Digital Commons Network^™

A High-Throughput Assay For Monitoring And Quantifying Amyloid-Β Accumulation And Clearance In Alzheimer's Disease Cell Models, Ajish Ariyath, Fraulein Denise Arigo, Anna Fyfe, W. M.A.D.Binosha Fernando, Ralph Martins, Prashant Bharadwaj

Research outputs 2022 to 2026

Amyloidogenic proteins, such as amyloid-β (Aβ), self-assemble into cross-β fibrils whose accumulation is central to Alzheimer's disease (AD). Measuring Aβ aggregation and clearance in living cells remains challenging using current cell-based assays, which are often low-throughput or not suited for real-time monitoring. This study aimed to (1) develop a robust, quantitative, and scalable fluorescence-based assay using Amytracker to monitor Aβ accumulation and clearance in an Aβ-producing neuronal cell model, and (2) validate its utility for mechanistic studies and therapeutic screening. We established a plate-based fluorescence assay using Amytracker in MC65 neuronal AD model expressing the Amyloid precursor protein C-terminal fragment …

Gender Disparities Among General Surgeons: A Comprehensive Review, Julie Holihan, Devi Bavishi, Kush Brahmbhatt, Rebecca Franks, Zuhair Ali, Karla Bernardi, Christine Castillo, Mike Liang, Rachel Wong, Michele Loor

Faculty, Staff and Student Publications

Background: Unlike in-house call, the Accreditation Council for Graduate Medical Education (ACGME) does not require a postcall day for "home call" shifts. Despite this, we hypothesize that on-call residents are still in the hospital for the majority of their shift despite having the luxury of home call and, thus, are not protected by ACGME postcall duty hour regulations.

Methods: A prospective single center survey study was conducted by surveying junior and senior residents who completed overnight call shifts from January 2023 to April 2023 at one of the busiest level 1 trauma centers in the United States. Data include number …

Factors Associated With Postpartum Depression Symptoms Following Antepartum Hospitalization, Alison N Goulding, Daniel Palacios, Sukru Aras, Hu Chen, Sasidhar Pasupuleti, Marika Toscano, Nicole Cirino, Israel C Christie, Zhandong Liu, Emily S Miller, Terri L Fletcher

Duncan NRI Faculty and Staff Publications

Background: Hospitalized antepartum patients are at increased risk for postpartum depression (PPD). Developing approaches to identify those at highest risk for PPD would enable timely and targeted intervention.

Objective: We aimed to identify factors associated with the development of PPD symptoms in hospitalized antepartum patients and to assess their predictive utility.

Study design: This retrospective cohort study included pregnant individuals hospitalized in a regional referral center due to medical or obstetric complications between 2012 and 2025. Data were extracted from the electronic health record, including demographics, medical and obstetric history, hospitalization characteristics, and postpartum Edinburgh Postnatal Depression Scale (EPDS) scores …

Novel Biomarker Discovery In Multiple Sclerosis, Manisha Gangasani

Honors Theses

Multiple Sclerosis (MS) is a chronic neuroinflammatory disorder affecting the brain, spinal cord, and optic nerve. Patients experience cognitive, motor, autonomic, and emotional symptoms that often overlap with other neurological conditions, making early diagnosis challenging. Current diagnostic criteria require evidence of lesions with dissemination in time and space. Racial disparities in MS outcomes are well documented, with Black individuals often exhibiting greater disease severity, higher relapse rates, and increased disability compared to White individuals. These differences likely reflect a combination of genetic, biological, environmental, and healthcare access factors, underscoring the need to improve early diagnosis and reduce inequities in care. …

An Investigation Of The Roles Aging, Gender And Age-Related Hearing Loss Play In Emotional Prosody Recognition, Giavanna Yowell

Undergraduate Honors Thesis Collection

Emotional prosody recognition is crucial for social interactions but is influenced by aging, gender, and age-related hearing loss (Lambrecht et al., 2012; Oerlemans et al., 2014; Palermo et al., 2013). No past studies have looked at all of these factors collectively. To address this shortcoming, the current study explored the relationships between aging, hearing loss and gender differences in emotional prosody recognition. The ability to recognize emotions through facial expressions was also included as a comparative measure. One hundred fifteen individuals (42 men and 73 women), ages 50 and older (M = 60.39, SD = 8.12), completed a hearing handicap …

