Susceptibility Genes Research Articles

Integrative Transcriptome-Wide Association Study With Expression Quantitative Trait Loci Colocalization Identifies a Causal VAMP8 Variant for Nasopharyngeal Carcinoma Susceptibility.

Nasopharyngeal carcinoma (NPC) is an Asia-prevalent malignancy, yet its genetic underpinnings remain incompletely understood. Here, a transcriptome-wide association study (TWAS) is conducted on NPC, leveraging gene expression prediction models based on epithelial tissues and genome-wide association study (GWAS) summary statistics from 1577 NPC cases and 6359 controls of southern Chinese descent. The TWAS identifies VAMP8 on chromosome 2p11.2 as a novel susceptibility gene for NPC. Further fine-mapping analyses pinpoint rs1058588, located within VAMP8, as a causal variant through eQTL colocalization, and GWAS analyses across multiple cohorts, achieving GWAS significance (OR=1.18, P=3.09 × 10-10). Functional assays demonstrate that VAMP8 exerts a tumorigenic role in NPC, enhancing cell proliferation, migration, and tumor growth. Mechanically, it is uncovered that rs1058588 modulates VAMP8 expression by altering its binding affinity to miR-185. Furthermore, the results show that VAMP8 interacts with DHX9 to facilitate the nuclear recruitment of p65, activating the NF-κB pathway. Collectively, the findings shed light on the genetic predisposition to NPC and underscore the critical role of the functional axis involving miR-185, VAMP8, DHX9, and the NF-κB pathway in NPC pathogenesis.

HLA-G Polymorphisms of The 3’-UTR Region Are Involved in Susceptibility to Non-Infectious Uveitis

ABSTRACT Purpose HLA-G is a non-classical HLA class I gene encoding a molecule endowed with immunomodulatory properties, playing important immunosuppressive and tolerogenic roles in immuno-privileged organs. Fluctuations in its expression levels have been correlated with the predisposition to autoinflammatory disorders, notably uveitis, characterized by inflammation of the uvea. In the present work, DNA was obtained from saliva samples of 147 Spanish patients with uveitis, with subsequent analysis focusing on the distribution of polymorphisms within the 3’UTR region of the HLA-G gene (a region known to modulate the expression of the HLA-G molecule). Methods Analysis techniques employed included PCR-RFLP or DNA sequencing. Comparative analysis was conducted against a control cohort comprising 117 healthy individuals. Results The frequency of the UTR-2 haplotype is increased in patients affected with anterior uveitis (OR (95% CI) 2.35 (1.06–5.21); p = 0.036). Additionally, a higher number of patients with posterior uveitis bearing in homozygosis the G allele of the 3142 C/G SNP (OR (95% CI) 2.67 (1.15–6.20); p = 0.023), was observed. Both markers are associated with diminished HLA-G expression. Conclusion These findings present the first evidence of the involvement of polymorphisms within the 3’UTR region of the HLA-G gene in susceptibility to uveitis.

Retraction Note: Screening and identification of susceptibility genes for cervical cancer via bioinformatics analysis and the construction of an mitophagy-related genes diagnostic model

Retraction Note: Screening and identification of susceptibility genes for cervical cancer via bioinformatics analysis and the construction of an mitophagy-related genes diagnostic model

Identifying New Susceptibility Genes of Non-Syndromic Orofacial Cleft Based on Syndromes Accompanied With Craniosynostosis.

Orofacial cleft (OC) can be classified into syndromic orofacial cleft (SOC) and non-syndromic orofacial cleft (NSOC), depending on whether there are other congenital deformities. Craniosynostosis, the premature closure of cranial sutures, is a common phenotype of SOC resulting in abnormal ossification of skull and brain development disorders. Its correlation with OC offers a promising approach to identify susceptibility genes for NSOC by examining causative genes of SOCs with craniosynostosis. This study included 2556 patients with NSOC and 2255 normal controls from western Han Chinese with their genomic DNA samples. We selected 31 causative genes of 34 syndromes with both craniosynostosis and OC as candidate genes and performed quality control. Allelic and genotypic association analyses and haplotype analysis were performed to identify statistically significant single nucleotide polymorphisms (SNPs). In allelic association analysis performed with 1265 qualified SNPs in 20 genes, only rs2239936, located in MYH3 gene, was statistically associated with non-syndromic cleft lip only (NSCLO) (P = 1.70×10-07, OR = 1.33, 95%CI: 1.17-1.52) and non-syndromic cleft palate only (NSCPO) (P = 6.43×10-05, OR = 1.33, 95%CI: 1.16-1.52). The higher frequency of allele G in NSCPO suggesting that minor allele G at rs2239936 will result in an elevated risk of NSCPO. However, rs2239936 only exhibited a statistical association with NSCPO in genotypic association analysis (P = 8.06×10-06) and haplotype analysis (P = 1.43×10-05). This study identified that allele G at rs2239936 in MYH3 gene was significantly associated with NSCPO as a risk factor and MYH3 was a new susceptibility gene for NSCPO in western Han Chinese population.

