Genetics and Genomics Commons^™

Prenatal Screening Decision-Making Facilitated Through An Online Patient Education Module, Erin Atkinson

Dissertations and Theses (Open Access)

As recommendations for prenatal genetic screening are expanded to include patients with pregnancies at low risk for aneuploidy, there is a need to develop accessible mechanisms to promote informed decision-making about genetic screening. The use of patient decision aids has been shown to promote informed decision-making. UTHealth Houston has developed and implemented an online module for pre-test triage for genetic counseling and education of low-risk pregnant patients about genetic screening, called the Prenatal Genetic Education Program (PGEP).

Here, through a retrospective chart review, we characterize the use of PGEP to triage previously presumed low-risk patients to genetic counseling, and whether …

The Need For Racial And Ethnic Health Disparity Curriculum In Genetic Counseling Programs, Yusra Aziz

Dissertations and Theses (Open Access)

Racial and ethnic health disparities (REHD) exist across all organized medicine, including the spectrum of genetic counseling, particularly in genomic testing and access to care. While cultural competency and health disparities have been included as a part of the Standards of Accreditation for Genetic Counseling, there have not been previous efforts to define what topics related to REHD are most important to include in graduate program curriculum. Therefore, this study aimed to determine what topics related to REHD should be taught in genetic counseling program curriculum by assessing what topics genetic counselors (GCs) learned about and in what settings, …

Genetic Regulation Of Müllerian Duct Regression, Malcolm Moses

Dissertations and Theses (Open Access)

Mammals, including humans, develop progenitor tissues for both male and female reproductive tract organs before they fully differentiate into a male or female tract. The progenitor tissue for the male reproductive tract is known as the Wolffian duct (WD), and the progenitor tissue for the female reproductive tract is the Müllerian duct (MD). The WD further differentiates into the vas deferens, epididymis, and seminal vesicle, while the MD differentiates into the oviduct, uterus and upper vagina. An essential step in sex differentiation for males is the regression of the MD. This regression initiates with anti-Müllerian hormone (Amh) transcription …

Functions Of The Trna Splicing Endonuclease And Other Adventures In Rna Processing, Jennifer Hurtig, Ambro Van Hoof

Dissertations and Theses (Open Access)

The tRNA splicing endonuclease (TSEN), has been studied for over three decades for its function in tRNA splicing. However, this enzyme has other functions that are just beginning to be characterized. Mutations in TSEN cause the neuronal disease pontocerebellar hypoplasia (PCH) that is characterized by atrophy of the cerebellum and pons, overall developmental failure, and usually results in death before adolescence. How mutations in TSEN cause these neuronal defects and disease is not understood. In yeast, TSEN has another essential function that is independent of tRNA splicing and is still unknown. In this thesis I strived to understand the other …

Dna Methylation Analysis Is Used To Identify Novel Genetic Loci Associated With Circulating Fibrinogen Levels In Blood, Julie Hahn, Jan Bressler, Arce Domingo-Relloso, Ming-Huei Chen, Daniel L Mccartney, Alexander Teumer, Jenny Van Dongen, Marcus E Kleber, Dylan Aïssi, Brenton R Swenson, Jie Yao, Wei Zhao, Jian Huang, Yujing Xia, Michael R Brown, Ricardo Costeira, Eco J C De Geus, Graciela E Delgado, Dre'von A Dobson, Paul Elliott, Hans J Grabe, Xiuqing Guo, Sarah E Harris, Jennifer E Huffman, Sharon L R Kardia, Yongmei Liu, Stefan Lorkowski, Riccardo E Marioni, Matthias Nauck, Scott M Ratliff, Maria Sabater-Lleal, Tim D Spector, Pierre Suchon, Kent D Taylor, Florian Thibord, David-Alexandre Trégouët, Kerri L Wiggins, Gonneke Willemsen, Jordana T Bell, Dorret I Boomsma, Shelley A Cole, Simon R Cox, Abbas Dehghan, Andreas Greinacher, Karin Haack, Winfried März, Pierre-Emmanuel Morange, Jerome I Rotter, Nona Sotoodehnia, Maria Tellez-Plaza, Ana Navas-Acien, Jennifer A Smith, Andrew D Johnson, Myriam Fornage, Nicholas L Smith, Alisa S Wolberg, Alanna C Morrison, Paul S De Vries

Faculty, Staff and Student Publications

Background:

Fibrinogen plays an essential role in blood coagulation and inflammation. Circulating fibrinogen levels may be determined by inter-individual differences in DNA methylation at CpG sites, and vice versa.

