Medicine and Health Sciences Commons^™

Affinity Purification Of Serum-Derived Anti-Ia-2 Autoantibodies In Type 1 Diabetes Using A Novel Mbp-Ia-2 Fusion Protein, Thilini Mendis, Barbora Filipova, Jing Jing Wang, Massimo Pietropaolo, Michael W Jackson

Faculty, Staff and Students Publications

Autoantibodies targeting epitopes contained within the intracellular domain (IC) of the protein phosphatase-like islet antigen 2 (IA-2) are a common marker of autoimmune type 1 diabetes (T1D), however the isolation of genuine, serum derived anti-IA-2 autoantibodies has proven challenging due to a lack of suitable bioassays. In the current study, an ELISA format was developed for affinity purification of human anti-IA-2ic autoantibodies utilizing a fusion protein (FP) incorporating maltose binding protein and the full-length IA-2IC domain. Using a T1D patient cohort validated for anti-IA-2ic autoantibodies by commercial ELISA, we demonstrate the MBP-IA-2ic FP ELISA detects serum anti-IA-2IC autoantibodies from 3 …

Apoptosis Of Hematopoietic Stem Cells Contributes To Bone Marrow Suppression Following Chimeric Antigen Receptor T Cell Therapy, Jay A Read, Rayne H Rouce, Feiyan Mo, Maksim Mamonkin, Katherine Y King

Faculty, Staff and Students Publications

Background: CAR-T therapy represents a revolutionary treatment for patients with relapsed/refractory hematologic malignancies. However, its use can result in significant toxicities, including cytokine release syndrome (CRS), a potentially life-threatening clinical syndrome resulting from release of pro-inflammatory cytokines upon T cell activation. In addition, patients who develop CRS often experience prolonged cytopenias and those with the most severe CRS also have the greatest delay in full marrow recovery. While an association between CRS and delayed bone marrow recovery has been established, the precise mechanism underlying this phenomenon remains unknown.

Objective: To test our hypothesis that delayed bone marrow recovery following CAR-T …

Outcomes Of Full And Partial Cardiac Autotransplantation For Complex Left-Sided Heart Tumors, Qasim Al Abri, Lamees I El Nihum, Areeba Ali, Duc T Nguyen, Edward A Graviss, Thomas E Macgillivray, Michael J Reardon

Faculty, Staff and Students Publications

Background: Complex or malignant left-sided heart tumors present a challenge for resection and reconstruction. Cardiac autotransplantation was developed to address this but is a complex technique. Partial autotransplantation was developed to simplify the procedure. This study evaluates the outcomes of partial cardiac autotransplantation compared with those of full cardiac autotransplantation.

Methods: We analyzed our prospectively collected cardiac tumor database for cases between 1998 and 2022 requiring full or partial cardiac autotransplantation. The primary end points for the study were morbidities including bleeding, total blood transfusions, renal failure, prolonged ventilation (>48 hours), arrhythmias, total cardiopulmonary bypass time, total aortic clamp …

The Pandemic Anxiety Inventory: A Validation Study, Irvin Sam Schonfeld, Tasmyn Prytherch, Mark Cropley, Renzo Bianchi

Publications and Research

The Pandemic Anxiety Inventory (PAI) assesses anxiety symptoms individuals attribute to the presence of a pandemic. We conducted this study of 379 British adults during the COVID-19 pandemic and found that the PAI exhibited excellent reliability and solid criterion validity. Pandemic anxiety was associated with reduced social support, anticipated life changes, financial strain, job loss, economic insecurity, and the hospitalization or death of a close friend or relative. Using correlational and bifactor analyses, we found that the PAI demonstrated solid convergent and discriminant validity. The findings suggest that the PAI can be used in research and clinical practice.

