Infective endocarditis presents unique challenges, particularly in individuals with congenital heart diseases, such as this case, where the patient had tetralogy of Fallot physiology secondary to double outlet right ventricle, and Fanconi anemia. This case describes how the combination of multiple factors necessitated multidisciplinary management. A 45-year-old South Asian male patient with a known history of tetralogy of Fallot physiology secondary to double outlet right ventricle presented to our emergency department with fatigue, fever, and neurological deficits suggestive of an embolic stroke. Transthoracic echocardiography revealed severe pulmonary stenosis and a significant subaortic ventricular septal defect with vegetations, indicative of infective endocarditis. Magnetic resonance imaging of the brain demonstrated multiple infarcts, suggestive of an embolic event. Blood cultures grew Streptococcus mitis. The patient was admitted to the intensive care unit and treated with aggressive antibiotic therapy. However, his clinical course was complicated by disseminated intravascular coagulation and acute kidney injury, requiring hemodialysis and transfusion support. Despite interventions, his condition deteriorated further. Genetic consultation indicated Fanconi anemia, adding complexity to his clinical management. This case is remarkable because the patient survived up into adulthood with double outlet right ventricle and tetralogy of Fallot physiology without prior corrective surgery, which is a rare occurrence. The embolic stroke, likely resulting from a septic embolus, and the presence of Fanconi anemia further complicated the clinical scenario. Despite aggressive treatment, the patient's progression to refractory sepsis and disseminated intravascular coagulation ultimately resulted in cardiac arrest. This case underscores the importance of early recognition, multidisciplinary collaboration, and tailored therapeutic strategies in managing complex congenital heart diseases with infective endocarditis and other comorbidities.

Polygenic variants in DNA repair genes are associated with neurodevelopmental disorders, regression and increased burdens of somatic variants and short tandem repeat expansions.

Fanconi anemia (FA) is characterized by bone marrow failure, congenital abnormalities, and cancer predisposition. Mutations in RAD51 paralogs have been identified in FA-like disorders and cancers. Although the role of RAD51 paralogs is well established in homologous recombination (HR)-mediated DNA repair, little is known about their role during replication stress responses. Here, we report that the RAD51C-XRCC3 (CX3) complex of RAD51 paralogs participates in the FA pathway of R-loop tolerance mechanism. CX3 complex suppresses R-loops, transcription-replication collisions (TRCs), and associated genome instability under physiological and replication stress conditions. Mechanistically, the CX3 complex physically interacts with FANCM and facilitates its recruitment to the R-loop sites to promote its resolution. Notably, cells expressing the RAD51C R258H pathological mutant exhibit defective interaction with FANCM and display inefficient R-loop processing. The CX3 complex-mediated R-loop resolution is independent of its fork maintenance function. Collectively, we demonstrate a previously unidentified role of the CX3 complex in preventing R-loop-induced genome instability by regulating FANCM-mediated R-loop resolution.

The BRCA2 c.8351G>A p.(Arg2784Gln) variant has long been classified as a variant of uncertain significance (VUS) due to conflicting evidence used in variant classification. This study aims to clarify its pathogenicity and associated risks for breast and ovarian cancer. This study was conducted by the international Evidence-based Network for the Interpretation of Germline Mutant Alleles consortium. We collected data from 29 informative families with this variant. Co-segregation likelihood ratios (LRs) were calculated using the full-likelihood method to assess pathogenicity, and cancer risks were estimated with modified segregation analysis. Co-segregation analysis using a grid search across scaled penetrance levels for BRCA2 truncating variants yielded the strongest evidence in favour of pathogenicity, with LR maximised at approximately 20% of full penetrance (LR=11.026). Furthermore, estimated breast cancer risks were markedly higher for early onset breast cancer; women diagnosed at <50 years had a HR of 4.5, compared with a HR of 1.65 for women diagnosed at ≥50 years. The estimated lifetime risks were 25% for breast cancer and 6% for ovarian cancer.Evidence of pathogenicity was also supported by the presence of the variant allele in two patients with Fanconi anaemia. Our results indicate that BRCA2 c.8351G>A p.(Arg2784Gln) has a disease-causing effect, with reduced penetrance, similar to other pathogenic variants in moderate risk breast cancer genes such as ATM and CHEK2. We also provide risk-adapted recommendations for clinical management. Importantly, one should be aware of a reduced penetrance as the underlying reason for conflicting results among pieces of evidence used for variant classification.