Methods:

We performed an epigenome-wide association study (EWAS) of circulating fibrinogen levels in 18,037 White, Black, American Indian, and Hispanic participants representing 14 studies from the CHARGE consortium. Circulating leukocyte DNA methylation was measured in 12,904 participants using the Illumina 450K array, and in 5,133 participants using the EPIC array. Each study performed an EWAS of fibrinogen using linear mixed models adjusted for potential confounders. Study-specific results were combined using array-specific …

Biallelic Variants In Adamts15 Cause A Novel Form Of Distal Arthrogryposis, Felix Boschann, Ozgur Cogulu, Davut Pehlivan, Saranya Balachandran, Pedro Vallecillo-Garcia, Christopher M Grochowski, Nils R Hansmeier, Zeynep H Coban Akdemir, Cesar A Prada-Medina, Ayca Aykut, Björn Fischer-Zirnsak, Simon Badura, Burak Durmaz, Ferda Ozkinay, René Hägerling, Jennifer E Posey, Sigmar Stricker, Gabriele Gillessen-Kaesbach, Malte Spielmann, Denise Horn, Knut Brockmann, James R Lupski, Uwe Kornak, Julia Schmidt

Faculty, Staff and Student Publications

No abstract provided.

Functional Screening Of Lysosomal Storage Disorder Genes Identifies Modifiers Of Alpha-Synuclein Neurotoxicity, Meigen Yu, Hui Ye, Ruth B De-Paula, Carl Grant Mangleburg, Timothy Wu, Tom V Lee, Yarong Li, Duc Duong, Bridget Phillips, Carlos Cruchaga, Genevera I Allen, Nicholas T Seyfried, Ismael Al-Ramahi, Juan Botas, Joshua M Shulman

Faculty, Staff and Students Publications

Heterozygous variants in the glucocerebrosidase (GBA) gene are common and potent risk factors for Parkinson's disease (PD). GBA also causes the autosomal recessive lysosomal storage disorder (LSD), Gaucher disease, and emerging evidence from human genetics implicates many other LSD genes in PD susceptibility. We have systemically tested 86 conserved fly homologs of 37 human LSD genes for requirements in the aging adult Drosophila brain and for potential genetic interactions with neurodegeneration caused by α-synuclein (αSyn), which forms Lewy body pathology in PD. Our screen identifies 15 genetic enhancers of αSyn-induced progressive locomotor dysfunction, including knockdown of fly homologs of GBA …

Cascade Testing After Exome Sequencing: Retrospective Analysis Of Linked Family Data At 2 Us Laboratories, Julie Stefka, Haley Streff, Pengfei Liu, Meghan Towne, Hadley Stevens Smith

Faculty, Staff and Students Publications

Purpose: Cascade testing, the process of testing a proband's at-risk relatives, is integral to realizing the full value of genomic sequencing. However, there is little empirical evidence on the uptake of cascade testing after a positive exome sequencing (ES) result in a population of probands with diverse clinical indications.

Methods: We retrospectively reviewed administrative data from 2 US clinical laboratories that perform ES. For each proband with a positive ES result, we used linked family data to describe the frequency of relatives' cascade testing performed at the same laboratory, variant detection yield of cascade tests, and characteristics of probands and …

Epigenetic Age Acceleration Among Survivors Of Pediatric Medulloblastoma And Primitive Neuroectodermal Tumor, Rachel D Harris, Melissa A Richard, Maria Monica J Gramatges, Kevin Wilhelm, Michael E Scheurer, Philip J Lupo, Austin L Brown

Faculty, Staff and Students Publications

Survivors of childhood central nervous system (CNS) tumors experience early-onset aging-related phenotypes. DNA methylation (DNAm) age is an emerging epigenetic biomarker of physiologic age and may be predictive of chronic health conditions in long-term survivors. This report describes the course of epigenetic age acceleration using post-diagnosis blood samples (median: 3.9 years post-diagnosis; range: 0.04–15.96) from 83 survivors of pediatric CNS tumors. Epigenetic age acceleration was detected in 72% of patients, with an average difference between chronologic and dnam age of 2.58 years (95% Ci: 1.75–3.41, p < 0.001). Time from diagnosis to sample collection correlated with the magnitude of epigenetic age acceleration.

