Baylor Genetics

Scoliidae are fossorial aculeate wasps (Hymenoptera: Apocrita) whose larvae develop as parasitoids of beetle grubs, mainly from the family Scarabaeidae. Despite their distinctive appearance and economic importance, the taxonomy and biology of Scoliidae are less well understood compared to other Hymenoptera. Recently, a new species of Scoliidae, Dielis tejensis Szafr., was described based on about a dozen male specimens from Texas (Nearctic realm). This article reports on mtDNA-verified discovery of the female D. tejensis. As in the case of other members of the tribe Campsomerini, D. tejensis exhibits strong sexual dimorphism in body structure and color pattern. Females of D. tejensis most closely resemble Dielis plumipes (Drury) and were previously confused with D. plumipes fossulana (Fabr.), with which D. tejensis is partially sympatric. D. tejensis has more than one generation per year, characterized by a male-biased sex ratio, perhaps resulting from the female immature stages entering a state of aestivation. The multi-generational developmental cycle of D. tejensis correlates with the existence of a partial seasonal polyphenism in this species. The data presented also shows a similarity in the distribution ranges of D. tejensis and one of its main nectaring plants, Hymenopappus artemisiifolius DC (Asteraceae), that may suggest similarity in the environmental requirements of both organisms or specialized trophic relationship between the still-unknown beetle host of the wasp larvae and H. artemisiifolius or another plant with a similar range. D. tejensis has been included in the accordingly modified key to the Nearctic species of Dielis Sauss. & Sichel, which is also presented here.

Richard Gibbs interviews James (Jim) Lupski about his training in New York and work in Houston to elucidate the role of complex genomic rearrangements in human genetic diseases. The challenges and excitement of developing human personalized genomics and the advantages of clinical translation of genome methods for both patients and researchers are discussed.

Abstract Background: Inflammatory breast cancer (IBC) is a rare and aggressive form of breast cancer with a distinct clinical presentation and poor prognosis. Diagnostic ambiguity remains a challenge, and recent literature has proposed structured criteria to improve case classification. Methods: We conducted a retrospective chart review of 83 patients diagnosed with IBC and 83 patients with non-inflammatory breast cancer (non-IBC), seen at the University of Texas Southwestern Medical Center as part of the Dallas Metastatic Cancer Study. Each IBC case was evaluated using a structured scoring system adapted from the diagnostic guidelines proposed by Omarini et al. (2022) to assess the degree of conformity to established IBC features. Clinical and pathological characteristics were compared across groups using appropriate statistical tests. Results: Our findings reinforce several established associations in the literature. Compared to non-IBC patients, those with IBC exhibited significantly higher Ki-67 proliferation indices (1.42-fold increase, p<0.0001, Mann-Whitney U test), greater number of metastatic sites (2-fold increase, p<0.0001, Mann-Whitney U test), and higher clinical stage at diagnosis (p = 0.04, Chi-square test). IBC cases were also associated with more aggressive disease biology as they were more likely to be ER negative (p = 0.003, Fisher test) and PR negative (p = 0.0184, Fisher test). Notably, we observed a novel pattern: IBC was significantly associated with specific metastatic sites, particularly the brain (4.5 times more likely in IBC patients, p<0.0001, Chi-square test) and lungs (2.08 times more likely in IBC, p = 0.0028, Chi-square test), suggesting a potentially distinct metastatic tropism. Conclusions: This study supports the diagnostic utility of a structured scoring system for IBC and confirms key clinical and molecular trends observed in prior research. The novel association with specific metastatic sites warrants further investigation and may inform future efforts in IBC classification and management. Citation Format: C. M. Atallah, A. Varner, C. J. Kang, P. Gowda, K. Anderson, D. Tovar, R. Morey, C. Hauer, R. Sridharan, S. Huang, K. Lei, S. M. Reddy, H. L. McArthur, J. Maués, C. Hodgdon, B. Zhang, X. Zhang, B. Lim, I. S. Chan. Evaluating clinical and molecular correlates of Inflammatory Breast Cancer using a scoring system-based chart review [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 PS1-09-14.

