Browsing by Author "Medical and Molecular Genetics, School of Medicine"
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Item 302 Diagnostic Evidence Gauge of Spatial Transcriptomics (DEGAS-ST): Using transfer learning to map clinical data to spatial transcriptomics in prostate cancer(Cambridge University Press, 2024-04-03) Couetil, Justin; Alomari, Ahmed K.; Zhang, Jie; Huang, Kun; Johnson, Travis S.; Medical and Molecular Genetics, School of MedicineOBJECTIVES/GOALS: The 'field effect' is a concept in pathology that pre-malignant tissue changes forecast health. Spatial transcriptomics could detect these changes earlier than histopathology, suggesting new early cancer screening methods. Knowing how normal tissue damage relates to cancer’s origin and progression may improve long-term outcomes. METHODS/STUDY POPULATION: We trained DEGAS, our machine learning framework, with prostate cancer data, combining both general cancer patterns and in-depth genetic information from individual tumors. The Tumor Cancer Genome Atlas (TCGA) shows how gene patterns in tumors relate to patient outcomes, emphasizing the differences between tumors from different patients (intertumor). On the other hand, spatial transcriptomics (ST) shows the genetic variety within a single tumor (intratumor) but has limited samples, making it hard to know which genetic differences are important for treatment. DEGAS bridges these areas by finding tissue sections that resemble those in TCGA profiles and are key indicators of patient survival. DEGAS serves as a valuable tool for generating clinically-important hypotheses. RESULTS/ANTICIPATED RESULTS: DEGAS identified benign-appearing glands in a normal prostate as being highly associated with poor progression-free survival. These glands have transcriptional signatures similar to high-grade prostate cancer. We confirmed this finding in a separate prostate cancer ST dataset. By integrating single cell (SC) data we demonstrated that cells annotated as cancerous in the SC data map to regions of benign glands in the ST dataset. We pinpoint several genes, chiefly Microseminoprotein-β (MSMB, PSP94), where reduced expression is highly correlated with poor progression-free survival. Cell type specific differential expression analysis further revealed that loss of MSMB expression associated with poor outcomes occurs specifically in luminal epithelia, the putative progenitor of prostate cancer. DISCUSSION/SIGNIFICANCE: DEGAS reveals that normal-appearing tissue can be highly-associated with tumor progression and underscores the importance of the 'field effect' in cancer research. Traditional analysis may miss such nuance, hiding key transitional cell states. Validating gene markers could boost early cancer detection and understanding of metastasis.Item 38766 Massively Parallel Reporter Assay Reveals Functional Impact of 3™-UTR SNPs Associated with Neurological and Psychiatric Disorders(Cambridge University Press, 2021) Chen, Andy B.; Thapa, Kriti; Gao, Hongyu; Reiter, Jill L.; Zhang, Junjie; Xuei, Xiaoling; Gu, Hongmei; Wang, Yue; Edenberg, Howard J.; Liu, Yunlong; Medical and Molecular Genetics, School of MedicineABSTRACT IMPACT: Screening the effect of thousands of non-coding genetic variants will help identify variants important in the etiology of diseases OBJECTIVES/GOALS: Massively parallel reporter assays (MPRAs) can experimentally evaluate the impact of genetic variants on gene expression. In this study, our objective was to systematically evaluate the functional activity of 3’-UTR SNPs associated with neurological disorders and use those results to help understand their contributions to disease etiology. METHODS/STUDY POPULATION: To choose variants to evaluate with the MPRA, we first gathered SNPs from the GWAS Catalog that were associated with any neurological disorder trait with p-value < 10-5. For each SNP, we identified the region that was in linkage disequilibrium (r2 > 0.8) and retrieved all the common 3’-UTR SNPs (allele-frequency > 0.05) within that region. We used an MPRA to measure the impact of these 3’-UTR variants in SH-SY5Y neuroblastoma cells and a microglial cell line. These results