A Weakly Structured Stem For Human Origins In Africa, Aaron P Ragsdale, Timothy D Weaver, Elizabeth G Atkinson, Eileen G Hoal, Marlo Möller, Brenna M Henn, Simon Gravel

Faculty, Staff and Students Publications

Despite broad agreement that Homo sapiens originated in Africa, considerable uncertainty surrounds specific models of divergence and migration across the continent1. Progress is hampered by a shortage of fossil and genomic data, as well as variability in previous estimates of divergence times1. Here we seek to discriminate among such models by considering linkage disequilibrium and diversity-based statistics, optimized for rapid, complex demographic inference2. We infer detailed demographic models for populations across Africa, including eastern and western representatives, and newly sequenced whole genomes from 44 Nama (Khoe-San) individuals from southern Africa. We infer a reticulated …

Alveolar Rhabdomyosarcoma Has Superior Response Rates To Vinorelbine Compared To Embryonal Rhabdomyosarcoma In Patients With Relapsed/Refractory Disease: A Meta-Analysis, Wendy Allen-Rhoades, Philip J Lupo, Michael E Scheurer, Yueh-Yun Chi, John F Kuttesch, Rajkumar Venkatramani, William H Meyer, Leo Mascarenhas

Faculty, Staff and Students Publications

BACKGROUND: Patients with alveolar rhabdomyosarcoma (ARMS) have inferior outcomes compared to patients with embryonal rhabdomyosarcoma (ERMS) and more effective chemotherapy options are needed for these patients. Vinorelbine is a semisynthetic vinca alkaloid that has clinical activity in relapsed rhabdomyosarcoma (RMS) when used alone or in combination with cyclophosphamide.

AIMS: The goal of our study was to evaluate whether RMS histology subtype influences response rate to vinorelbine alone or in combination.

MATERIALS & METHODS: Five Phase 2 trials that enrolled RMS patients were included in the meta-analysis. Two studies evaluated vinorelbine alone, two studies evaluated vinorelbine in combination with low dose …

Adad2 Functions In Spermiogenesis And Pirna Biogenesis In Mice, Yonggang Lu, Ippei Nagamori, Hisato Kobayashi, Kanako Kojima-Kita, Kenjiro Shirane, Hsin-Yi Chang, Toru Nishimura, Takayuki Koyano, Zhifeng Yu, Julio M Castañeda, Makoto Matsuyama, Satomi Kuramochi-Miyagawa, Martin M Matzuk, Masahito Ikawa

Faculty, Staff and Students Publications

BACKGROUND: Adenosine deaminase domain containing 2 (ADAD2) is a testis-specific protein composed of a double-stranded RNA binding domain and a non-catalytic adenosine deaminase domain. A recent study showed that ADAD2 is indispensable for the male reproduction in mice. However, the detailed functions of ADAD2 remain elusive.

OBJECTIVES: This study aimed to investigate the cause of male sterility in Adad2 mutant mice and to understand the molecular functions of ADAD2.

MATERIALS AND METHODS: Adad2 homozygous mutant mouse lines, Adad2

RESULTS: Adad2–/– and Adad2Δ/Δ mice exhibit male-specific sterility due to abnormal spermiogenesis. ADAD2 interacts with multiple RNA-binding proteins involved in …

Exosomes, Microvesicles, And Other Extracellular Vesicles-A Keystone Symposia Report, Jennifer Cable, Kenneth W Witwer, Robert J Coffey, Aleksandar Milosavljevic, Ariana K Von Lersner, Lizandra Jimenez, Ferdinando Pucci, Maureen M Barr, Niek Dekker, Bahnisikha Barman, Daniel Humphrys, Justin Williams, Michele De Palma, Wei Guo, Nuno Bastos, Andrew F Hill, Efrat Levy, Michael P Hantak, Clair Crewe, Elena Aikawa, Alan M Adamczyk, Tamires M Zanotto, Matias Ostrowski, Tanina Arab, Daniel C Rabe, Aadil Sheikh, Danilo Rodrigues Da Silva, Jennifer C Jones, Chioma Okeoma, Thomas Gaborski, Qin Zhang, Olesia Gololobova