Population Pharmacokinetics And Dosing Simulations Of Pentobarbital In The Pediatric Population, Victoria Etges Helfer, Lorena Medina-Aymerich, William J. Muller, Marisa Meyer, Amira Al-Uzri, Russell Mcculloh, Chi D. Hornik, Stephen J. Balevic, Rachel G. Greenberg, Daniel K. Benjamin, Sarah G. Anderson, Daniel Gonzalez

Department of Pediatrics Faculty Papers

Pentobarbital is a barbiturate with sedative and anticonvulsant properties, occasionally used in pediatric patients for preoperative sedation, deep sedation during mechanical ventilation, and seizure control. Despite its long-standing clinical use, age-appropriate dosing remains challenging due to variability across studies and limited pediatric pharmacokinetic (PK) data. This study (NCT01431326) aimed to characterize the population pharmacokinetics of pentobarbital in pediatric patients (birth to 21 years) and evaluate dosing strategies using model-based simulations. A two-compartment population PK model, allometrically scaled to total body weight, adequately described pentobarbital plasma concentrations, with no additional covariates identified as significant. Simulations were conducted across four age groups: …

Prefrontal Engagement In Cognitive Flexibility Across Paradigms, Katarina Kalajzic

Honors Scholar Theses

Cognitive flexibility is an executive function that involves dynamically adapting behavior in the face of changing environmental circumstances to achieve a particular goal. Disrupted in numerous psychiatric disorders such as Alzheimer’s disease, schizophrenia, OCD, and depression, the neural correlates of cognitive flexibility are not well understood. However, the prefrontal cortex (PFC) is strongly implicated in executive function and attentional control processes. Thus, we sought to examine the neural circuitry involved in distinct cognitive flexibility tasks – the attentional set-shifting task and the probabilistic 2-armed bandit task. Through optogenetic suppression, we targeted pyramidal neurons of the rodent medial prefrontal cortex, an …

Validation Of A Real-Time Pcr Laboratory Developed Test For The Detection Of Pneumocystis Jirovecii In Bronchoalveolar Lavage Samples, Caitlyn Moon

Honors Scholar Theses

Pneumocystis jirovecii is an opportunistic, host-obligate fungal pathogen responsible for causing P. jirovecii pneumonia (PJP) in humans. PJP is treated with trimethoprim-sulfamethoxazole (TMP-SMX), a strong broad-spectrum antibiotic that carries risk of renal and hepatotoxicity. Therefore, rapid diagnosis or exclusion of PJP is crucial to ensure PJP-positive patients receive effective treatment and PJP-negative patients avoid unnecessary antibiotics. Unlike most microorganisms, P. jirovecii cannot be cultured, presenting complications for the typical methods of diagnosing fungal pathogens. Historically, the gold standard for diagnosis was direct microscopic examination with stains such as methenamine silver and calcofluor white, but this diagnostic technique requires highly skilled …

The Development Of A Crispr-Based Calibrated Functional Assay For Classifying Pathogenicity Of Msh2 And Msh6 Variants In Lynch Syndrome, Olivia N. Amodeo

Honors Scholar Theses

Lynch syndrome is a hereditary disease caused by the inheritance of a mismatch repair gene variant. Individuals with this condition are predisposed to cancer development, most commonly colorectal cancer. Current guidelines for variant classification are based on numerous evidence categories, including functional evidence. However, many novel clinical variants are not well characterized, and evidence is difficult to obtain if functional assays are not calibrated.

To address this, our lab created a calibrated functional assay that calculates an odds of pathogenicity score for MSH2 and MSH6 gene variants that can be used as evidence for classifying variants of uncertain significance. This …

Surgical Timing After Acromioclavicular Joint Separation: Association With Clinical Outcomes, Mallory B Lane, Jacob Siahaan, James M Gregory

Faculty, Staff and Student Publications

Background: Treatment of acromioclavicular joint (ACJ) separations continually lacks consensus between providers, and while low-grade injuries generally respond well to conservative management, high-grade injury management is more complex. For patients requiring surgery, the effect of the timing of surgery with respect to the original injury on clinical outcomes remains unclear.

Hypothesis: Clinical outcome measures would worsen as the time between ACJ dislocation injury and surgery increased.

Study design: Cohort study; Level of evidence, 3.