Cognitive And Academic Performance Of Rural Zambian Youth Exposed To Hiv, Sophie Jago, Joseph Mwaba Chirwa, Mei Tan, Philip E Thuma, Elena L Grigorenko

Faculty, Staff and Students Publications

Studies focusing on children affected by HIV have shown that they have generally lower academic performance, however, few studies separate children who are HIV exposed and infected (CHEI) and those who are HIV exposed but uninfected (CHEU). Importantly, in rural sub-Saharan Africa, the majority of studies on CHEI and CHEU examine academic performance indirectly based on cognitive test scores. Therefore, studies assessing the effects of HIV on academic achievement directly for CHEI and CHEU are needed. This article evaluates the effects of HIV-infection on cognitive and academic performance by comparing CHEI (n = 82) and CHEU (n = 1045) aged …

Long-Chain Polyunsaturated Lipids Associated With Responsiveness To Anti-Pd-1 Therapy Are Colocalized With Immune Infiltrates In The Tumor Microenvironment, Mary E King, Robert Yuan, Jeremy Chen, Komal Pradhan, Isabel Sariol, Shirley Li, Ashish Chakraborty, Oscar Ekpenyong, Jennifer H Yearley, Janica C Wong, Luis Zúñiga, Daniela Tomazela, Maribel Beaumont, Jin-Hwan Han, Livia S Eberlin

Faculty, Staff and Students Publications

The programmed cell death protein-1 (PD-1) is highly expressed on the surface of antigen-specific exhausted T cells and, upon interaction with its ligand PD-L1, can result in inhibition of the immune response. Anti-PD-1 treatment has been shown to extend survival and result in durable responses in several cancers, yet only a subset of patients benefit from this therapy. Despite the implication of metabolic alteration following cancer immunotherapy, mechanistic associations between antitumor responses and metabolic changes remain unclear. Here, we used desorption electrospray ionization mass spectrometry imaging to examine the lipid profiles of tumor tissue from three syngeneic murine models with …

Incidence Of Hypotension During Sevoflurane Induction In Children With Down Syndrome; A Prospective Observational Study, Adam C Adler, Hai-Yen Nguyen, Brian H Nathanson, Arvind Chandrakantan

Faculty, Staff and Students Publications

No abstract provided.

2022 American College Of Rheumatology Guideline For Vaccinations In Patients With Rheumatic And Musculoskeletal Diseases, Anne R Bass, Eliza Chakravarty, Elie A Akl, Clifton O Bingham, Leonard Calabrese, Laura C Cappelli, Sindhu R Johnson, Lisa F Imundo, Kevin L Winthrop, Reuben J Arasaratnam, Lindsey R Baden, Roberta Berard, S Louis Bridges, Jonathan T L Cheah, Jeffrey R Curtis, Polly J Ferguson, Ida Hakkarinen, Karen B Onel, Grayson Schultz, Vidya Sivaraman, Benjamin J Smith, Jeffrey A Sparks, Tiphanie P Vogel, Eleanor Anderson Williams, Cassandra Calabrese, Joanne S Cunha, Joann Fontanarosa, Miriah C Gillispie-Taylor, Elena Gkrouzman, Priyanka Iyer, Kimberly S Lakin, Alexandra Legge, Mindy S Lo, Megan M Lockwood, Rebecca E Sadun, Namrata Singh, Nancy Sullivan, Herman Tam, Marat Turgunbaev, Amy S Turner, James Reston

Faculty, Staff and Students Publications

Objective: To provide evidence-based recommendations on the use of vaccinations in children and adults with rheumatic and musculoskeletal diseases (RMDs).

