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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 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 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.Item A genetic risk score and diabetes predict development of alcohol-related cirrhosis in drinkers(Elsevier, 2022) Whitfield, John B.; Schwantes-An, Tae-Hwi; Darlay, Rebecca; Aithal, Guruprasad P.; Atkinson, Stephen R.; Bataller, Ramon; Botwin, Greg; Chalasani, Naga P.; Cordell, Heather J.; Daly, Ann K.; Day, Christopher P.; Eyer, Florian; Foroud, Tatiana; Gleeson, Dermot; Goldman, David; Haber, Paul S.; Jacquet, Jean-Marc; Liang, Tiebing; Liangpunsakul, Suthat; Masson, Steven; Mathurin, Philippe; Moirand, Romain; McQuillin, Andrew; Moreno, Christophe; Morgan, Marsha Y.; Mueller, Sebastian; Müllhaupt, Beat; Nagy, Laura E.; Nahon, Pierre; Nalpas, Bertrand; Naveau, Sylvie; Perney, Pascal; Pirmohamed, Munir; Seitz, Helmut K.; Soyka, Michael; Stickel, Felix; Thompson, Andrew; Thursz, Mark R.; Trépo, Eric; Morgan, Timothy R.; Seth, Devanshi; GenomALC Consortium; Medical and Molecular Genetics, School of MedicineBackground & aims: Only a minority of excess alcohol drinkers develop cirrhosis. We developed and evaluated risk stratification scores to identify those at highest risk. Methods: Three cohorts (GenomALC-1: n = 1,690, GenomALC-2: n = 3,037, UK Biobank: relevant n = 6,898) with a history of heavy alcohol consumption (≥80 g/day (men), ≥50 g/day (women), for ≥10 years) were included. Cases were participants with alcohol-related cirrhosis. Controls had a history of similar alcohol consumption but no evidence of liver disease. Risk scores were computed from up to 8 genetic loci identified previously as associated with alcohol-related cirrhosis and 3 clinical risk factors. Score performance for the stratification of alcohol-related cirrhosis risk was assessed and compared across the alcohol-related liver disease spectrum, including hepatocellular carcinoma (HCC). Results: A combination of 3 single nucleotide polymorphisms (SNPs) (PNPLA3:rs738409, SUGP1-TM6SF2:rs10401969, HSD17B13:rs6834314) and diabetes status best discriminated cirrhosis risk. The odds ratios (ORs) and (95% CIs) between the lowest (Q1) and highest (Q5) score quintiles of the 3-SNP score, based on independent allelic effect size estimates, were 5.99 (4.18-8.60) (GenomALC-1), 2.81 (2.03-3.89) (GenomALC-2), and 3.10 (2.32-4.14) (UK Biobank). Patients with diabetes and high risk scores had ORs of 14.7 (7.69-28.1) (GenomALC-1) and 17.1 (11.3-25.7) (UK Biobank) compared to those without diabetes and with low risk scores. Patients with cirrhosis and HCC had significantly higher mean risk scores than patients with cirrhosis alone (0.76 ± 0.06 vs. 0.61 ± 0.02, p = 0.007). Score performance was not significantly enhanced by information on additional genetic risk variants, body mass index or coffee consumption. Conclusions: A risk score based on 3 genetic risk variants and diabetes status enables the stratification of heavy drinkers based on their risk of cirrhosis, allowing for the provision of earlier preventative interventions. Lay summary: Excessive chronic drinking leads to cirrhosis in some people, but so far there is no way to identify those at high risk of developing this debilitating disease. We developed a genetic risk score that can identify patients at high risk. The risk of cirrhosis is increased >10-fold with just two risk factors - diabetes and a high genetic risk score. Risk assessment using this test could enable the early and personalised management of this disease in high-risk patients.Item A multi-disciplinary, comprehensive approach to management of children with heterotaxy(BMC, 2022-09-09) Saba, Thomas G.; Geddes, Gabrielle C.; Ware, Stephanie M.; Schidlow, David N.; del Nido, Pedro J.; Rubalcava, Nathan S.; Gadepalli, Samir K.; Stillwell, Terri; Griffiths, Anne; Bennett Murphy, Laura M.; Barber, Andrew T.; Leigh, Margaret W.; Sabin, Necia; Shapiro, Adam J.; Medical and Molecular Genetics, School of MedicineHeterotaxy (HTX) is a rare condition of abnormal thoraco-abdominal organ arrangement across the left-right axis of the body. The pathogenesis of HTX includes a derangement of the complex