DNA methylation profiling at base-pair resolution reveals unique epigenetic features of early-onset colorectal cancer in underrepresented populations

BackgroundThe incidence of early-onset colorectal cancer (EOCRC) has been rising at an alarming rate in the USA, and EOCRC disproportionately affects racial/ethnic minorities. Here, we construct comprehensive profiles of EOCRC DNA methylomes at base-pair resolution for a cohort of Hispanic and African American patients.ResultsWe show the epigenetic landscape of these EOCRC patients differs from that of late-onset colorectal cancer patients, and methylation canyons in EOCRC tumor tissue preferentially overlapped genes in cancer-related pathways. Furthermore, we identify epigenetic alterations in metabolic genes that are specific to our racial/ethnic minority EOCRC cohort but not Caucasian patients from TCGA. Top genes differentially methylated between these cohorts included the obesity-protective MFAP2 gene as well as cancer risk susceptibility genes APOL3 and RNASEL.ConclusionsIn this study, we provide to the scientific community high-resolution DNA methylomes for a cohort of EOCRC patients from underrepresented populations. Our exploratory findings in this cohort highlight epigenetic mechanisms underlying the pathogenesis of EOCRC and nominate novel biomarkers for EOCRC in underrepresented populations.

RYR3 Variants Are Potentially Associated With Idiopathic (Non-Lesional) Partial Epilepsy/Susceptibility of Seizures, Toward Understanding the Gene-Disease Association by Genetic Dependent Nature.

The RYR3 gene encodes a brain-type ryanodine receptor that functions to release calcium from intracellular storage and plays an essential role in calcium signaling. The associations between RYR3 variants and brain disorders remain unknown. We performed whole-exome sequencing in patients with idiopathic (non-lesional) partial epilepsy of unknown etiology. One de novo missense and six biallelic missense RYR3 variants were identified in seven unrelated cases. These variants had no or extremely low allele frequencies in the general population and were predicted to alter hydrogen bonds/decrease protein stability. Patients presented with partial seizures or secondarily generalized tonic-clonic seizures. All patients were seizure-free with/without anti-seizure treatment. Four showed antecedent febrile seizures, a typical susceptibility disorder that is related to the precipitating factor of fever. The genetic dependence nature (GDN) of RYR3, which is defined as the distinct impact of the absence of a gene on normal life, is "obligatory" (causing disease phenotypes). Complete abolishing of RYR3 results in abnormal phenotypes instead of lethality, whereas partial/mild impairment (usually more common) is associated with mild disease or increased susceptibility to disease, consistent with our findings. RYR3 is therefore potentially a candidate disease gene or susceptibility gene for idiopathic partial epilepsy.

Glycosylation Pathways Targeted by Deregulated miRNAs in Autism Spectrum Disorder.

Autism Spectrum Disorder (ASD) is a complex condition with a multifactorial aetiology including both genetic and epigenetic factors. MicroRNAs (miRNAs) play a role in ASD and may influence metabolic pathways. Glycosylation (the glycoconjugate synthesis pathway) is a necessary process for the optimal development of the central nervous system (CNS). Congenital Disorders of Glycosylation (CDGs) (CDGs) are linked to over 180 genes and are predominantly associated with neurodevelopmental disorders (NDDs) including ASD. From a literature search, we considered 64 miRNAs consistently deregulated in ASD patients (ASD-miRNAs). Computational tools, including DIANA-miRPath v3.0 and TarBase v8, were employed to investigate the potential involvement of ASD-miRNAs in glycosylation pathways. A regulatory network constructed through miRNet 2.0 revealed the involvement of these miRNAs in targeting genes linked to glycosylation. Protein functions were further validated through the Human Protein Atlas. A total of twenty-five ASD-miRNAs were identified, including nine miRNAs that were differentially expressed in cells or brain tissue in ASD patients and associated with glycosylation pathways, specifically protein N- and O-glycosylation and glycosaminoglycan biosynthesis (heparan sulfate). A number of CDG genes and/or ASD-risk genes, including DOLK, GALNT2, and EXT1, were identified as targets, along with validated interactions involving four key miRNAs (hsa-miR-423-5p, hsa-miR-30c-5p, hsa-miR-195-5p, and hsa-miR-132-5p). B4GALT1, an ASD susceptibility gene, emerged as a central regulatory hub, reinforcing the link between glycosylation and ASD. In sum, the evidence presented here supports the hypothesis that ASD-miRNAs mediate the epigenetic regulation of glycosylation, thus unveiling possible novel patho-mechanisms underlying ASD.