were then used to train a deep-learning model to predict the impact of variants and identify features that contribute to the predictions. RESULTS/ANTICIPATED RESULTS: Of the 13,515 3’-UTR SNPs tested, 400 and 657 significantly impacted gene expression in SH-SY5Y and microglia, respectively. Of the 84 SNPs significantly impacted in both cells, the direction of impact was the same in 81. The direction of eQTL in GTEx tissues agreed with the assay SNP effect in SH-SY5Y cells but not microglial cells. The deep-learning model predicted sequence activity level correlated with the experimental activity level (Spearman’s corr = 0.45). The deep-learning model identified several predictive motifs similar to motifs of RNA-binding proteins. DISCUSSION/SIGNIFICANCE OF FINDINGS: This study demonstrates that MPRAs can be used to evaluate the effect of non-coding variants, and the results can be used to train a machine learning model and interpret its predictions. Together, these can help identify causal variants and further understand the etiology of diseases.Item 5. Collaborative Study on the Genetics of Alcoholism: Functional genomics(Wiley, 2023) Gameiro-Ros, Isabel; Popova, Dina; Prytkova, Iya; Pang, Zhiping P.; Liu, Yunlong; Dick, Danielle; Bucholz, Kathleen K.; Agrawal, Arpana; Porjesz, Bernice; Goate, Alison M.; Xuei, Xiaoling; Kamarajan, Chella; COGA Collaborators; Tischfield, Jay A.; Edenberg, Howard J.; Slesinger, Paul A.; Hart, Ronald P.; Medical and Molecular Genetics, School of MedicineAlcohol Use Disorder is a complex genetic disorder, involving genetic, neural, and environmental factors, and their interactions. The Collaborative Study on the Genetics of Alcoholism (COGA) has been investigating these factors and identified putative alcohol use disorder risk genes through genome-wide association studies. In this review, we describe advances made by COGA in elucidating the functional changes induced by alcohol use disorder risk genes using multimodal approaches with human cell lines and brain tissue. These studies involve investigating gene regulation in lymphoblastoid cells from COGA participants and in post-mortem brain tissues. High throughput reporter assays are being used to identify single nucleotide polymorphisms in which alternate alleles differ in driving gene expression. Specific single nucleotide polymorphisms (both coding or noncoding) have been modeled using induced pluripotent stem cells derived from COGA participants to evaluate the effects of genetic variants on transcriptomics, neuronal excitability, synaptic physiology, and the response to ethanol in human neurons from individuals with and without alcohol use disorder. We provide a perspective on future studies, such as using polygenic risk scores and populations of induced pluripotent stem cell-derived neurons to identify signaling pathways related with responses to alcohol. Starting with genes or loci associated with alcohol use disorder, COGA has demonstrated that integration of multimodal data within COGA participants and functional studies can reveal mechanisms linking genomic variants with alcohol use disorder, and potential targets for future treatments.Item 65 Gene-specific risk of syndrome-associated cancers in first-degree relatives of pancreatic cancer patients with pathogenic/likely pathogenic variants(Cambridge University Press, 2023-04-24) Chen, Xuan; Rabe, Kari G.; Meyer, Margaret A.; Kemppainen, Jennifer L.; Horibe, Masayasu; Chandra, Shruti; Majumder, Shounak; Peterson, Gloria M.; Medical and Molecular Genetics, School of MedicineThis abstract is based on unpublished data. OBJECTIVES/GOALS: The estimates of unbiased first-degree relatives (FDRs) risk of cancers would enhance genetic counseling of at-risk FDRs in families where the pancreatic cancer (PC) proband carrying a germline variant. This study aims at quantifying gene-specific risks of six cancers among FDRs of PC patients with germline variants in cancer-associated genes. METHODS/STUDY POPULATION: In the prospective, clinic-based Mayo Clinic Biospecimen Resource for Pancreas Research registry, 4,562 PC patients had previously undergone germline genetic testing for