In-utero cell and gene therapies may offer prenatal treatment options for inherited diseases. Preclinical data suggests in-utero (IU) hematopoietic stem cell transplantation (HSCT) could prevent Fanconi anemia (FA) related bone marrow failure without genotoxic conditioning or immune suppression. This study surveyed patient and caregiver attitudes within the FA community toward prenatal diagnosis, interventions, and clinical trials. A multidisciplinary team created and distributed an online survey through the leading FA patient advocacy group. Respondents' demographic, history, and treatment data were collected, and their attitudes toward prenatal diagnosis, IU therapies, and pregnancy termination were analyzed using univariable ordinal logistic regression. 72 members from 18 countries completed the survey. Among the respondents, 76% were willing to undergo IU-HSCT if it was FDA approved, whereas 68% would consider enrolling in a clinical trial to assess the safety and efficacy of IU-HSCT or IU-gene therapy. 71% would undergo invasive prenatal testing in any at risk pregnancy to confirm FA and 56% were unlikely to terminate an affected pregnancy. In-utero therapy is a developing alternate treatment strategy for rare, inherited diseases. Although electronic surveys have inherent limitations, this tool enabled efficient assessment of FA community attitudes with a favorable response to prenatal diagnosis and therapies. These insights encourage efforts to advance IU-cell and gene therapy clinical trials and to continue to evaluate community attitudes as these therapies develop. This work may also provide insights into the attitudes of other rare inherited disease communities.

Abstract Purpose: To characterize the prevalence of germline pathogenic or likely pathogenic (PLP) variants in Fanconi Anemia (FA) pathway genes among patients with invasive breast cancer (IBC) and evaluate opportunities for clinical actionability through germline and somatic analysis. Background: Disruption of the FA DNA repair pathway can impair homologous recombination (HR). While high-penetrance PLP variants in BRCA1, BRCA2, and PALB2 are established breast cancer susceptibility genes and contribute to HR deficiency (HRD), the clinical consequences of other FA germline PLP variants remain unclear. Using the updated cohort from the City of Hope INSPIRE Study, we assessed the prevalence and functional impact of germline PLP variants in 17 FA pathway genes. HRD, mutational signatures, and loss of heterozygosity were used to evaluate effects on HR integrity. These findings may have implications for HRD-related precision therapeutic intervention and clinical trial eligibility. Methods: This retrospective study included consented patients with histologically confirmed IBC enrolled in the INSPIRE Study as of January 14, 2025. Germline sequencing of 155 cancer predisposition genes was performed; patients with multiple FA variants were classified according to the FA gene of the highest penetrance. A cohort subset underwent paired tumor-normal whole exome sequencing (&amp;gt;400x tumor, &amp;gt;180x normal), including HRD scoring (scarHRD), LOH determination, and SBS3 assessment (SigProfiler). Clinical data were obtained from cancer registries and medical records. Clinical trial eligibility criteria were evaluated using ClinicalTrials.gov. Results: Of 8,242 patients with IBC, 7,982 underwent germline sequencing; 592 (7.4%) had a PLP variant in an FA gene, including 197 (33.3%) in non-high-penetrance (non-HP) genes. Among 1,833 patients with paired tumor-normal sequencing, 145 (7.9%) had an FA PLP variant, of which 53 (2.89%) were in non-HP genes. HRD scores were ≥42 in 45.3% of non-HP carriers (Table 1). 24 of 53 patients (45.3%) with a non-HP FA germline PLP variant had HRD-positive (≥42) tumors. HRD-positivity is more likely among patients with germline PLP variants in non-HP FA pathway genes compared to those without a variant in any FA gene (RR 1.51, 95% CI 1.12 to 2.05; p &amp;lt; 0.0077). Stage data were available for 1,548 patients; 128 (8.3%) were stage IV at diagnosis, including 7/128 (5.5%) with non-HP FA gene PLP variants. Conclusion: Germline PLPs in non-HP FA genes are present in a meaningful subset of patients with IBC and may be functionally relevant. These findings support the value of expanded germline testing and trial eligibility criteria that encompass the broader FA pathway and suggest that non-HP FA gene variants may serve as biomarkers for identifying patients likely to benefit from HRD-targeted therapies. Citation Format: L. Naghi, K. G. Roth, S. Lindsey, A. Seuylemezian, J. Bonner, L. Kruper, S. B. Gruber, J. Mortimer, K. McDonnell. Lower Penetrance Germline Fanconi Anemia Variants in Breast Cancer: Opportunities for Expanded Genetic Testing and Therapeutic Targeting in the Updated INSPIRE Study Cohort [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS4-01-27.