Methods: This guideline follows American College of Rheumatology (ACR) policy guiding management of conflicts of interest and disclosures and the ACR guideline development process, which includes the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology. It also adheres to the Appraisal of Guidelines for Research and Evaluation (AGREE) criteria. A core leadership team consisting of adult and pediatric rheumatologists and a guideline methodologist drafted clinical population, intervention, comparator, outcomes (PICO) questions. A review team performed a systematic literature review …

Normal Ranges Of Right Atrial Strain: A Systematic Review And Meta-Analysis, Chayakrit Krittanawong, Neil Sagar Maitra, Hafeez Ul Hassan Virk, Ann Farrell, Ihab Hamzeh, Basant Arya, Gregg S Pressman, Zhen Wang, Thomas H Marwick

Faculty, Staff and Students Publications

Background: Standard measures for the clinical assessment of right atrial (RA) function are lacking.

Objectives: In this systematic review and meta-analysis, the authors sought to report a reference range for RA deformation parameters in healthy subjects and to identify factors that contribute to reported variations.

Methods: The authors conducted a comprehensive search of MEDLINE; MEDLINE In-Process & Other Non-Indexed Citations; Embase; Scopus; and the Cochrane Central Register of Controlled Trials from database inception through October 2021. Studies were included if they reported RA strain or strain rate (SR) using 2-dimensional speckle-tracking echocardiography in healthy volunteers or apparently healthy control patients. …

Inflammatory Signalling In Atrial Cardiomyocytes: A Novel Unifying Principle In Atrial Fibrillation Pathophysiology, Dobromir Dobrev, Jordi Heijman, Roddy Hiram, Na Li, Stanley Nattel

Faculty, Staff and Students Publications

Inflammation has been implicated in atrial fibrillation (AF), a very common and clinically significant cardiac rhythm disturbance, but its precise role remains poorly understood. Work performed over the past 5 years suggests that atrial cardiomyocytes have inflammatory signalling machinery - in particular, components of the NLRP3 (NACHT-, LRR- and pyrin domain-containing 3) inflammasome - that is activated in animal models and patients with AF. Furthermore, work in animal models suggests that NLRP3 inflammasome activation in atrial cardiomyocytes might be a sufficient and necessary condition for AF occurrence. In this Review, we evaluate the evidence for the role and pathophysiological significance …

Response To: A True Point-Of-Care Molecular Testing Method For Tailored Therapy For Helicobacter Pylori Eradication, David Y Graham, Theodore Rokkas

Faculty, Staff and Students Publications

No abstract provided.

Hereditary Angioedema And Covid-19 During Pregnancy: Two Case Reports, Amanda Salih, Aaron Chin, Manisha Gandhi, Amir Shamshirsaz, Hennie Lombaard, Joud Hajjar

Faculty, Staff and Students Publications

No abstract provided.

Asthma And Cardiovascular Disease: A Bidirectional Association?, Muhammad Adrish, Nicola A Hanania

Faculty, Staff and Students Publications

No abstract provided.

Ferroptosis In Life: To Be Or Not To Be, Ling Xu, Yu'e Liu, Xi Chen, Hua Zhong, Yi Wang

Faculty, Staff and Students Publications

Ferroptosis is a novel type of programmed cell death, characterized by a dysregulated iron metabolism and accumulation of lipid peroxides. It features the alteration of mitochondria and aberrant accumulation of excessive iron as well as loss of the cysteine-glutathione-GPX4 axis. Eventually, the accumulated lipid peroxides result in lethal damage to the cells. Ferroptosis is induced by the overloading of iron and the accumulation of ROS and can be inhibited by the activation of the GPX4 pathway, FS1-CoQ10 pathway, GCH1-BH4 pathway, and the DHODH pathway, it is also regulated by the oncogenes and tumor suppressors. Ferroptosis involves various physiological and pathological …

Sociodemographic Determinants Of Oral Anticoagulant Prescription In Patients With Atrial Fibrillations: Findings From The Pinnacle Registry Using Machine Learning, Zahra Azizi, Andrew T Ward, Donghyun J Lee, Sanchit S Gad, Kanchan Bhasin, Robert J Beetel, Tiago Ferreira, Sushant Shankar, John S Rumsfeld, Robert A Harrington, Salim S Virani, Ty J Gluckman, Rajesh Dash, Fatima Rodriguez

Faculty, Staff and Students Publications

Background: Current risk scores that are solely based on clinical factors have shown modest predictive ability for understanding of factors associated with gaps in real-world prescription of oral anticoagulation (OAC) in patients with atrial fibrillation (AF).