TALome and phenotypic analysis of Pakistani Xanthomonas oryzae pv. oryzae population revealed novel virulent TALEs contributing to bacterial blight of rice

Bacterial blight (BB) of rice caused by Xanthomonas oryzae pv. oryzae (Xoo), is an important disease in rice-growing countries, including Pakistan, where it was first reported in the mid-1970s. Transcription activator-like effectors (TALEs) play vital roles in many plant diseases caused by Xanthomonas spp.; however, Pakistani Xoo TALome diversity and their contribution to pathogenicity is largely unknown. In this study, 101 Xoo strains were screened using specific PCR primers. The genomic DNA from these strains underwent BamHI digestion and hybridized with the internal SphI fragment of PthXo1. Southern blot analysis revealed 16 to 20 putative tale fragments among the tested strains. These strains were further classified into 11 genotypes based on the number and size of the hybridizing bands. Genotypes 1, 2, 3, and 4 represented 24, 2, 51, and 17 strains, respectively. Pathogenicity assays on near-isogenic lines (NILs) containing different resistance (R) genes exhibited that CBB23 was incompatible with all tested Pakistani-Xoo genotypes, whereas IRBB5 and IRBB4 showed resistance against specific genotypes. In contrast, paddy trails on NILs containing single, double, and triple mutants of OsSWEET11a, OsSWEET13, and OsSWEET14 in the effector binding elements (EBEs) of cv. Kitaake revealed that KP-22 and LD-5 harbor novel virulent TAL effector/s. Interestingly, the expression analysis of six clade-III OsSWEET genes suggests that novel TALE/s targeting unidentified susceptibility gene/s. Altogether, this study highlights gene-for-gene relationships between tested rice lines and Pakistani-Xoo strains. This is the first report providing the diversity of TALEs and their relationship to R and S (susceptibility) genes. Further identification of novel virulent TALE/s and their cognate target/s is warranted to precisely elucidate their role in BB.

Association of the tomato co-chaperone gene Sldnaj harboring a promoter deletion with susceptibility to Tomato spotted wilt virus (TSWV)

Abstract Tomato spotted wilt virus (TSWV) poses a significant threat as a devastating pathogen to the global production and quality of tomato (Solanum lycopersicum). Mining novel resistance genes within the tomato germplasm is an effective and environmentally friendly approach to combat TSWV. In this study, we investigated the mechanisms underlying high TSWV resistance in a specific tomato line after experimental inoculation, despite not possessing any known TSWV resistance genes. The candidate causal genes of disease resistance traits were finely mapped by constructing different genetic populations and performing bulk segregant analysis sequencing. This approach identified SlDnaJ (Solyc10g081220) as a key locus potentially regulating TSWV resistance. We determined a structural variant of SlDnaJ (designated Sldnaj) containing a 61-bp promoter sequence deletion that was specifically present in the germplasm of the susceptible M82 tomato plant lines. Sldnaj-knockout transgenic plants were significantly more resistant to TSWV than wild-type plants. Up-regulated expression of Sldnaj affected the salicylic acid/jasmonic acid signaling pathway, which induced and promoted the systemic infection of TSWV in M82 susceptible plants. In summary, this study identified a new candidate TSWV susceptibility gene with a natural deletion variation in tomato. These findings provide insights into the molecular mechanism underlying pathogen resistance while offering a target for breeding strategies of tomato with TSWV resistance.

Joint analysis of genome-wide cross-trait and multi-omics reveals molecular mechanisms of inflammatory bowel disease and nominates its novel therapeutic genes.