Faculty, Staff and Students Publications

Extracellular vesicles (EVs) are small, lipid-bilayer-bound particles released by cells that can contain important bioactive molecules, including lipids, RNAs, and proteins. Once released in the extracellular environment, EVs can act as messengers locally as well as to distant tissues to coordinate tissue homeostasis and systemic responses. There is a growing interest in not only understanding the physiology of EVs as signaling particles but also leveraging them as minimally invasive diagnostic and prognostic biomarkers (e.g., they can be found in biofluids) and drug-delivery vehicles. On October 30-November 2, 2022, researchers in the EV field convened for the Keystone symposium "Exosomes, Microvesicles, …

Genome-Wide Analysis Of Structural Variants In Parkinson Disease, Kimberley J Billingsley, Jinhui Ding, Pilar Alvarez Jerez, Anastasia Illarionova, Kristin Levine, Francis P Grenn, Mary B Makarious, Anni Moore, Daniel Vitale, Xylena Reed, Dena Hernandez, Ali Torkamani, Mina Ryten, John Hardy, Uk Brain Expression Consortium (Ukbec), Ruth Chia, Sonja W Scholz, Bryan J Traynor, Clifton L Dalgard, Debra J Ehrlich, Toshiko Tanaka, Luigi Ferrucci, Thomas G Beach, Geidy E Serrano, John P Quinn, Vivien J Bubb, Ryan L Collins, Xuefang Zhao, Mark Walker, Emma Pierce-Hoffman, Harrison Brand, Michael E Talkowski, Bradford Casey, Mark R Cookson, Androo Markham, Mike A Nalls, Medhat Mahmoud, Fritz J Sedlazeck, Cornelis Blauwendraat, J Raphael Gibbs, Andrew B Singleton

Faculty, Staff and Students Publications

OBJECTIVE: Identification of genetic risk factors for Parkinson disease (PD) has to date been primarily limited to the study of single nucleotide variants, which only represent a small fraction of the genetic variation in the human genome. Consequently, causal variants for most PD risk are not known. Here we focused on structural variants (SVs), which represent a major source of genetic variation in the human genome. We aimed to discover SVs associated with PD risk by performing the first large-scale characterization of SVs in PD.

METHODS: We leveraged a recently developed computational pipeline to detect and genotype SVs from 7,772 …

Prevalence And Descriptive Epidemiology Of Turner Syndrome In The United States, 2000-2017: A Report From The National Birth Defects Prevention Network, Bailey A Martin-Giacalone, Angela E Lin, Sonja A Rasmussen, Russell S Kirby, Eirini Nestoridi, Rebecca F Liberman, A J Agopian, John C Carey, Janet D Cragan, Nina Forestieri, Vinita Leedom, Aubree Boyce, Wendy N Nembhard, Monika Piccardi, Theresa Sandidge, Xiaoyi Shan, Charles J Shumate, Erin B Stallings, Roger Stevenson, Philip J Lupo

Faculty, Staff and Students Publications

The lack of United States population-based data on Turner syndrome limits assessments of prevalence and associated characteristics for this sex chromosome abnormality. Therefore, we collated 2000-2017 data from seven birth defects surveillance programs within the National Birth Defects Prevention Network. We estimated the prevalence of karyotype-confirmed Turner syndrome diagnosed within the first year of life. We also calculated the proportion of cases with commonly ascertained birth defects, assessed associations with maternal and infant characteristics using prevalence ratios (PR) with 95% confidence intervals (CI), and estimated survival probability. The prevalence of Turner syndrome of any pregnancy outcome was 3.2 per 10,000 …

A Small Secreted Protein Nicol Regulates Lumicrine-Mediated Sperm Maturation And Male Fertility, Daiji Kiyozumi, Kentaro Shimada, Michael Chalick, Chihiro Emori, Mayo Kodani, Seiya Oura, Taichi Noda, Tsutomu Endo, Martin M Matzuk, Daniel H Wreschner, Masahito Ikawa