Methods: A large nationwide insurance claims database was queried for patients who had an ACJ dislocation injury using International Classification of Diseases, Ninth and Tenth Revision …

Multidisciplinary Approach To Complex Lower Extremity Limb Salvage In Pyogenic Arthritis, Pyoderma Gangrenosum, And Acne (Papa) Syndrome: A Case Report, Michael M Talanker, Anthony V Basta, Tien Do, Robert Tung, Addison Allen, Morgan Martin, Bryan L Ruygrok, Patrick J Kellam, Jeffrey G Trost, Mohin A Bhadkamkar

Faculty, Staff and Student Publications

Limb salvage using free tissue transfer in patients with rare autoinflammatory syndromes is poorly described, and the safety of microvascular reconstruction in this population remains uncertain. Hereditary pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome is characterized by dysregulated inflammation, pathergy, and impaired wound healing, raising concern for flap compromise and postoperative complications. We report a rare case of lower extremity free tissue transfer in a patient with PAPA syndrome. A 66-year-old woman with rheumatoid arthritis and PAPA syndrome presented with rapid wound breakdown, violaceous ulceration, exposed hardware, and periprosthetic joint infection following left total knee arthroplasty (TKA). Examination revealed …

Assessment Of Skin In Patients With Systemic Sclerosis Using High-Frequency Ultrasound And Shear Wave Elastography: A Comparative Study With Histology, Molecular, And Clinical Parameters, Ruhani Desai, Filemon Tan, Minghua Wu, Jeffery L Browning, Samuel Theodore, Meng Zhang, Brian Skaug, Harshdeep Singh Chawla, Manmohan Singh, Salavat Aglyamov, Kirill V Larin, Maureen Mayes, Shervin Assassi

Faculty, Staff and Student Publications

Objective: Ultrasound (US) has been proposed as a potential tool for assessing skin fibrosis in systemic sclerosis (SSc). However, a large-scale comparison of US-based assessment with histologic markers of skin fibrosis has not been reported. We evaluated US-based skin assessments for their face validity (differentiation between involved SSc and healthy control [HC] skin), construct validity (comparison to modified Rodnan skin score [mRSS]), and criterion validity (comparison to histologic and gene expression fibrosis markers).

Methods: Twenty HCs and 52 patients with SSc underwent clinical and US assessment followed by a forearm skin biopsy. Predefined areas were assessed on the finger, hand, …

Brief Report: Hepatitis B Vaccination Histories In Persons With Hiv Needing Revaccination, Minhee Kang, Triin Umbleja, Anchalee Avihingsanon, Sandra W Cardoso, Josphat Kosgei, Karen J Vigil, Ta Thi Dieu Ngan, Unoda Chakalisa, Stephanie Caruso, Kenneth E Sherman, Kristen M Marks

Faculty, Staff and Student Publications

Introduction: Past studies of hepatitis B vaccines in people with HIV (PWH) have shown mixed results about improving responses with increases in dose or dose frequency, leading to inconsistent guidelines and practice. We examined vaccine series completion and revaccinations in PWH lacking a seroprotective response.

Methods: Hepatitis B vaccination histories were evaluated as a retrospective study in 561 participants of A5379 trial (NCT04193189). Individuals in 41 sites in Africa, Asia, South America, and the United States qualified for the trial with antibody titers below the seroprotective level (< 10 mIU/mL) despite past hepatitis B vaccinations. The primary measure of interest was the number of vaccines in the past vaccination records.

Results: Of the 1098 trial candidates, 561 (51%) did not …

Quantitative Muscle Magnetic Resonance Imaging Demonstrates Resolution Of Muscle Edema In Refractory Dermatomyositis: A Post Hoc Analysis Of A Proof-Of-Concept Clinical Trial Of Tofacitinib, Mona Dabiri, Anshula Nallapati, Marwin Groener, Patrick Debs, Jemima Albayda, Eleni Tiniakou, Lisa Christopher-Stine, Laura Fayad, Julie J Paik

Faculty, Staff and Student Publications

Objective: To evaluate changes in muscle edema using short-tau inversion recovery (STIR) imaging and quantitative diffusion-weighted imaging (DWI) with apparent diffusion coefficient (ADC) mapping in patients with refractory dermatomyositis (DM) treated with tofacitinib.