signaling at the left-right organizer early in embryogenesis involving motile and non-motile cilia. It can be inherited as a single-gene disorder, a phenotypic feature of a known genetic syndrome or without any clear genetic etiology. Most patients with HTX have complex cardiovascular malformations requiring surgical intervention. Surgical risks are relatively high due to several serious comorbidities often seen in patients with HTX. Asplenia or functional hyposplenism significantly increase the risk for sepsis and therefore require antimicrobial prophylaxis and immediate medical attention with fever. Intestinal rotation abnormalities are common among patients with HTX, although volvulus is rare and surgical correction carries substantial risk. While routine screening for intestinal malrotation is not recommended, providers and families should promptly address symptoms concerning for volvulus and biliary atresia, another serious morbidity more common among patients with HTX. Many patients with HTX have chronic lung disease and should be screened for primary ciliary dyskinesia, a condition of respiratory cilia impairment leading to bronchiectasis. Mental health and neurodevelopmental conditions need to be carefully considered among this population of patients living with a substantial medical burden. Optimal care of children with HTX requires a cohesive team of primary care providers and experienced subspecialists collaborating to provide compassionate, standardized and evidence-based care. In this statement, subspecialty experts experienced in HTX care and research collaborated to provide expert- and evidence-based suggestions addressing the numerous medical issues affecting children living with HTX.Item A proteogenomic view of Parkinson's disease causality and heterogeneity(Springer Nature, 2023-02-11) Kaiser, Sergio; Zhang, Luqing; Mollenhauer, Brit; Jacob, Jaison; Longerich, Simonne; Del-Aguila, Jorge; Marcus, Jacob; Raghavan, Neha; Stone, David; Fagboyegun, Olumide; Galasko, Douglas; Dakna, Mohammed; Bilican, Bilada; Dovlatyan, Mary; Kostikova, Anna; Li, Jingyao; Peterson, Brant; Rotte, Michael; Sanz, Vinicius; Foroud, Tatiana; Hutten, Samantha J.; Frasier, Mark; Iwaki, Hirotaka; Singleton, Andrew; Marek, Ken; Crawford, Karen; Elwood, Fiona; Messa, Mirko; Serrano-Fernandez, Pablo; Medical and Molecular Genetics, School of MedicineThe pathogenesis and clinical heterogeneity of Parkinson’s disease (PD) have been evaluated from molecular, pathophysiological, and clinical perspectives. High-throughput proteomic analysis of cerebrospinal fluid (CSF) opened new opportunities for scrutinizing this heterogeneity. To date, this is the most comprehensive CSF-based proteomics profiling study in PD with 569 patients (350 idiopathic patients, 65 GBA + mutation carriers and 154 LRRK2 + mutation carriers), 534 controls, and 4135 proteins analyzed. Combining CSF aptamer-based proteomics with genetics we determined protein quantitative trait loci (pQTLs). Analyses of pQTLs together with summary statistics from the largest PD genome wide association study (GWAS) identified 68 potential causal proteins by Mendelian randomization. The top causal protein, GPNMB, was previously reported to be upregulated in the substantia nigra of PD patients. We also compared the CSF proteomes of patients and controls. Proteome differences between GBA + patients and unaffected GBA + controls suggest degeneration of dopaminergic neurons, altered dopamine metabolism and increased brain inflammation. In the LRRK2 + subcohort we found dysregulated lysosomal degradation, altered alpha-synuclein processing, and neurotransmission. Proteome differences between idiopathic patients and controls suggest increased neuroinflammation, mitochondrial dysfunction/oxidative stress, altered iron metabolism and potential neuroprotection mediated by vasoactive substances. Finally, we used proteomic data to stratify idiopathic patients into “endotypes”. The identified endotypes show differences in cognitive and motor disease progression based on previously reported protein-based risk scores.Our findings not only contribute to the identification of new therapeutic targets but also to shape personalized medicine in CNS neurodegeneration.