Faculty, Staff and Students Publications

The mammalian spermatozoa produced in the testis require functional maturation in the epididymis for their full competence. Epididymal sperm maturation is regulated by lumicrine signalling pathways in which testis-derived secreted signals relocate to the epididymis lumen and promote functional differentiation. However, the detailed mechanisms of lumicrine regulation are unclear. Herein, we demonstrate that a small secreted protein, NELL2-interacting cofactor for lumicrine signalling (NICOL), plays a crucial role in lumicrine signalling in mice. NICOL is expressed in male reproductive organs, including the testis, and forms a complex with the testis-secreted protein NELL2, which is transported transluminally from the testis to the …

Synthetic Errα/Β/Γ Agonist Induces An Errα-Dependent Acute Aerobic Exercise Response And Enhances Exercise Capacity, Cyrielle Billon, Sadichha Sitaula, Subhashis Banerjee, Ryan Welch, Bahaa Elgendy, Lamees Hegazy, Tae Gyu Oh, Melissa Kazantzis, Arindam Chatterjee, John Chrivia, Matthew E Hayes, Weiyi Xu, Angelica Hamilton, Janice M Huss, Lilei Zhang, John K Walker, Michael Downes, Ronald M Evans, Thomas P Burris

Faculty, Staff and Students Publications

Repetitive physical exercise induces physiological adaptations in skeletal muscle that improves exercise performance and is effective for the prevention and treatment of several diseases. Genetic evidence indicates that the orphan nuclear receptors estrogen receptor-related receptors (ERRs) play an important role in skeletal muscle exercise capacity. Three ERR subtypes exist (ERRα, β, and γ), and although ERRβ/γ agonists have been designed, there have been significant difficulties in designing compounds with ERRα agonist activity. Additionally, there are limited synthetic agonists that can be used to target ERRs in vivo. Here, we report the …

An Altered Extracellular Matrix-Integrin Interface Contributes To Huntington’S Disease-Associated Cns Dysfunction In Glial And Vascular Cells, Sarah J Hernandez, Ryan G Lim, Tarik Onur, Mark A Dane, Rebecca Smith, Keona Wang, Grace En-Hway Jean, Andrea Reyes-Ortiz, Kaylyn Devlin, Ricardo Miramontes, Jie Wu, Malcolm Casale, David Kilburn, Laura M Heiser, James E Korkola, David Van Vactor, Juan Botas, Katherine L Thompson-Peer, Leslie M Thompson

Faculty, Staff and Students Publications

Astrocytes and brain endothelial cells are components of the neurovascular unit that comprises the blood-brain barrier (BBB) and their dysfunction contributes to pathogenesis in Huntington's disease (HD). Defining the contribution of these cells to disease can inform cell-type-specific effects and uncover new disease-modifying therapeutic targets. These cells express integrin (ITG) adhesion receptors that anchor the cells to the extracellular matrix (ECM) to maintain the integrity of the BBB. We used HD patient-derived induced pluripotent stem cell (iPSC) modeling to study the ECM-ITG interface in astrocytes and brain microvascular endothelial cells and found ECM-ITG dysregulation in human iPSC-derived cells that may …

Sptssa Variants Alter Sphingolipid Synthesis And Cause A Complex Hereditary Spastic Paraplegia, Siddharth Srivastava, Hagar Mor Shaked, Kenneth Gable, Sita D Gupta, Xueyang Pan, Niranjanakumari Somashekarappa, Gongshe Han, Payam Mohassel, Marc Gotkine, Elizabeth Doney, Paula Goldenberg, Queenie K G Tan, Yi Gong, Benjamin Kleinstiver, Brian Wishart, Heidi Cope, Claudia Brito Pires, Hannah Stutzman, Rebecca C Spillmann, Undiagnosed Disease Network, Reza Sadjadi, Orly Elpeleg, Chia-Hsueh Lee, Hugo J Bellen, Simon Edvardson, Florian Eichler, Teresa M Dunn

Faculty, Staff and Students Publications

Sphingolipids are a diverse family of lipids with critical structural and signalling functions in the mammalian nervous system, where they are abundant in myelin membranes. Serine palmitoyltransferase, the enzyme that catalyses the rate-limiting reaction of sphingolipid synthesis, is composed of multiple subunits including an activating subunit, SPTSSA. Sphingolipids are both essential and cytotoxic and their synthesis must therefore be tightly regulated. Key to the homeostatic regulation are the ORMDL proteins that are bound to serine palmitoyltransferase and mediate feedback inhibition of enzymatic activity when sphingolipid levels become excessive. Exome sequencing identified potential disease-causing variants in SPTSSA in three children presenting …