Objective: In this study, we sought to identify the role of social and geographic determinants, beyond clinical factors associated with variation in OAC prescriptions using a large national registry of ambulatory patients with AF.

Methods: Between January 2017 and June 2018, we identified patients with AF from the American College of Cardiology PINNACLE (Practice Innovation and Clinical Excellence) Registry. We examined associations between patient …

The Importance Of Low-Density Lipoprotein Cholesterol Measurement And Control As Performance Measures: A Joint Clinical Perspective From The National Lipid Association And The American Society For Preventive Cardiology, Salim S Virani, Karen Aspry, Dave L Dixon, Keith C Ferdinand, Paul A Heidenreich, Elizabeth J Jackson, Terry A Jacobson, Janice L Mcalister, David R Neff, Martha Gulati, Christie M Ballantyne

Faculty, Staff and Students Publications

Despite the established role of low-density lipoprotein cholesterol (LDL-C) as a major risk factor for cardiovascular disease (CVD), and the persistence of CVD as the leading cause of morbidity and mortality in the United States, national quality assurance metrics no longer include LDL-C measurement as a required performance metric. This clinical perspective reviews the history of LDL-C as a quality and performance metric and the events that led to its replacement. It also presents patient, healthcare provider, and health system rationales for re-establishing LDL-C measurement as a performance measure to improve cholesterol control in high-risk groups and to stem the …

Bacteremia, Liver Injury, And Pneumonitis: Strongyloides Unleashed By A Supplement, Emily Y Xiao, Robert L Pecha, Zaven Sargsyan

Faculty, Staff and Students Publications

No abstract provided.

Types Of Diagnostic Errors Reported By Paediatric Emergency Providers In A Global Paediatric Emergency Care Research Network, Prashant Mahajan, Joseph A Grubenhoff, Jim Cranford, Maala Bhatt, James M Chamberlain, Todd Chang, Mark Lyttle, Rianne Oostenbrink, Damian Roland, Richard M Rudy, Kathy N Shaw, Robert Velasco Zuniga, Apoorva Belle, Nathan Kuppermann, Hardeep Singh

Faculty, Staff and Students Publications

Background: Diagnostic errors, reframed as missed opportunities for improving diagnosis (MOIDs), are poorly understood in the paediatric emergency department (ED) setting. We investigated the clinical experience, harm and contributing factors related to MOIDs reported by physicians working in paediatric EDs.

Methods: We developed a web-based survey in which physicians participating in the international Paediatric Emergency Research Network representing five out of six WHO regions, described examples of MOIDs involving their own or a colleague's patients. Respondents provided case summaries and answered questions regarding harm and factors contributing to the event.

Results: Of 1594 physicians surveyed, 412 (25.8%) responded (mean age=43 …

Peripheral Nerve Stimulation: A New Horizon For Traumatic Brachial Plexus Injury, A Case Report, Christian Vangeison, Colton Reeh, Daniel Briggi, Royce Copeland, Loc Lam, Ryan D'Souza, Abdulhammeed Qashqary, Emanuel Narcis Husu

Faculty, Staff and Students Publications

Background: The management of traumatic brachial plexus injury is challenging. Treatment options consisting of physical therapy, pharmacologic therapy, and injection therapy often provide inadequate analgesia. Peripheral nerve stimulation (PNS) has emerged as a potential therapy for treatment of pain related to brachial plexus injury.

Case report: We present a case of a 37-year-old man with painful ballistic trauma to multiple cords of the left brachial plexus refractory to medications and therapies. The patient was treated with a temporary 60-day PNS targeting the brachial plexus providing 90% improvement in pain intensity persisting 7 months postintervention.