Methods: This post hoc imaging analysis included patients from a 12-week, open-label trial of tofacitinib 11 mg daily in refractory DM. Bilateral thigh magnetic resonance imaging was obtained at baseline and week 12 using standardized STIR, T1-weighted, and DWI sequences. Muscle edema (ME) and fascial edema were assessed qualitatively on STIR imaging. ADC values were measured in muscles demonstrating baseline STIR hyperintensity using three nonoverlapping regions of …

Race To Mitigate Aortic Dissection: Exercise, Pde5a, And The Dissecting Aorta, Siddharth K Prakash

Faculty, Staff and Student Publications

No abstract provided.

The Impact Of Rapid Infusers On The Hemostatic Potential Of Cryoprecipitate Products, Connor D Purvis, Samantha Redden, Andrew Jacobson, Yao-Wei Wang, Julie Campbell, Jessica Cardenas, Jan-Michael Van Gent, Bryan A Cotton

Faculty, Staff and Student Publications

Background: In cases of massive transfusion, intravenous access can be limited. Additionally, delivering different products through separate lines and infusion methods adds unnecessary steps. RBC, plasma, and whole blood (WB) are delivered via rapid infusers; cryoprecipitate (CRYO) is infused through separate access and is not approved with these devices.

Study design and methods: We examined the impact of different transfusion methods on hemostatic performance and factor activity using two available CRYO products. Ten bags of CRYO, ten bags pathogen-reduced CRYO (Intercept® Fibrinogen Complex, IFC), and 20 units of WB were obtained. Each CRYO bag was infused with one unit of …

Estrogen As A Therapeutic Agent: Targeting Endotheliopathy And Coagulopathy In Trauma, Niruktha Raghavan, Mira Patel, Bryan A Cotton, Julia Coleman, Donald Jenkins

Faculty, Staff and Student Publications

Background: Traumatic injury remains a leading cause of death, often due to uncontrolled hemorrhage and trauma-induced coagulopathy (TIC). TIC is critically triggered by the endotheliopathy of trauma, involving endothelial cell injury and glycocalyx degradation. Despite conventional advances, the stable casualty rate underscores the urgent need for new precision resuscitation strategies that acknowledge factors like biological sex.

Design: The central hypothesis is that estrogen confers a survival advantage in hormonally active females through a dual action: endothelial cell stabilization (halting glycocalyx shedding) and its inherent procoagulant effect. The analysis assesses the therapeutic potential of both exogenous estrogen and female-derived blood products …

Declaring Futility After Traumatic Injury And The Burden Of Failure On The Surgeon, Jan-Michael Van Gent, Bryan A Cotton

Faculty, Staff and Student Publications

In this edition of the THOR supplement in Transfusion, there are two articles that deal with resuscitation futility and transfusion. In one article, Yazer et al. delve into the details of the studies outlined in this editorial and summarize the literature on the topic of transfusion and futility. The second article by Dr. Jay Malone discusses the ethical issues surrounding massive transfusion and resuscitation. Taken together, these articles address the clinical and ethical issues surrounding this very emotive and difficult topic.

Neurointerventional Advances In 2025, Amol Mehta, Sunil A Sheth, Ashutosh P Jadhav

Faculty, Staff and Student Publications

No abstract provided.

Creating Space For New Ideas And Advancing Gender Equity In Physical Activity And Health Research: Reflections On The Nature Portfolio Physical Activity Series, Andrea Ramírez Varela, Deborah Salvo, Pedro C Hallal, Erica Hinckson

Faculty, Staff and Student Publications

No abstract provided.

Are Drains After Trauma Splenectomy Associated With Organ Space Surgical Site Infections?, Stephanie Martinez Ugarte, Mokunfayo O Fajemisin, Seokhun Kim, William D Rieger, Renee W Green, Gabrielle E Hatton, Lillian S Kao

Faculty, Staff and Student Publications

Introduction: Left upper quadrant (LUQ) drain use after trauma splenectomy varies, with minimal existing data to guide practice. We aimed to investigate the association of LUQ drains with organ space surgical site infection (OS-SSI) after splenectomy. We hypothesized that LUQ drains after trauma splenectomy are associated with increased odds of OS-SSI.

Patients and methods: A retrospective study of adult blunt trauma patients who underwent splenectomy from 7/2018 to 6/2024 was performed. We excluded patients who survived < 5 days after operation, and those with an intraoperatively identified pancreatic injury. Demographics, surgical details, and drain information were abstracted from the medical record. Inverse probability of treatment weighting (IPTW) was used to balance variables between patients who did and did not receive an LUQ drain after splenectomy. Multivariable logistic regression with IPTW was performed to estimate the association of LUQ drains with OS-SSI.