We recently identified variants in 10 genes that are members of either the p53 pathway or Fanconi Anemia Complex (FAC), regulators of the DNA repair (DNA damage response; DDR) in 17 cases with Pediatric Acute-Onset Neuropsychiatry Syndrome (PANS) or regression in autism spectrum disorder (ASD) and other neurodevelopmental disorders (NDD). We aimed to identify additional cases with genetic vulnerabilities in DDR and related pathways. Whole exome sequencing (WES) and whole genome sequencing (WGS) data from 32 individuals were filtered and analyzed to identify ultrarare pathogenic or likely pathogenic variants. Variants affecting DDR were found in 14 cases diagnosed with PANS or regression (CUX1, USP45, PARP14, UVSSA, EP300, TREX1, SAMHD1, STK19, MYTl1, TEP1, PIDD1, ADNP, FANCD2, and RAD54L). The CUX1 variant is de novo, as are two cases who had mutations in genes that affect mitochondrial functions that are connected directly or indirectly to mitophagy (PRKN and POLG), which can trigger the same innate immune pathways when disrupted as abnormal DDR. We also found pathogenic or likely pathogenic secondary mutations in several genes that are primarily expressed in the gut that have been implicated in gut microbiome homeostasis (e.g., LGALS4, DUOX2, CCR9). These findings align with previous genetic findings and strengthen the hypothesis that abnormal DDR and mitochondrial dysfunction underly pathogenic processes in neuropsychiatric decompensation. The potential involvement of genetic variants in gut microbiome homeostasis is a novel aspect of our study. Functional characterization of the downstream impact of DDR deficits may point to novel treatment strategies.

Expression of Concern: Rad18 E3 ubiquitin ligase activity mediates Fanconi anemia pathway activation and cell survival following DNA Topoisomerase 1 inhibition

Patients with Fanconi Anemia Have an Increased Incidence of Diabetes Mellitus After Allogeneic Stem Cell Transplantation.

Increased Vascular Age in Patients with Fanconi Anemia after Hematopoietic Cell Transplantation: Results of a Single-Center Descriptive Analysis.

Genetic Syndromes Associated With Congenital Upper Limb Differences.

Statement of Retraction: A novel role for fanconi anemia (FA) pathway effector protein FANCD2 in cell cycle progression of untransformed primary human cells

Timeless prevents senescence-associated phenotypes and enhances DNA repair to promote esophageal cancer cell growth.