Conclusions: The case supports the efficacy …

Paid Sick Leave, Chronic Disease, And Systemic Racism: A Systematic Review, Lauren Yee

University Honors Theses

The purpose of this systematic review is to assess the impact of paid sick leave (PSL) availability on chronic disease prevention, treatment, and recovery. Furthermore, this study aims to investigate the role of race on this relationship as a possible source of systemic racism. The findings of this review show a growing body of evidence that affirms the statistically significant association between PSL and chronic disease-related outcomes. The availability of PSL has the potential to remove financial barriers allowing employees to access preventative services for chronic diseases. Access to PSL also increases work resumption by improving financial stability after being …

Effects Of Occupationally Military-Relevant Particle Mixtures (Sio2, Cdo, Cr2O3) On A549 Human Pulmonary Epithelial Cells, Isabella M. Muffoletto

Theses and Dissertations

In the course of maintaining a safe, mission-ready aircraft fleet and operational runways, United States Airmen experience a range of occupational risks. These risks include inhalable hazards generated from oft-used maintenance practices, such as blasting which emits silica from the media abrasives as well as contaminants from the exterior coatings. Additional inhalation hazards range from engine and fuel emissions, chemical agents, radiation, and explosives, to naturally occurring and human-manufactured biopathogens. Of notable concern are emissions in forward-deployment areas, including urban pollution, particulates released from runway construction and maintenance activities, and combustion from burn pits containing hazardous and unknown combinations of …

Egr1 Drives Cell Proliferation By Directly Stimulating Tfeb Transcription In Response To Starvation, Marcella Cesana, Gennaro Tufano, Francesco Panariello, Nicolina Zampelli, Susanna Ambrosio, Rossella De Cegli, Margherita Mutarelli, Lorenzo Vaccaro, Micheal J Ziller, Davide Cacchiarelli, Diego L Medina, Andrea Ballabio

Duncan NRI Faculty and Staff Publications

The stress-responsive transcription factor EB (TFEB) is a master controller of lysosomal biogenesis and autophagy and plays a major role in several cancer-associated diseases. TFEB is regulated at the posttranslational level by the nutrient-sensitive kinase complex mTORC1. However, little is known about the regulation of TFEB transcription. Here, through integrative genomic approaches, we identify the immediate-early gene EGR1 as a positive transcriptional regulator of TFEB expression in human cells and demonstrate that, in the absence of EGR1, TFEB-mediated transcriptional response to starvation is impaired. Remarkably, both genetic and pharmacological inhibition of EGR1, using the MEK1/2 inhibitor Trametinib, significantly reduced the …

Patterns Of Co-Occurring Birth Defects In Children With Anotia And Microtia, Jeremy M Schraw, Renata H Benjamin, Charles J Shumate, Mark A Canfield, Daryl A Scott, Scott D Mclean, Hope Northrup, Angela E Scheuerle, Christian P Schaaf, Joseph W Ray, Han Chen, A J Agopian, Philip J Lupo

Faculty, Staff and Student Publications

Many infants with anotia or microtia (A/M) have co-occurring birth defects, although few receive syndromic diagnoses in the perinatal period. Evaluation of co-occurring birth defects in children with A/M could identify patterns indicative of undiagnosed/unrecognized syndromes. We obtained information on co-occurring birth defects among infants with A/M for delivery years 1999-2014 from the Texas Birth Defects Registry. We calculated observed-to-expected ratios (OER) to identify birth defect combinations that occurred more often than expected by chance. We excluded children diagnosed with genetic or chromosomal syndromes from analyses. Birth defects and syndromes/associations diagnosed ≤1 year of age were considered. We identified 1310 …

Novel And Replicated Clinical And Genetic Risk Factors For Toxicity From High-Dose Methotrexate In Pediatric Acute Lymphoblastic Leukemia, Mark Zobeck, M Brooke Bernhardt, Kala Y Kamdar, Karen R Rabin, Philip J Lupo, Michael E Scheurer

Faculty, Staff and Students Publications

STUDY OBJECTIVE: Methotrexate (MTX) is a key component of treatment for high-risk pediatric acute lymphoblastic leukemia (ALL) but may cause acute kidney injury and prolonged hospitalization due to delayed clearance. The purpose of this study is to identify clinical and genetic factors that may predict which children are at risk for creatinine increase and prolonged MTX clearance.