pancreatic cancer-associated genes through either research studies or clinical testing. Of these, 234 PC probands were found to carry germline pathogenic/likely pathogenic variants (PLPV) among 9 genes of interest and had provided detailed demographic and cancer data on their FDRs by questionnaire. We focused on six cancer types (ovary, breast, uterus, pancreas, colon, and malignant melanoma) in FDRs as reported by the probands. Standardized incidence ratios were calculated to estimate risk of six cancers among FDRs of PC patients carrying PLPV by gene. RESULTS/ANTICIPATED RESULTS: 1,670 FDRs (mean age 58.1+17.8SD; 48.9% female) were included in the study. We found significantly increased risk of ovarian cancer in female FDRs of PC probands who carry PLPV in BRCA1 (SIR 9.49, 95%CI:3.06-22.14) or BRCA2 (3.72, 95%CI:1.36-8.11), and breast cancer risks were higher with BRCA2 (2.62, 95%CI:1.89-3.54). Uterine cancer risk was increased in FDRs of PC probands who carry PLPV for Lynch Syndrome mismatch repair (MMR) (6.53, 95%CI:2.81-12.86). PC risk was also increased (ATM 4.53, 95% CI:2.69-7.16; BRCA2 3.45, 95%CI:1.72-6.17; CDKN2A 7.38, 95%CI:3.18-14.54; PALB2 5.39, 95%CI:1.45-13.79). Increased colon cancer risk was observed in FDRs of probands who carried MMR PLPV (5.83, 95%CI:3.70-8.75), while melanoma risk was elevated for FDRs of probands with CDKN2A PLPV (7.47, 95%CI:3.97-12.77). DISCUSSION/SIGNIFICANCE: PLPV in nine syndrome-associated genes in PC probands are associated with increased risk of six cancers in FDRs. The findings underscore the importance of risk estimation of various other cancers in PC families for screening, early detection, intervention, and cascade genetic testing.Item 7519 Withdrawal of DCCR (Diazoxide Choline) Extended-Release Tablets Worsens Hyperphagia and Increases Weight and BMI in a 16-week Double-blind, Placebo-controlled, Randomized Withdrawal Period in Patients with Prader Willi Syndrome(Oxford University Press, 2024-10-05) Gevers, Evelien F.; Miller, Jennifer Lynne; Bridges, Nicola Anne; Felner, Eric Ian; Salehi, Parisa; Stevenson, David; Yanovski, Jack; Bird, Lynne; Kimonis, Virginia; Hall Shoemaker, Ashley; Stephens Obrynba, Kathryn; Lah, Melissa; Littlejohn, Elizabeth; Cowen, Neil; Yen, Kristen; Ballal, Shaila; Hirano, Patricia; Huang, Michael; Bhatnagar, Anish; Medical and Molecular Genetics, School of MedicineBackground: Prader-Willi syndrome (PWS) is a rare genetic neurobehavioral-metabolic disease characterized by hyperphagia, endocrinopathies, weight gain, hypotonia, behavioral problems, and an increased risk of mortality and reduced life expectancy. There are currently no approved treatments for hyperphagia in PWS. Diazoxide choline extended-release (DCCR) is a novel, once daily oral therapy being developed for the treatment of PWS. Herein, we present results of the Randomized Withdrawal Period (RWP) of Clinical Study C602, a long-term treatment study of DCCR in people with PWS. Objectives and Methods: This was a 16-week multi-center, double-blind, placebo-controlled RWP that enrolled participants ≥4 years of age who were actively enrolled in the open label period of Clinical Study C602 and had received 2-4 years of DCCR treatment (target dose: ≥3.3 mg/kg; optimal range: 4.2-5.8 mg/kg) at the time of RWP entry. RWP-eligible participants were randomized 1:1 to continue DCCR or withdraw from DCCR and receive Placebo. The primary objective was to evaluate the effect of continued DCCR administration versus Placebo on hyperphagia based on the change in Hyperphagia Questionnaire for Clinical Trials (HQ-CT) Total Score from Baseline to Week 16. Additional endpoints included: the Clinical Global Impression of Severity (CGI-S) and Clinical Global Impression of Improvement (CGI-I) at Week 16; changes in body composition (weight, BMI, and BMI z-scores) at Week 16; and the safety profile of DCCR. Results: DCCR (n=38) and Placebo (n=39) groups were generally balanced for demographic and baseline characteristics. At Week 16, a statistically significant difference in change from baseline in HQ-CT Total Score was observed between DCCR and Placebo groups with HQ-CT Total Scores increasing