Inflammatory bowel disease (IBD) with the two predominant endophenotypes-Crohn's disease (CD) and ulcerative colitis (UC)-represents a group of chronic gastrointestinal inflammatory conditions. Since most genetic associations with IBD are often limited to independent subtypes, we reported a genome-wide association study (GWAS) cross-trait analysis combined with CD and UC to enhance statistical power. Initially, we detected 256 association signals at 54 genomic susceptibility loci and further characterized the functionality of variants within these regions. Subsequently, we revealed tissue and cell-specific heritability enrichment, particularly in whole blood, small intestine terminal ileum, spleen, lung, and colon transverse. Leveraging multi-omics datasets, we adopted a two-pronged approach comprising summary data-based Mendelian randomization (SMR) and transcriptome-wide association study (TWAS) to pinpoint likely causal genes and variants. Further, RNA-seq analysis facilitated the evaluation of differential expression and co-expression in intestinal tissues. Through a multi-stage prioritization strategy, compelling evidence for putative targets was nominated; notably highlighting several potential susceptibility genes such as IL27 and SBNO2. Finally, we utilized Mendelian randomization (MR) analysis with diverse datasets to verify the convergence of these two endophenotype-driven genes. Our investigation yields valuable insights to inform genetic mechanisms in IBD and reveal potential causal gene targets.

Activation of three targets by a TAL effector confers susceptibility to bacterial blight of cotton

Bacterial transcription activator-like effectors (TALEs) promote pathogenicity by activating host susceptibility (S) genes. To understand the pathogenicity and host adaptation of Xanthomonas citri pv. malvacearum (Xcm), we assemble the genome and the TALE repertoire of three recent Xcm Texas isolates. A newly evolved TALE, Tal7b, activates GhSWEET14a and GhSWEET14b, different from GhSWEET10 targeted by a TALE in an early Xcm isolate. Activation of GhSWEET14a and GhSWEET14b results in water-soaked lesions. Transcriptome profiling coupled with TALE-binding element prediction identify a pectin lyase gene as an additional Tal7b target, quantitatively contributing to Xcm virulence alongside GhSWEET14a/b. CRISPR-Cas9 gene editing supports the function of GhSWEETs in cotton bacterial blight and the promise of disrupting the TALE-binding site in S genes for disease management. Collectively, our findings elucidate the rapid evolution of TALEs in Xanthomonas field isolates and highlight the virulence mechanism wherein TALEs induce multiple S genes to promote pathogenicity.

Networks of pre-diagnostic circulating RNA in testicular germ cell tumour

Testicular germ cell tumour (TGCT) is a malignancy with known inherited risk factors, affecting young men. We have previously identified several hundred differentially abundant circulating RNAs in pre-diagnostic serum from TGCT cases compared to healthy controls. In this study, we performed Weighted Gene Co-expression Network Analysis (WGCNA) on mRNA and miRNA data from these samples. Central genes (hub genes) enriched functional pathways, and regulatory feature prediction were identified for all TGCT subtypes together and according to histology. The TGCT susceptibility genes TEX14, NARS2, and G3BP2, were identified as hub genes in both seminoma and non-seminoma networks. We also identified UBCA1, RCC1, FMR1, OAS3, and UBE2W as hub genes associated with TGCT. The genes OAS3 and UBE2W have previously been associated with testicular dysgenesis. Furthermore, network module analysis indicated transcription factors for oestrogen-related receptors to have a potential role during development of TGCT. The overlap between mRNA network hub genes and TGCT susceptibility genes indicates a common role in TGCT development.

A Comprehensive Analysis of Sex-Biased Gene Expression in the Aging Human Retina Through a Combination of Single-Cell and Bulk RNA Sequencing.

Previous studies have reported divergent sexual responses to aging; however, specific variations in gene expression between aging males and females and their potential association with age-related retinal diseases remain unclear. This study collected data from public databases and developed a comprehensive comparison of retina between aging females and males. Single-cell RNA (scRNA) and bulk RNA sequencing data of the aging retina from females and males in public databases were utilized for integrated analysis to investigate sex-biased expression in retina. Additionally, in vitro experiments were conducted on individuals with retinitis pigmentosa (RP) to validate the sex difference in degenerative retina. Bulk RNA analysis revealed sex-biased expression of specific genes in retina of aging individuals, with immune pathway-related genes exhibiting higher expression in females compared to males. The scRNA analysis demonstrated that sex-biased gene expression was cell-type specific in aging retina. Furthermore, susceptibility genes for age-related macular degeneration and RP exhibited variation across different cell types and sexes. Cell-to-cell communication unveiled an increased interaction associated with TGFB1, CCL7, and VEGFA in Müller glia, microglia, and astrocytes of female retina. Notably, we observed female-biased chemokine expression in microglia contributing to heightened susceptibility to immune inflammation in female retina. Finally, we confirmed a more pronounced inflammatory response during degeneration in female rd10 mouse retina compared to males. This study provides a comprehensive comparison of retina between females and males in healthy aging human retina and highlights the significance of sex as an influential factor in retinal diseases.