During a latent tuberculosis infection, there exists a dynamic equilibrium between the host and the 'dormant' bacterium wherein they mutually influence each other. An understanding of the host genetic response to 'dormant' tubercle bacilli during infection is necessary for developing targeted strategies against them. A previously established infection model based on Vitamin C-induced Mtb dormancy was utilized in the present study to identify host responses to 'dormant' Mycobacterium tuberculosis (Mtb) infection by analyzing host transcriptomic data generated from Mtb-infected THP-1 cells. Principal Component Analysis and hierarchical cluster analysis of expression profiles in three cell infection models, namely, 'Active Mtb' (no treatment), 'Vitamin C Mtb' (Vitamin C treatment), and 'Vit C-induced Dormant Mtb' (Vitamin C and isoniazid treatment) infection models at 2-, 24- and 96-hours (h) post-Mtb-infection revealed a discrete clustering of host responses. Co-treatment of infected cells with Vitamin C and isoniazid enabled the capture of host transcriptome response to exclusively 'dormant' (isoniazid-tolerant) bacteria. Pleiotropic modulations in host pathways were observed at 96h that were either unique to the 'Vit C-induced Dormant Mtb' model or common to the 'Vit C-induced Dormant Mtb' and 'Active Mtb' models of infection. Unique pathways identified in the 'Vit C-induced Dormant Mtb' model included (i) induction of antigen processing and presentation for promotion of host defense machinery, and (ii) decreased expression of genes in 'Fanconi anemia' and 'Homologous Recombination' pathways, indicating an impairment of DNA damage responses. Pathways that were commonly involved in 'Vit C-induced Dormant Mtb' and 'Active Mtb' models included (i) suppression of p53 signaling pathway resulting in a downregulation of pro-apoptotic factors and inhibition of cell apoptosis, (ii) upregulation of p57 leading to cell cycle arrest at the G0/G1 phase and subsequent suppression of DNA replication, and (iii) induction of IDO/TDO-mediated tryptophan catabolism. Host transcriptome analysis of Mtb-infected cells has revealed that key pathways involved in immune surveillance, DNA repair, and apoptosis are altered, leading to an environment that favors infection. Despite these perturbations, the induction of antigen processing and presentation pathways in the 'Vit C-induced Dormant Mtb' model suggests an attempt by the host to counteract infection. These findings provide valuable insights into how the host cellular environment undergoes extensive modifications during Mtb infection and thereby creates conditions that support bacterial persistence.

Hematologic malignancies in pediatric patients with RUNX1-Familial Platelet Disorder with Associated Myeloid Malignancy.

A Rare Case of Co-occurring Fanconi Anemia and Primary Ciliary Dyskinesia.

Matched Sibling Hematopoietic Stem Cell Transplantation for Pediatric Fanconi Anemia: Experience from A Tertiary Care Centre in India

Fanconi anemia (FA) is an inherited bone marrow failure syndrome with cancer predisposition. Most FA patients develop aplastic anemia during childhood and have an extremely high cumulative risk to develop cancer during their lifespan. Myeloid malignancy is one of the main neoplastic risks for patients with FA, including high-risk myelodysplastic syndrome (MDS), recently renamed as myelodysplastic neoplasm, and acute myeloid leukemia (AML). Although bone marrow transplantation is the treatment of choice for FA patients that develop aplastic anemia, patients with a more stable bone marrow remain not transplanted and at a high risk of presenting MDS/AML, these patients therefore should be monitored for appearance of myeloid malignant clones. Markers for an as-early-as-possible identification of emerging myeloid malignant cells are needed for the monitoring of patients with FA, since quick medical action after detection of neoplastic transformation is needed. In this work we have developed a deep neural network (DNN) model that was trained with publicly available single cell RNA-seq (scRNA-seq) datasets of patients with AML and used to predict the presence of AML-like cells in scRNA-seq datasets obtained from bone marrow samples of patients with FA. The predictor displayed high sensitivity, specificity, and accuracy for the detection of single-cell resolution myeloid malignant transcriptional profiles. Functional analyses of the predicted-AML cells from FA patients showed enrichment of lympho-myeloid-primed progenitor (LMPP) and granulocyte-monocyte progenitor (GMP) populations, as well as transcriptional profiles associated with malignant transformation. Cues of immune evasion were also detected using single cell pathway analysis (SCPA) and cell-cell communication profiles.