Pepquery2 Democratizes Public Ms Proteomics Data For Rapid Peptide Searching, Bo Wen, Bing Zhang

Faculty, Staff and Students Publications

We present PepQuery2, which leverages a new tandem mass spectrometry (MS/MS) data indexing approach to enable ultrafast, targeted identification of novel and known peptides in any local or publicly available MS proteomics datasets. The stand-alone version of PepQuery2 allows directly searching more than one billion indexed MS/MS spectra in the PepQueryDB or any public datasets from PRIDE, MassIVE, iProX, or jPOSTrepo, whereas the web version enables users to search datasets in PepQueryDB with a user-friendly interface. We demonstrate the utilities of PepQuery2 in a wide range of applications including detecting proteomic evidence for genomically predicted novel peptides, validating novel and …

Ethnic-Specific Predictors Of Neurotoxicity Among Patients With Pediatric Acute Lymphoblastic Leukemia After High-Dose Methotrexate, Rachel D Harris, Melanie Brooke Bernhardt, Mark C Zobeck, Olga A Taylor, Maria Monica Gramatges, Eric S Schafer, Philip J Lupo, Karen R Rabin, Michael E Scheurer, Austin L Brown

Faculty, Staff and Students Publications

High-dose methotrexate (HD-MTX; 5,000 mg/m2) is an important component of curative therapy in many treatment regimens for high-risk pediatric acute lymphoblastic leukemia (ALL). However, methotrexate therapy can result in dose-limiting neurotoxicity which may disproportionately affect Latino children. Thus, we evaluated risk factors for neurotoxicity in an ethnically diverse population of 351 patients (58.1% Latino) who received 1,183 HD-MTX infusions. Overall, thirty-five patients (10%) experienced neurotoxicity, 71% of whom were Latino. After adjusting for clinical risk factors, we found that serum creatinine elevations ≥50% of baseline were associated with a 3-fold increased odds (OR = 3.32, 95% CI: 0.98-11.21, p=0.05) for …

Low And Differential Polygenic Score Generalizability Among African Populations Due Largely To Genetic Diversity, Lerato Majara, Allan Kalungi, Nastassja Koen, Kristin Tsuo, Ying Wang, Rahul Gupta, Lethukuthula L Nkambule, Heather Zar, Dan J Stein, Eugene Kinyanda, Elizabeth G Atkinson, Alicia R Martin

Faculty, Staff and Students Publications

African populations are vastly underrepresented in genetic studies but have the most genetic variation and face wide-ranging environmental exposures globally. Because systematic evaluations of genetic prediction had not yet been conducted in ancestries that span African diversity, we calculated polygenic risk scores (PRSs) in simulations across Africa and in empirical data from South Africa, Uganda, and the United Kingdom to better understand the generalizability of genetic studies. PRS accuracy improves with ancestry-matched discovery cohorts more than from ancestry-mismatched studies. Within ancestrally and ethnically diverse South African individuals, we find that PRS accuracy is low for all traits but varies across …

Physio-Psycho-Social Interaction Mechanism In Dyadic Health Of Young And Middle-Aged Stroke Survivors And Their Spousal Caregivers: A Longitudinal Observational Study Protocol, Dandan Xiang, Zhen-Xiang Zhang, Song Ge, Wen Na Wang, Bei-Lei Lin, Su-Yan Chen, Er-Feng Guo, Peng-Bo Zhang, Zhi-Wei Liu, Hui Li, Yong-Xia Mei

Faculty, Staff and Student Publications

Introduction: In recent years, stroke has become more common among young people. Stroke not only has a profound impact on patients' health but also incurs stress and health threats to their caregivers, especially spousal caregivers. Moreover, the health of stroke survivors and their caregivers is interdependent. To our knowledge, no study has explored dyadic health of young and middle-aged stroke survivors and their spousal caregivers from physiological, psychological and social perspectives. Therefore, this proposed study aims to explore the mechanism of how physiological, psychological and social factors affect dyadic health of young and middle-aged stroke survivors and their spousal caregivers. …