Research advances on the genetic pathogenesis and gene therapy for pancreatitis

Pancreatitis is an inflammatory disease influenced by both environmental and genetic factors. It has a high prevalence and mortality rate worldwide, with no radical cure. Breakthroughs have been recently made in genetic research of pancreatitis. Susceptibility genes and pathways have been continuously discovered, which highlighted the roles of genetic factors in hypertriglyceridemic and chronic pancreatitis. Gene therapy may offer radical cure for pancreatitis, though it has remained at the research phase. This article has reviewed the genetic pathogenesis of pancreatitis and current status of gene therapy research, with an aim to provide a reference for attaining definitive cure for the disease.

Assessment of candidate high-grade serous ovarian carcinoma predisposition genes through integrated germline and tumour sequencing

High-grade serous ovarian carcinoma (HGSOC) has a significant hereditary component, only half of which is explained. Previously, we performed germline exome sequencing on BRCA1 and BRCA2-negative HGSOC patients, revealing three proposed and 43 novel candidate genes enriched with rare loss-of-function variants. For validation, we undertook case-control analyses using genomic data from disease-free controls. This confirms enrichment for nearly all previously identified genes. Additionally, one-hundred-and-eleven HGSOC tumours from variant carriers were sequenced alongside other complementary studies, seeking evidence of biallelic inactivation as supportive evidence. PALB2 and ATM validate as HGSOC predisposition genes, with 6/8 germline carrier tumours exhibiting biallelic inactivation accompanied by characteristic mutational signatures. Among candidate genes, only LLGL2 consistently shows biallelic inactivation and protein expression loss, supporting it as a novel HGSOC susceptibility gene. The remaining candidate genes fail to validate. Integrating case-control analyses with tumour sequencing is thus crucial for accurate gene discovery in familial cancer studies.

Genetic Risk Factors for Metabolic Dysfunction-Associated Steatotic Liver Disease.

Metabolic dysfunction-associated steatotic liver disease (MASLD), is the most common cause of liver disease, and its burden on health systems worldwide continues to rise at an alarming rate. MASLD is a complex disease in which the interactions between susceptible genes and the environment influence the disease phenotype and severity. Advances in human genetics over the past few decades have provided new opportunities to improve our understanding of the multiple pathways involved in the pathogenesis of MASLD. Notably, the PNPLA3, TM6SF2, GCKR, MBOAT7 and HSD17B13 single nucleotide polymorphisms have been demonstrated to be robustly associated with MASLD development and disease progression. These genetic variants play crucial roles in lipid droplet remodeling, secretion of hepatic very low-density lipoprotein and lipogenesis, and understanding the biology has brought new insights to this field. This review discusses the current body of knowledge regarding these genetic drivers and how they can lead to development of MASLD, the complex interplay with metabolic factors such as obesity, and how this information has translated clinically into the development of risk prediction models and possible treatment targets.

GERMLINE PATHOGENIC VARIANTS IN PATIENTS WITH PANCREATIC DUCTAL ADENOCARCINOMA AND EXTRA-PANCREATIC MALIGNANCIES: A NATIONWIDE DATABASE ANALYSIS.

Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease. About 10% of affected individuals have an inherited component. Deleterious germline variants increase the lifetime risk for PDAC and are often associated with an elevated risk for extra-pancreatic malignancies. In this study, we aim to determine the prevalence and impact of germline pathogenic variants (gPVs) in patients with PDAC and extra-pancreatic malignancies. Using tissue samples and longitudinal data from a nationwide pathology database, we identified patients with PDAC and a set of seven extra-pancreatic malignancies to investigate the presence of gPVs in 25 cancer susceptibility genes with targeted next-generation sequencing. Of 473 PDAC patients with at least one extra-pancreatic malignancy, 75 (16%) had gPVs. These were predominantly in ATM (n=22), CDKN2A (n=14), BRCA2 (n=10), or CHEK2 (n=10) genes. The combination of PDAC and ovarian carcinoma carried the highest prevalence of gPVs (4 of 10; 40%), followed by PDAC and melanoma (15 of 53; 28%), and PDAC and gastric cancer (2 of 9; 22%). PDAC patients with certain extra-pancreatic malignancies carry a higher burden of gPVs than unselected PDAC cohorts. This is a group that very likely benefits from genetic testing since germline status can have important diagnostic and therapeutic implications for affected individuals and their family members.