Inactivating genomic alterations (GA) of the FANCC gene are associated with genomic instability, DNA cross-linking, and homologous DNA repair deficiency. Here, we evaluated the incidence of FANCC GA in renal tumors (RT). A total of 463 546 clinically advanced cancer (CAC) cases underwent hybrid capture-based comprehensive genomic profiling using the FDA-approved F1CDx assay to detect all classes of GA. Microsatellite instability (MSI) status, tumor mutational burden (TMB), genomic loss of heterozygosity, prediction of germline status, and genomic signature were determined with algorithm-based analysis. Clinically advanced cancers (0.43% of 1993) featured FANCC GA; 27 of these FANCC-mutated tumors (20 males, mean age 57) were RT (0.35% of 7668 RT). The primary tumor was sequenced in 9 cases and a metastatic site in 18 (5 lymph nodes, 4 soft tissues, 3 brains, 2 livers, 1 each lung, adrenal, eye, bone). Only 1 of 25 tested FANCC-mutated RT was MSI-high; 4 cases (15%) featured TMB ≥10 mutations/Mb. The genomic signature could be assessed in 5 cases: 4 were MMR-deficient. The FANCC mutations included inactivating short variant mutations in 24 cases (10 nonsense, 10 frameshift, 2 non-frame, and 2 splice-site mutations) and 3 truncating rearrangements (FANCC: SUSD3, FANCC: FANCC, and FANCC: C20orf24). Interestingly, 14 (52%) of the FANCC-mutated RT were predicted to be germline. Somatic and germline mutations in FANCC occur in an exceedingly small subset of clinically advanced RT but at a similar rate to other cancers, and the genomic landscape does not appear to be different from RT with wild-type FANCC. Germline testing is warranted, as we see a high frequency of germline FANCC mutations. Our study highlights the rate of FANCC mutation in kidney cancer, which may be a therapeutic target and awaits further assessment and drug development. Also, it shows that FANCC mutations are more germline, requiring further genetic testing.

NRG1 fusions are oncogenic drivers in non-small cell lung cancer (NSCLC), with therapeutic relevance highlighted by the FDA's designation of Zenocutuzumab for NRG1 fusion-positive cases. However, the molecular and clinical features of different NRG1 fusion types remain unclear. We retrospectively analyzed 435 NSCLC patients (78 NRG1 fusion-positive, 357 wild-type) from June 2016 to December 2023, using broad-panel DNA/RNA sequencing to assess mutational profiles, tumor mutation burden (TMB), chromosomal instability scores (CIS), and gene expression. Survival analyses were conducted in our cohort (N = 47) and the TCGA dataset (N = 526). Among NRG1-positive patients, 65.8% harbored recurrent fusion partners (e.g., CD74-NRG1, SLC3A2-NRG1), with CD74-NRG1 most frequent (48.1%). These patients showed fewer EGFR/KRAS mutations and lower TMB and CIS compared to wild-type cases (P < 0.01). The remaining 26 patients had unique singleton fusion partners, including 23 novel events such as CEBPD-NRG1 and BMP1-NRG1. This group exhibited significant enrichment of mutations in genes linked to DNA repair and oncogenic pathways (KRAS, MSH2, FANCI, etc.), affecting Fanconi anemia, mismatch repair, PI3K-AKT, and MAPK pathways (P < 0.01). RNA profiling revealed upregulation of DNAJB1 (P < 0.01) and LMNA (P = 0.02) in the singleton group, both associated with worse overall survival in TCGA (HR = 1.52). No significant difference in progression-free survival was seen following first-line EGFR TKI therapy between uncommon and wild-type groups. Our findings highlight the heterogeneity of NRG1 fusions in NSCLC, revealing novel fusions, unique pathway enrichments, and expression profiles that may inform future personalized treatment strategies.