Results: Of 179 patients, 68% (n = 121) were male, the median age was 38 years (interquartile range 28, 55), and 27% (n = …

An Assessment Of Green Plasma: The In Vitro Hemostatic Superiority Of A Currently Discarded Blood Product, Samantha C Redden, David J Sun, Yao-Wei W Wang, Elizabeth Hartwell, Jessica C Cardenas, Scott D Olson, Bryan A Cotton

Faculty, Staff and Student Publications

Introduction: Recent studies have linked trauma patient outcomes to the plasma donor's sex, with premenopausal females associated with improved survival and lower organ failure. Currently, green-colored plasma (due to oral contraceptive use) is removed from the donor pool. We set out to evaluate the hemostatic potential of green plasma.

Study design & methods: We obtained 90 units of plasma from our regional blood center: 30 units of visible green plasma and 60 units of standard-color plasma divided between male and female donors. We collected clinical data such as age, sex, ethnicity, and number of pregnancies. We then assessed the hemostatic …

Intravenous Buprenorphine Reversed Opioid-Induced Respiratory Depression Without Precipitating Withdrawal In Emergency Department Patients, Anthony Spadaro, Nicholas Imperato, Jaclyn Scalgione, Cynthia Santos

Faculty, Staff and Student Publications

Objective: Buprenorphine is a high-affinity partial agonist that can displace full opioid agonists and could be used to reverse opioid-induced respiratory depression. There is scant evidence to support the use of buprenorphine in an acute opioid overdose to reverse respiratory depression in the era of high fentanyl prevalence in the drug supply. This is a case series of four patients with signs and symptoms of an opioid overdose who showed clinical improvement after receiving intravenous buprenorphine.

Method: A case series of adult emergency department patients treated at a single urban academic medical center was reviewed by the authors, who determined …

Circulating Sphingomyelins Correlate With Plasma T-Tau In Cognitively Unimpaired Older Adults At Risk Of Developing Alzheimer's Disease, Tahmida Sharmin, James D. Doecke, Pratishtha Chatterjee, Steve Pedrini, Hamid R. Sohrabi, Nicholas J. Ashton, Henrik Zetterberg, Manohar L. Garg, Kaj Blennow, Ralph N. Martins

Research outputs 2022 to 2026

Alterations in plasma sphingomyelin (SM) levels have been reported in Alzheimer's disease (AD), pointing to disturbances in lipid metabolism that may contribute to disease pathogenesis. Neuronal damage in early AD triggers tau release into central and peripheral systems. Despite influence from peripheral contributions, alterations in plasma total-tau (T-tau) remain valuable in indicating AD-related neurodegeneration. Investigating relationships between SM metabolism and tau release during preclinical AD may uncover important biochemical processes and support advancing early non-invasive detection and treatment approaches. This cross-sectional study investigated cognitively unimpaired (CU) older adults from the KARVIAH cohort, grouped by cortical amyloid-β (Aβ) status through positron …

The Relationship Between Mc1r Gene Variants For Red Hair And Clinical Responses To Anesthesia, Analgesia, And Pain: A Systematic Review Of The Literature, Mary Clark Allen

The Eleanor Mann School of Nursing Undergraduate Honors Theses

Background: Genetic variations of the melanocortin-1 receptor (MC1R) are commonly associated with red hair and pale skin. Research has linked MC1R variants with alterations in anesthetic response, pain perception, opioid sensitivity, and pain-related fear. Existing literature presents inconclusive findings, highlighting the need for further investigation.

Purpose: This review aims to synthesize current evidence concerning the role of MC1R variants in altering physiologic responses.

Methods: A systematic literature review was conducted by accessing CINAHL, MEDLINE, and PubMed through the University of Arkansas Libraries OneSearch platform. After applying inclusion and exclusion criteria, a total of 20 peer-reviewed articles were extracted for review. …

Dean's Research Newsletter, May 2026, Neil W. Schluger

SOM Dean's Research Newsletter

No abstract provided.