markedly (indicating worsening hyperphagia) in the Placebo group compared to the DCCR group (LSMean difference [SE] -5.0 [1.57], p=0.002). CGI-S and CGI-I showed trends towards worsening in the Placebo group versus the DCCR group (p=0.079 and 0.092, respectively). The Placebo group also experienced significantly greater increases in weight, BMI, and BMI z-scores (p=0.035, 0.034, and 0.023, respectively) than the DCCR group. DCCR was well-tolerated, with no new or unexpected safety signals, and no serious adverse events or discontinuations due to adverse events in the DCCR group. Conclusions: In this 16-week RWP, the Placebo group experienced significant worsening in hyperphagia and increases in body weight, BMI, and BMI z-scores, along with worsening trends for the CGI-S and CGI-I, compared to the DCCR group. DCCR was well tolerated, with a safety profile that was consistent with prior experience. These data suggest treatment with DCCR may lead to clinical benefits in people with PWS by reducing hyperphagia and improving body composition.Item A 9.8 Mb deletion at 7q31.2q31.31 downstream of FOXP2 in an individual with speech and language impairment suggests a possible positional effect(Wiley, 2022-11-19) Iwata-Otsubo, Aiko; Klee, Victoria H.; Ahmad, Aaliya A.; Walsh, Laurence E.; Breman, Amy M.; Medical and Molecular Genetics, School of MedicineHaploinsufficiency of FOXP2 causes FOXP2-related speech and language disorder. We report a 9.8 Mb deletion downstream of FOXP2 in a girl with speech and language impairment, developmental delay, and other features. We propose involvement of FOXP2 in pathogenesis of these phenotypes, likely due to positional effects on the gene.Item A 9.8 Mb deletion at 7q31.2q31.31 downstream of FOXP2 in an individual with speech and language impairment suggests a possible positional effect(Wiley, 2022-11-19) Iwata-Otsubo, Aiko; Klee, Victoria H.; Ahmad, Aaliya A.; Walsh, Laurence E.; Breman, Amy M.; Medical and Molecular Genetics, School of MedicineHaploinsufficiency of FOXP2 causes FOXP2-related speech and language disorder. We report a 9.8 Mb deletion downstream of FOXP2 in a girl with speech and language impairment, developmental delay, and other features. We propose involvement of FOXP2 in pathogenesis of these phenotypes, likely due to positional effects on the gene.Item A clinically validated method to separate and quantify underivatized acylcarnitines and carnitine metabolic intermediates using mixed-mode chromatography with tandem mass spectrometry(Elsevier, 2022-01-25) Luna, Carolina; Griffin, Chandler; Miller, Marcus J.; Medical and Molecular Genetics, School of MedicineAcylcarnitines are intermediate metabolites of the mitochondria that serve as biomarkers for inherited disorders of fatty acid oxidation and amino acid metabolism. The prevailing clinical method used to quantify acylcarnitines involves flow-injection tandem mass spectrometry, an approach with a number of limitations; foremost the inability to separate and therefore distinguish key isobaric acylcarnitine species. To address these issues, we report a clinically validated liquid chromatography tandem mass spectrometry method to quantify acylcarnitines, free carnitine, and carnitine metabolic intermediates in human plasma. Importantly, this method resolves clinically relevant isobaric and isomeric acylcarnitine species in a single 22 min analysis without the use of ion pairing or derivatization reagents. This unique combination of features is not achievable by existing acylcarnitine methods and is made possible by the use of a novel mixed-mode chromatographic separation. Further clinical validation studies demonstrate excellent limits of quantification, linearity, accuracy, and inter-assay precision for analyses of 38 different calibrated analytes. An additional 28 analytes are semi-quantitatively analyzed using surrogate calibrators. The study of residual patient specimens confirms the clinical utility of this method and suggests expanded applicability to the diagnosis of peroxisomal disorders. In summary, we report a clinically validated acylcarnitine method that utilizes a novel mixed-mode chromatographic