Parkinson’s disease (PD) is a genetically complex disorder in which combinations of heterozygous risk variants may contribute to pathogenesis. Many PD risk loci encode lysosomal genes, such as GBA1, a common and potent risk factor, conferring at least a 5-fold increase. However, the mechanisms of GBA1 penetrance remain poorly understood. Using Drosophila melanogaster, we performed a genetic interaction screen of lysosomal storage disorder (LSD) genes to identify dominant modifiers of Gba1b (fly homolog of GBA1). Age-dependent locomotor assessments, electroretinograms (ERG), transmission electron microscopy (TEM) analyses and quantification of dopaminergic (DA) neurons were used to assess the neurodegenerative phenotypes of double heterozygous animals. By combining immunostaining, lipidomics, metabolomics and pharmacological approaches we showed how partial loss of anne (fly homolog of ATP13A2) and Gba1b drives neurodegeneration. By interrogating genetic data from local and international PD cohorts we identified double heterozygous pathogenic variants in ATP13A2 and GBA1 in individuals with PD. We show that anne is expressed in neurons, whereas Gba1b is expressed in glia. Flies heterozygous for anne exhibit mild neurodegenerative phenotypes, and Gba1b strongly enhances this haploinsufficiency. Double heterozygous (Gba1bT2A/+;anneT2A/+) flies exhibit a slow and progressive neurodegeneration associated with accumulation and impaired acidification of lysosomes in photoreceptors and other neurons. Obvious morphological defects are first observed in glia at day 15 after eclosion and include vacuolization and neuronal detachment. These defects are accompanied by an elevation of glucosylceramide (GlcCer) and followed by loss of neuronal function and degenerative features by day 30. These phenotypes are neuronal activity-dependent. The neurodegenerative phenotypes are rescued by: ML-SA1, an agonist of the lysosomal TRPML1 channel that has been reported to promote lysosomal membrane trafficking; myriocin, a compound that inhibits GlcCer production; and DFMO, a drug which inhibits polyamine synthesis. Based on surveys of genetic data, we identify multiple PD cases harboring digenic variants in GBA1 and ATP13A2. Our study reveals that partial loss of Gba1b in glia and anne in neurons synergistically disrupts lysosomal pH and neuron-glia GlcCer homeostasis, triggering neurodegeneration. Our results provide evidence that GBA1 penetrance is influenced by additional genetic modifiers, consistent with a putative digenic mechanism for GBA1-PD penetrance. These findings highlight lysosomal acidification, sphingolipid clearance, and polyamine regulation as critical intervention points in digenic PD.

Cerebrotendinous xanthomatosis (CTX) is an inherited metabolic disorder caused by variants in CYP27A1 leading to loss of sterol-27-hydroxylase activity. Sterol-27-hydroxylase generates two classes of bioactive signaling molecules: bile acids and oxysterols. The broader metabolic consequences resulting from perturbations in bile acid and oxysterol signaling and their reversibility with FDA-approved treatment chenodeoxycholic acid (CDCA), are not fully described. To establish a comprehensive map of metabolic consequences of CTX, we performed large-scale, untargeted plasma metabolomics in a single subject with CTX, both before and after 6 months of CDCA therapy, and compared results with a reference cohort of over 1100 individuals. Data were analyzed for significant metabolite changes and pathway alterations. Untreated CTX exhibited marked depletion of bile acid intermediates and elevations in sterol precursors, consistent with the known enzymatic block in this pathway. Metabolomics highlighted additional pathways affected by bile acid and oxysterol signaling such as fatty acid metabolism, NAD+ de novo synthesis, phosphatidylethanolamines, sphingolipids and ferroptosis. Following six months of CDCA therapy, sterol precursors normalized, bile acid intermediates partially recovered, and phosphatidylethanolamines were restored toward reference ranges, while steroid and phosphatidylcholine metabolites remained largely unchanged. This study exposes the comprehensive nature of metabolic disturbance in CTX beyond the bile acids pathway, revealing perturbations in bile acids, steroids, fatty acids, phospholipids and NAD+ synthesis and highlights the dynamic early response to CDCA therapy. The metabolomic profile of untreated CTX can be leveraged for diagnostic screening. These findings report new candidate biomarkers for diagnosis and monitoring and underscore the potential of metabolomics to uncover broader metabolic consequences in rare disease.

Abstract Meningiomas are among the most prevalent tumors of the central nervous system and are typically driven by a limited set of mutually exclusive genetic alterations. We report molecular characterization of seven meningiomas with fusions between LMNA and FOSB, in the absence of other canonical meningioma-associated mutations. LMNA, encoding nuclear envelope protein Lamin A/C, plays a central role in chromatin architecture and is widely expressed across differentiated tissues. FOSB, an AP-1 transcription factor, regulates genes involved in cellular growth and differentiation. Using integrated genomic analyses—including targeted DNA sequencing, whole-genome sequencing, and RNA-seq—we validated near identical fusions involving exons 1–2 of LMNA (chr1) and exons 2–4 of FOSB (chr19). This rearrangement retains key functional domains from both genes, notably the Ser22 phosphorylation site in Lamin A/C that associates with active enhancers, and the DNA-binding region of FOSB. Transcript levels of LMNA and FOSB remained largely unaltered in fusion-positive tumors, suggesting oncogenic activity may stem from a neomorphic fusion protein rather than dysregulated gene expression. Expression of LMNA-FOSB constructs in CH157 and IOMM-LEE meningioma cell lines led to significant alterations in chromatin structure and transcriptional profiles. Gene set enrichment analysis of upregulated genes (FC > 1, P < 0.05) shared between transfected CH157 and IOMM-LEE lines revealed enrichment of pathways related to laminin, fibronectin, and collagen binding—components commonly elevated in the meningioma extracellular matrix—as well as growth factor binding (P < 0.05). These findings were corroborated by Hi-C and ChIP-seq profiling of patient-derived frozen tumors, which demonstrated changes in chromatin conformation and transcriptional regulation. Our data establish LMNA-FOSB fusions as a novel and recurrent genetic alteration in meningiomas, illuminating a potential oncogenic mechanism involving chromatin remodeling and transcriptional reprogramming, and expanding the known functional scope of FOSB fusions in cancer.