Genome-wide assessment of rare protein-coding variants identifies associations with non-syndromic cleft lip/palate.

Evaluating the Role of VAX1, MAFB, and NOG in Non-Syndromic Cleft Palate Only Among Japanese Individuals.

Non-syndromic cleft palate only (NSCPO) is a distinct clinical and etiological entity within the spectrum of orofacial clefts. While genome-wide association studies (GWAS) have identified numerous risk loci for nonsyndromic cleft lip with or without cleft palate (NSCL/P), the genetic architecture of NSCPO remains less understood, particularly in the Japanese population. This study aimed to investigate the association of three candidate genes, VAX1, MAFB, and NOG, with NSCPO risk. A case-control study was carried out involving 65 Japanese NSCPO patients and 119 ethnically matched healthy controls. Three single-nucleotide polymorphisms (SNPs), rs7078160 (VAX1), rs13041247 (MAFB), and rs227731 (NOG), were selected based on previous GWAS and minor allele frequency. Statistical associations were evaluated using chi-squared or Fisher's exact tests. The VAX1 rs7078160 polymorphism showed a significant association with NSCPO under a recessive model (OR = 2.10, 95% CI = 1.05-4.22, p = 0.034), with the AA genotype showing a higher risk. No significant associations were found for MAFB rs13041247 or NOG rs227731 (p > 0.05). Our findings identify VAX1 rs7078160 as a potential risk factor for NSCPO in the Japanese population. These results show the need for larger studies to further explain the molecular pathways of NSCPO.

Genomic landscape of rare variants in a Chinese autism cohort and discovery of novel risk genes.

A whole-genome sequencing analysis of 3109 samples across 1033 Chinese ASD families expands the ASD genetic landscape and suggest convergent pathogenic axes involving transcriptional regulation, synaptic signaling and plasticity, and neuroimmune interactions.

Genetic architecture of lung cancer revealed by common and rare variant analyses across population-scale biobanks.

Genome-wide association studies have predominantly implicated common variants in lung cancer susceptibility, whereas the contribution of rare non-coding variation remains incompletely defined. This study comprised 52,550 cases and 1,617,173 controls across three whole-genome sequencing (WGS) cohorts (UK Biobank, the 100,000 Genomes Project, and All of Us) and five imputed genotype-array datasets aimed to identify rare non-coding determinants of lung cancer risk. Two complementary approaches were applied: position-based single-variant testing for variants with adequate allele counts, and gene-based testing aggregating rare and ultra-rare ncRNA variants to increase power. Single-variant meta-analysis identified two novel rare non-coding variants reaching sequencing-based genome-wide significance: rs763076863C22orf46 at 22q13.2 [OR (95% CI): 5.94 (3.46-10.19), P = 4.55 × 10-9] and rs1014871851WWOX at 16q23.1 [OR (95% CI): 7.55 (4.50-12.67), P = 3.71 × 10-9]. Functional annotation-informed gene-based analyses prioritized 37 candidate ncRNAs using eQTL, expression, proteomics, prognosis, cis-Mendelian randomization drug-target evidence, and external replication. CLEC12A-AS1 ranked highest; multi-omics association and chain mediation analyses supported an indirect pathway linking CLEC12A-AS1 burden to lung cancer risk via modulation of CLEC12A. Collectively, results indicate contributions from both individually detectable rare variants and cumulative ultra-rare functional burden within ncRNA regions, highlighting the CLEC12A-AS1/CLEC12A axis as a potential biomarker and translational target.

Monoallelic loss-of-function variants in ZNF536 are associated with a neurodevelopmental disorder with prominent behavioral features.

ZNF536 encodes a C2H2 zinc-finger transcription factor that functions as a transcriptional repressor. While common noncoding variants at the ZNF536 locus have been reported to be associated with schizophrenia in a genome-wide association study (GWAS), the contribution of rare, protein-altering variants to human disease has not been systematically investigated. Through an international collaboration, we assembled a cohort of 21 affected individuals carrying 18 unique, rare, heterozygous, protein-altering ZNF536 variants. Most variants (15/18) were predicted loss-of-function (LoF) alleles, with the remainder being missense variants. Among families with available inheritance data (17/20), most variants arose de novo (12/17), while others were inherited from mosaic or mildly affected parents (5/17). Clinically, affected individuals presented with developmental delay along with high rates of autism spectrum disorder, intellectual disability, hyperactivity, aggressive behavior, anxiety, and hyperphagia; epilepsy and sleep disturbances were also frequently observed. To assess functional consequences of a proband-associated ZNF536 variant, we generated a Zfp536p.Gln169Ter knock-in mouse model. Homozygous mutants were non-viable, while heterozygotes survived but displayed autism-like behaviors, increased anxiety, and impaired recognition memory. Embryonic brain analysis revealed reduced cortical size, cortical thickness, and decreased deep-layer neuronal density. These features are consistent with phenotypes of a publicly available mouse knockout model and support our clinical cohort findings that rare monoallelic LoF variants in ZNF536 underlie a genetic neurodevelopmental disorder characterized by developmental delay, autism, and behavioral dysregulation. The pathogenicity of missense variants in disease remains to be determined. These results support a role for ZNF536 as a dosage-sensitive regulator of cortical development.

Prioritizing Genes and Rare Protein-Coding Variants in Acute Myeloid Leukemia via Whole Genome Sequencing Data

Whole-Genome Sequencing Identifies Potentially Causative Variants in SOX30, AKAP4, and RNF220 in Non-Obstructive Azoospermia

The co-occurrence of variants in AKAP4 and RNF220 may suggest an oligogenic etiology of NOA and contribute to the phenotypic variability associated with AKAP4 variants.