserve lineage identity while remaining responsive to developmental cues. Here, we discuss the hypothesis that ATRX condensates help organize enhancer-centered nuclear microenvironments in NPCs. ATRX has long been studied in heterochromatin maintenance, histone variant deposition, and chromatin remodeling; earlier work has also shown that ATRX can occupy euchromatic and active regulatory regions and contribute to transcriptional regulation. Recent evidence in human NPCs indicates that ATRX forms nuclear puncta with condensate-like properties, associates with neurogenic enhancer-rich regions, and incorporates regulatory factors such as CHD7 and p300. Perturbation of ATRX condensate formation is associated with changes in enhancer-associated ATRX occupancy, neural gene-expression programs, and neuroepithelial organization, suggesting a regulatory mode that may complement canonical heterochromatin-associated functions. We propose a dual-mode model in which folded domains contribute to chromatin anchoring at repressive regions, whereas intrinsically disordered regions support condensate-associated organization at active developmental enhancers. We emphasize that whether ATRX condensates activate enhancers de novo, stabilize pre-existing enhancer states, buffer transcriptional variability, or primarily organize cofactor localization remains unresolved. We also discuss limitations of the current evidence and outline acute, locus-specific experiments needed to test the model.

X-linked Nuclear Protein↗
PubMed2025

Landscape genomics analysis reveals the genetic basis underlying cashmere goats and dairy goats adaptation to frigid environments.

Understanding the genetic mechanism of cold adaptation in cashmere goats and dairy goats is very important to improve their production performance. The purpose of this study was to comprehensively analyze the genetic basis of goat adaptation to cold environments, clarify the impact of environmental factors on genome diversity, and lay the foundation for breeding goat breeds to adapt to climate change. A total of 240 dairy goats were subjected to genome resequencing, and the whole genome sequencing data of 57 individuals from 6 published breeds were incorporated. By integrating multiple approaches such as phylogenetic analysis, population structure analysis, gene flow and population history exploration, selection signal analysis, and genome-environment association analysis, an in-depth investigation was carried out. Phylogenetic analysis unraveled the genetic relationships and differentiation patterns among dairy goats and other goat breeds. Through signal analysis (θπ, FST, XP-CLR), we identified numerous candidate genes associated with cold adaptation in dairy goats (STRIP1, ALX3, HTR4, NTRK2, MRPL11, PELI3, DPP3, BBS1) and cashmere goats (MED12L, MARC2, MARC1, DSG3, C6H4orf22, CHD7, MYPN, KIAA0825, MITF). Genome-environment association (GEA) analysis confirmed the link between these genes and environmental factors. Moreover, a detailed analysis of the critical genes C6H4orf22 and STRIP1 demonstrated their significant roles in the geographical variations of cold adaptation and allele frequency differences among different breeds. This study contributes to understanding the genetic basis of cold adaptation, providing crucial theoretical support for precision breeding programs aimed at improving production performance in cold regions by leveraging adaptive alleles, thereby ensuring sustainable animal husbandry.

Environmental adaptation↗
PubMed2025

Novel Protein-Altering Variants in Cleft Genes Transmitted in Families With NSCL±P.

BACKGROUND: Pathogenic protein-altering variants play a role in the etiology of nonsyndromic cleft lip with or without palate (nsCL±P), one of the most common craniofacial anomalies. However, the genetic basis of many cases remains unclear, complicating risk prediction for affected families. PURPOSE: This study utilized whole-genome sequencing (WGS) of 150 case-families with nsCL±P from sub-Saharan Africa to identify pathogenic risk variants. STUDY DESIGN, SETTING, SAMPLE: This study utilized whole-genome sequencing (WGS) of 150 case-families with nsCL±P from sub-Saharan Africa to identify risk variants. PREDICTOR/EXPOSURE/INDEPENDENT VARIABLE: Genetic variants. MAIN OUTCOME VARIABLES: Nonsyndromic cleft lip with or without palate (nsCL±P). ANALYSES: Genomes were sequenced at a mean ×30 coverage, and variants were prioritized using CADD (≥20), REVEL (≥0.5), and ACMG/AMP clinical significance criteria. RESULTS: We identified pathogenic protein-altering variants in CHD7 (p.Arg1345His), LRP2 (p.Asp3245Asn), RYR1 (p.Arg2163Leu, p.Pro2903Thr), SHH (p.Met114Val), and WNT3 (p.Ser112Pro) highlighting the role of hedgehog signaling pathway (FDR=5.32e-12) in nsCL±P. These variants were inherited from unaffected parents suggesting an incomplete penetrance of the variant effect. Although mouse data showed that knockout of these genes produces cleft phenotypes, in vivo studies will help us better understand how the consequences of these variants differ from benign mutations. The presence of these protein-altering variants in unaffected parents-incomplete penetrance, provides additional evidence supporting the trait complexity. CONCLUSIONS AND RELEVANCE: This study identified rare, pathogenic protein-altering variants in genes involved in key developmental pathways in African families affected by nsCL±P. These findings highlight the critical role of the hedgehog signaling pathway and related networks in the etiology of nsCL±P. These findings underscore the importance of whole-genome sequencing in genetically diverse populations to uncover novel risk variants. These findings enhance our understanding of the genetic etiology of nsCL±P, particularly in under-represented African populations and support the multifactorial inheritance and the involvement of developmental pathways, such as hedgehog signaling in the etiology of clefting.