DESIGN: We conducted a single-center, retrospective cohort study of pediatric patients with ALL who received 4000-5000 mg/m

MAIN RESULTS: Hispanic ethnicity, body mass index (BMI) < 3%, BMI between 85%-95%, and Native American genetic ancestry were found to be associated with an increased risk for creatinine elevation. Older age, Black race, and use of the intensive monitoring protocol were associated with a decreased risk for creatinine elevation. Older age, B- compared to T-ALL, and the minor alleles of rs2838958/SLC19A1 and rs7317112/ABCC4 were associated with an increased risk for delayed clearance. Black race, MTX dose reduction, and the minor allele of rs2306283/SLCO1B1 were found to be associated with a decreased risk for delayed clearance.

CONCLUSIONS: These predictors of MTX toxicities may allow for more precise individualized toxicity risk prediction.

Coronary Artery Bypass Grafting At Safety-Net Versus Non-Safety-Net Hospitals, William C Frankel, Christopher B Sylvester, Sainath Asokan, Christopher T Ryan, Rodrigo Zea-Vera, Qianzi Zhang, Matthew J Wall, Sandeep Markan, Joseph S Coselli, Todd K Rosengart, Subhasis Chatterjee, Ravi K Ghanta

Faculty, Staff and Students Publications

OBJECTIVES: Safety-net hospitals (SNHs) provide essential services to predominantly underserved patients regardless of their ability to pay. We hypothesized that patients who underwent coronary artery bypass grafting (CABG) would have inferior observed outcomes at SNHs compared with non-SNHs but that matched cohorts would have comparable outcomes.

METHODS: We queried the Nationwide Readmissions Database for patients who underwent isolated CABG from 2016 to 2018. We ranked hospitals by the percentage of all admissions in which the patient was uninsured or insured with Medicaid; hospitals in the top quartile were designated as SNHs. We used propensity-score matching to mitigate the effect of …

Profiling Disease-Selective Drug Targets: From Proteomics To Ligandomics, Prabuddha Waduge, Hong Tian, Keith A Webster, Wei Li

Faculty, Staff and Students Publications

Despite advancements in omics technologies, including proteomics and transcriptomics, identification of therapeutic targets remains challenging. Ligandomics recently emerged as a unique technology of functional proteomics for global profiling of cell-binding protein ligands. When applied to diseased versus healthy vasculatures, comparative ligandomics systematically maps novel disease-restricted ligands that allow selective targeting of pathological but not physiological pathways, providing high efficacy with intrinsic safety. In this review, we discuss the potential of cellular ligands as therapeutic targets and summarize the development of ligandomics. We further compare the advantages and limitations of different omics technologies for drug target discovery and discuss target selection …

Failure Of Nasal Defect Closures Following The Use Of Continuous Positive Airway Pressure, Yelena Dokic, Emily Powell, John Kohorst, Ikue Shimizu

Faculty, Staff and Students Publications

In this paper, we report a case series of three patients who developed nasal tip necrosis following Mohs micrographic surgery (MMS), complicated by the concomitant use of a continuous positive airway pressure (CPAP) machine for sleep apnea.