Advances in the genetics of myasthenia gravis: insights from cutting-edge neuroscience research.

Myasthenia gravis (MG) is an autoimmune disorder involving complex interactions between genetic and environmental factors. Genome-wide association studies (GWAS), transcriptome-wide association studies (TWAS), and other methods have identified multiple novel susceptibility loci and genes, providing crucial insights into the genetic etiology of MG. Moreover, the pivotal roles of epigenetic mechanisms, such as DNA methylation, histone modifications, and non-coding RNAs, in the pathogenesis of MG are gradually being unveiled. This review comprehensively summarizes the latest advances in MG genetic research, focusing on the discovery and validation of susceptibility genes, genetic heterogeneity and subtype-specific genetic factors, gene-environment interactions, epigenetic mechanisms, and progress in genetics-based diagnostic and prognostic biomarkers.

Emerging antifungal resistance in Trichophyton mentagrophytes: insights from susceptibility profiling and genetic mutation analysis

ABSTRACT Trichophyton species, the leading cause of dermatophytosis globally, are increasingly resistant to antifungal treatments, concerns about effective management strategies. In light of the absence of established resistance criteria for terbinafine and azoles, coupled with a dearth of research on resistance mechanisms in Trichophyton, antifungal susceptibility and drug resistance gene diversity were analyzed across 64 T. mentagrophytes, 65 T. interdigitale, and 2 T. indotineae isolates collected in China between 1999 and 2024 and 101 published T. indotineae strains. Analyses of the minimum inhibitory concentrations (MICs) of terbinafine, itraconazole, voriconazole, posaconazole, and isavuconazole revealed a concerning increase in T. indotineae with terbinafine resistance, including two novel isolates from China. Compared with T. interdigitale, T. mentagrophytes presented higher terbinafine MICs but similar azole susceptibility. Notably, 27 T. interdigitale isolates were classified as non-wild-type for terbinafine. Genetic diversity was analyzed for the SQLE, CYP51A and CYP51B gene. Specifically, T. indotineae isolates presented SQLE protein changes linked to terbinafine resistance. SQLE diversity was linked to terbinafine sensitivity, whereas alterations in CYP51A were associated with itraconazole sensitivity, with notable statistical significance evident across various protein isoforms. The relationship between protein diversity and drug sensitivity is presented in detail. Together, these findings highlight a growing prevalence of antibiotic resistance among Trichophyton and identify potential target genes for new therapies, underscoring the need for ongoing monitoring and offering directions for novel therapeutics.

Application of genetic testing criteria for hereditary breast cancer in South Africa.

Breast cancer (BC) is the commonest cancer in South African women. A proportion are associated with a pathogenic or likely pathogenic (P/LP) variant in a BC susceptibility gene. Clinical guidelines for genetic testing are used to optimise variant detection while containing costs. We assessed the detection rate in women of diverse ancestries who met the South African National Department of Health (NDOH) testing guidelines, and analysed relationships between testing criteria, participant characteristics and presence of a BRCA1/2 P/LP variant. Records from 376 women with BC who met NDOH criteria and had genetic testing were included. Demographic, clinical and test result data were collated to describe detection rates according to criteria met, and a multivariate analysis conducted to find variables most frequently associated with a P/LP variant. P/LP variant prevalence in women meeting NDOH testing criteria was 19.9% (75/376). Women meeting ≥ 2 guideline criteria were over twice as likely to have a P/LP variant (OR 2.27, 95%CI 1.27-4.07, p = 0.006), highlighting the guidelines' capacity to stratify risk. Family history (OR 1.97; 95%CI 1.05-3.70, p = 0.03) and Black African ancestry (OR 2.58; 95%CI 1.28-5.18, p < 0.01) were independently associated with having a BRCA1/2 P/LP variant when controlling for other variables. Notably, although Black African participants were less likely to report a family history, those that did had higher odds of a P/LP variant in BRCA1/2. These results demonstrate the usefulness of the NDOH guidelines in women of diverse ancestries and provide insight into the factors associated with P/LP variants in understudied African populations.