Humans↗
PubMed2026

PSIP1::TBL1X: a recurrent gene fusion in pancreatic neuroendocrine tumors.

Effective treatment of metastatic neuroendocrine tumors (NETs) is limited by a lack of targeted therapies and clinically useful predictive biomarkers. We applied complementary genomic profiling technologies, including optical genome mapping (OGM) and whole exome sequencing (WES), to 70 liver metastases of NETs from multiple anatomical primary sites to identify actionable genomic alterations. We detected recurrent fusions involving TBL1X (PSIP1::TBL1X) and BEND2 (CHD7::BEND2 and NEO1::BEND2) by OGM in pancreatic neuroendocrine tumors (pNETs). The expression of the PSIP1::TBL1X fusion was confirmed by PacBio Iso-Seq long-read transcriptome sequencing and nested rtPCR, and fusion protein expression was established by western blotting. Expression of the PSIP1::TBL1X fusion was also assayed in a separate cohort of 31 specimens from 28 pNET cases by rtPCR. Across both cohorts, PSIP1::TBL1X was identified in 11% of pNET patients with available metastatic tissue, but was not detected in primary tumor specimens. All PSIP1::TBL1X fusion isoforms were found to retain early exons of PSIP1 and the complete coding sequence of TBL1X. Consistent with prior reports, BEND2 fusions were associated with high-grade tumors and may represent a clinically useful biomarker for aggressive disease. Notably, TBL1X and BEND2 fusions did not co-occur with ATRX/DAXX mutations, defining a distinct molecular subgroup of pNETs. This study highlights the importance of structural variant profiling in molecular profiling studies and supports a revised view of the role of gene fusions in neuroendocrine malignancies.

Humans↗
PubMed2026

Genetic Heterogeneity of Inborn Errors of Immunity Revealed by Whole-Genome Sequencing: Insights from a Russian Patient Cohort.

Identifying genetic cause(s) is a key step for management and treatment of patients with inborn errors of immunity (IEI). Here, in an observational cross-sectional genomic study, we analyzed whole-genome sequencing (WGS) data of 72 IEI patients from Saint Petersburg and Northwestern Russia: 42 patients with common variable immunodeficiency (CVID)-like phenotypes, 6 patients with clinically diagnosed X-linked agammaglobulinemia (XLA or Bruton's disease), and 24 patients with other forms of IEI. Causative pathogenic and likely pathogenic variants in BTK, CYBB, CHD7, AIRE, ATM, SBDS, NFKB1, and CTLA4 genes were identified in 14 (19%) patients. Variants of uncertain significance that could be linked to observed clinical phenotypes were detected in 6 patients. These included a BTK variant in a patient with Bruton's disease, variants in SH2D1A, SOCS1, and IKBKB in patients with CVID, and variants in CARD11 and CD40LG in patients with other forms of IEI. Additional rare variants that were mostly unique to individual patients were found in multiple IEI genes from the International Union of Immunological Societies (IUIS) Expert Committee 2024 list. In the CVID-like subcohort, pathway-level analysis of these rare variants revealed patterns associated with clinical manifestations. Taken together, our results expand the genetic characterization of an understudied regional IEI cohort, particularly of patients with CVID-like phenotypes, and identify genetic factors that are implicated in or may contribute to the disease.

Humans↗