High Molecular Diagnostic Yields And Novel Phenotypic Expansions Involving Syndromic Anorectal Malformations, Raymond Belanger Deloge, Xiaonan Zhao, Pamela N Luna, Chad A Shaw, Jill A Rosenfeld, Daryl A Scott

Faculty, Staff and Students Publications

Evidence suggests that genetic factors contribute to the development of anorectal malformations (ARMs). However, the etiology of the majority of ARMs cases remains unclear. Exome sequencing (ES) may be underutilized in the diagnostic workup of ARMs due to uncertainty regarding its diagnostic yield. In a clinical database of ~17,000 individuals referred for ES, we identified 130 individuals with syndromic ARMs. A definitive or probable diagnosis was made in 45 of these individuals for a diagnostic yield of 34.6% (45/130). The molecular diagnostic yield of individuals who initially met criteria for VACTERL association was lower than those who did not (26.8% …

2022 American College Of Rheumatology Guideline For Vaccinations In Patients With Rheumatic And Musculoskeletal Diseases, Anne R Bass, Eliza Chakravarty, Elie A Akl, Clifton O Bingham, Leonard Calabrese, Laura C Cappelli, Sindhu R Johnson, Lisa F Imundo, Kevin L Winthrop, Reuben J Arasaratnam, Lindsey R Baden, Roberta Berard, S Louis Bridges, Jonathan T L Cheah, Jeffrey R Curtis, Polly J Ferguson, Ida Hakkarinen, Karen B Onel, Grayson Schultz, Vidya Sivaraman, Benjamin J Smith, Jeffrey A Sparks, Tiphanie P Vogel, Eleanor Anderson Williams, Cassandra Calabrese, Joanne S Cunha, Joann Fontanarosa, Miriah C Gillispie-Taylor, Elena Gkrouzman, Priyanka Iyer, Kimberly S Lakin, Alexandra Legge, Mindy S Lo, Megan M Lockwood, Rebecca E Sadun, Namrata Singh, Nancy Sullivan, Herman Tam, Marat Turgunbaev, Amy S Turner, James Reston

Faculty, Staff and Students Publications

OBJECTIVE: To provide evidence-based recommendations on the use of vaccinations in children and adults with rheumatic and musculoskeletal diseases (RMDs).

METHODS: This guideline follows American College of Rheumatology (ACR) policy guiding management of conflicts of interest and disclosures and the ACR guideline development process, which includes the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology. It also adheres to the Appraisal of Guidelines for Research and Evaluation (AGREE) criteria. A core leadership team consisting of adult and pediatric rheumatologists and a guideline methodologist drafted clinical population, intervention, comparator, outcomes (PICO) questions. A review team performed a systematic literature review …

A Biallelic Frameshift Indel In Ppp1r35 As A Cause Of Primary Microcephaly, Moez Dawood, Gulsen Akay, Tadahiro Mitani, Dana Marafi, Jawid M Fatih, Alper Gezdirici, Hossein Najmabadi, Kimia Kahrizi, Jaya Punetha, Christopher M Grochowski, Haowei Du, Angad Jolly, He Li, Zeynep Coban-Akdemir, Fritz J Sedlazeck, Jill V Hunter, Shalini N Jhangiani, Donna Muzny, Davut Pehlivan, Jennifer E Posey, Claudia M B Carvalho, Richard A Gibbs, James R Lupski

Faculty, Staff and Student Publications

Protein phosphatase 1 regulatory subunit 35 (PPP1R35) encodes a centrosomal protein required for recruiting microtubule-binding elongation machinery. Several proteins in this centriole biogenesis pathway correspond to established primary microcephaly (MCPH) genes, and multiple model organism studies hypothesize PPP1R35 as a candidate MCPH gene. Here, using exome sequencing (ES) and family-based rare variant analyses, we report a homozygous, frameshifting indel deleting the canonical stop codon in the last exon of PPP1R35 [Chr7: c.753_*3delGGAAGCGTAGACCinsCG (p.Trp251Cysfs*22)]; the variant allele maps in a 3.7 Mb block of absence of heterozygosity (AOH) in a proband with severe MCPH (-4.3 SD at birth, -6.1 SD by …