Development And Pilot Testing Of Transdiagnostic Exposure Therapy/Behavioral Activation For Autistic Adolescents With Internalizing Disorders, Andrew G Guzick, Elizabeth A Kaplan-Kahn, Jessica Szu-Chi Cheng, Callie Murphy, Ogechi C Onyeka, David Riddle, Tracy Dibbs, Leandra N Berry, Robin P Goin-Kochel, Eric A Storch

Faculty, Staff and Students Publications

Internalizing disorders disproportionately affect autistic adolescents, though limited research has focused on tailoring therapy for this population. The purposes of this paper were (1) to describe the development of a transdiagnostic exposure therapy/behavioral activation intervention for autistic adolescents with internalizing disorders, and (2) to present a pilot test of feasibility, acceptability, and efficacy of the intervention. The development of this therapy is described in detail, which prioritized the following domains: (1) building on the existing evidence base of exposure-based cognitive behavioral therapy for autistic youth with anxiety disorders, (2) involving caregivers considerably, (3) incorporating autism-specific considerations into case conceptualization and …

Determining Zap-70 Signaling Pathways Mediated By Ccr7 In Tcr T Cell Activation, Vivian Torres

Open Access Theses & Dissertations

Activation of T lymphocytes is the main event that occurs in the adaptive immune response after engagement of the T cell receptor (TCR) with the peptide of the major histocompatibility complex (pMHC) molecules that are demonstrated by antigen presenting cells [1]. A key step in this process is the recruitment and activation of the zeta chain associated protein of 70 kDa (ZAP-70). ZAP-70 couples TCR engagement to downstream intracellular signaling pathways through phosphorylation of tyrosine residues within intracellular tyrosine activation motifs (ITAMs) [2]. Although there have been extensive studies on the signaling response through TCR activation, the regulatory influence of …

Reducing Transfusions In Neuromuscular Spinal Fusion: A National Surgical Quality Improvement Program-Pediatrics Quality Improvement Project, Holden Archer, Venessa L Pinto, Farrah Russell, Valentina Briceño, Melissa Ard, Lisa Hensch, Jun Teruya, Tanisha G Daugherty, Wallis Molchen, Ryan D Coleman, Darrell Hanson, Frank T Gerow, Nicole I Montgomery

Faculty, Staff and Students Publications

Background: Pediatric spinal fusion can result in substantial blood loss, particularly in patients with scoliosis related to underlying neuromuscular (NM) disease. Transfusion is frequently required but carries risks including transfusion reactions, alloimmunization, volume overload, and infection.

Local problem: The American College of Surgeons National Surgical Quality Improvement Program-Pediatrics (ACS NSQIP-P) is a nationally validated, risk-adjusted national outcomes registry. At our institution, ACS NSQIP-P data identified our institution as a high outlier in transfusion for neuromuscular scoliosis patients.

Methods: A multidisciplinary group convened from January 2024 to June 2024 to design and implement a perioperative pathway with the primary goal of …

High-Penetrance Rare Variants Underlying Familial Lung Cancer Risk: Insights From Genetic Epidemiology Of Lung Cancer Consortium, Yanhong Liu, Yafang Li, Jinyoung Byun, Vikram R Shaw, Claudio Pikielny, Bo Peng, Chao Cheng, Spiridon Tsavachidis, Xiangjun Xiao, Dakai Zhu, Younghun Han, Ivan P Gorlov, Olga Y Gorlova, Michael Cole, Colette R Gaba, Erin L Crawford, Kristen Purrington, Ellen L Goode, Ping Yang, James Mckay, John K Field, Geoffrey Liu, Rayjean J Hung, Jun Xia, Jiyeon Choi, Matthew B Schabath, Jaclyn Lopiccolo, David C Christiani, Joan Bailey-Wilson, Ann G Schwartz, James C Willey, Diptasri Mandal, Susan M Pinney, Christopher I Amos

Faculty, Staff and Students Publications

Introduction: Rare, deleterious germline variants are key contributors to inherited lung cancer (LC) risk. The Genetic Epidemiology of LC Consortium (GELCC) has curated valuable high-risk LC families and is uniquely positioned to uncover rare, high-penetrance variants underlying familial LC (FLC).

Methods: We performed whole-genome and exome sequencing on germline DNA from 120 high-risk LC families (177 FLC cases, 309 unaffected relatives). We prioritized rare (allele frequency < 1% in the genome aggregation database), potentially deleterious variants present in two or more FLC cases. These variants were then validated in 10,085 sporadic LC (SLC) cases and 612,970 controls.

Results: We identified 118 candidate variants, 28 of which were validated in SLC with strong statistical support. We discovered a novel pathogenic axis of three truncating variants in GALNT6, MUC4, and ERBB3 genes, which …