separation to provide a number of advantages in terms of specificity, accuracy, sample preparation time, and clinical utility.Item A cross-disorder dosage sensitivity map of the human genome(Elsevier, 2022) Collins, Ryan L.; Glessner, Joseph T.; Porcu, Eleonora; Lepamets, Maarja; Brandon, Rhonda; Lauricella, Christopher; Han, Lide; Morley, Theodore; Niestroj, Lisa-Marie; Ulirsch, Jacob; Everett, Selin; Howrigan, Daniel P.; Boone, Philip M.; Fu, Jack; Karczewski, Konrad J.; Kellaris, Georgios; Lowther, Chelsea; Lucente, Diane; Mohajeri, Kiana; Nõukas, Margit; Nuttle, Xander; Samocha, Kaitlin E.; Trinh, Mi; Ullah, Farid; Võsa, Urmo; Epi25 Consortium; Estonian Biobank Research Team; Hurles, Matthew E.; Aradhya, Swaroop; Davis, Erica E.; Finucane, Hilary; Gusella, James F.; Janze, Aura; Katsanis, Nicholas; Matyakhina, Ludmila; Neale, Benjamin M.; Sanders, David; Warren, Stephanie; Hodge, Jennelle C.; Lal, Dennis; Ruderfer, Douglas M.; Meck, Jeanne; Mägi, Reedik; Esko, Tõnu; Reymond, Alexandre; Kutalik, Zoltán; Hakonarson, Hakon; Sunyaev, Shamil; Brand, Harrison; Talkowski, Michael E.; Medical and Molecular Genetics, School of MedicineRare copy-number variants (rCNVs) include deletions and duplications that occur infrequently in the global human population and can confer substantial risk for disease. In this study, we aimed to quantify the properties of haploinsufficiency (i.e., deletion intolerance) and triplosensitivity (i.e., duplication intolerance) throughout the human genome. We harmonized and meta-analyzed rCNVs from nearly one million individuals to construct a genome-wide catalog of dosage sensitivity across 54 disorders, which defined 163 dosage sensitive segments associated with at least one disorder. These segments were typically gene dense and often harbored dominant dosage sensitive driver genes, which we were able to prioritize using statistical fine-mapping. Finally, we designed an ensemble machine-learning model to predict probabilities of dosage sensitivity (pHaplo & pTriplo) for all autosomal genes, which identified 2,987 haploinsufficient and 1,559 triplosensitive genes, including 648 that were uniquely triplosensitive. This dosage sensitivity resource will provide broad utility for human disease research and clinical genetics.Item A cross-sectional survey of genetic counselors providing carrier screening regarding GBA variants and Parkinson disease susceptibility(Springer, 2022) Jones, Tara A.; Schulze, Jeanine; Aufox, Sharon; Rothstein, Jason; Arjunan, Aishwarya; Medical and Molecular Genetics, School of MedicinePurpose: Adult-onset disease risks associated with carriers of recessive disease have and will continue to be identified. As carrier screening becomes more broadly utilized, providers face the dilemma of whether they should discuss these risks during discussions with prospective parents. This study aimed to understand whether preconception/prenatal genetic counselors (PPGCs) were aware of the risk of Parkinson disease in carriers of, and persons with, Gaucher disease and the reasons behind choosing whether to discuss this risk with patients. Methods: Eligible participants included board-certified or board-eligible genetic counselors who had counseled preconception/prenatal patients within the past 3 years. An online survey was distributed via the National Society of Genetic Counselors in November of 2017. Results: One hundred twenty genetic counselors completed the quantitative survey, distributed in Fall of 2017. While the majority of respondents knew of the Gaucher-related Parkinson's link (n = 78; 65%), just over one-third reported discussing it in preconception/prenatal settings (n = 30; 38.5%). Respondents reported discussing these links more consistently when disclosing positive results or when the patient/family approached the topic. Respondents cited the lack of professional guidelines as one of the main reasons for not discussing the link. Conclusion: These results highlight an inconsistency in PPGCs' discussions of the Parkinson's risk in Gaucher disease carriers, and the need to develop guidelines regarding these issues to help standardize the care and education of patients.