Foxi3 Pathogenic Variants Cause One Form Of Craniofacial Microsomia, Ke Mao, Christelle Borel, Muhammad Ansar, Angad Jolly, Periklis Makrythanasis, Christine Froehlich, Justyna Iwaszkiewicz, Bingqing Wang, Xiaopeng Xu, Qiang Li, Xavier Blanc, Hao Zhu, Qi Chen, Fujun Jin, Harinarayana Ankamreddy, Sunita Singh, Hongyuan Zhang, Xiaogang Wang, Peiwei Chen, Emmanuelle Ranza, Sohail Aziz Paracha, Syed Fahim Shah, Valentina Guida, Francesca Piceci-Sparascio, Daniela Melis, Bruno Dallapiccola, Maria Cristina Digilio, Antonio Novelli, Monia Magliozzi, Maria Teresa Fadda, Haley Streff, Keren Machol, Richard A Lewis, Vincent Zoete, Gabriella Maria Squeo, Paolo Prontera, Giorgia Mancano, Giulia Gori, Milena Mariani, Angelo Selicorni, Stavroula Psoni, Helen Fryssira, Sofia Douzgou, Sandrine Marlin, Saskia Biskup, Alessandro De Luca, Giuseppe Merla, Shouqin Zhao, Timothy C Cox, Andrew K Groves, James R Lupski, Qingguo Zhang, Yong-Biao Zhang, Stylianos E Antonarakis

Faculty, Staff and Students Publications

Craniofacial microsomia (CFM; also known as Goldenhar syndrome), is a craniofacial developmental disorder of variable expressivity and severity with a recognizable set of abnormalities. These birth defects are associated with structures derived from the first and second pharyngeal arches, can occur unilaterally and include ear dysplasia, microtia, preauricular tags and pits, facial asymmetry and other malformations. The inheritance pattern is controversial, and the molecular etiology of this syndrome is largely unknown. A total of 670 patients belonging to unrelated pedigrees with European and Chinese ancestry with CFM, are investigated. We identify 18 likely pathogenic variants in 21 probands (3.1%) in …

Bi-Allelic Variants In The Esam Tight-Junction Gene Cause A Neurodevelopmental Disorder Associated With Fetal Intracranial Hemorrhage, Mauro Lecca, Davut Pehlivan, Damià Heine Suñer, Karin Weiss, Thibault Coste, Markus Zweier, Yavuz Oktay, Nada Danial-Farran, Vittorio Rosti, Maria Paola Bonasoni, Alessandro Malara, Gianluca Contrò, Roberta Zuntini, Marzia Pollazzon, Rosario Pascarella, Alberto Neri, Carlo Fusco, Dana Marafi, Tadahiro Mitani, Jennifer Ellen Posey, Sadik Etka Bayramoglu, Alper Gezdirici, Jessica Hernandez-Rodriguez, Emilia Amengual Cladera, Elena Miravet, Jorge Roldan-Busto, María Angeles Ruiz, Cristofol Vives Bauzá, Liat Ben-Sira, Sabine Sigaudy, Anaïs Begemann, Sheila Unger, Serdal Güngör, Semra Hiz, Ece Sonmezler, Yoav Zehavi, Michael Jerdev, Alessandra Balduini, Orsetta Zuffardi, Rita Horvath, Hanns Lochmüller, Anita Rauch, Livia Garavelli, Elisabeth Tournier-Lasserve, Ronen Spiegel, James R Lupski, Edoardo Errichiello

Faculty, Staff and Students Publications

The blood-brain barrier (BBB) is an essential gatekeeper for the central nervous system and incidence of neurodevelopmental disorders (NDDs) is higher in infants with a history of intracerebral hemorrhage (ICH). We discovered a rare disease trait in thirteen individuals, including four fetuses, from eight unrelated families associated with homozygous loss-of-function variant alleles of ESAM which encodes an endothelial cell adhesion molecule. The c.115del (p.Arg39Glyfs∗33) variant, identified in six individuals from four independent families of Southeastern Anatolia, severely impaired the in vitro tubulogenic process of endothelial colony-forming cells, recapitulating previous evidence in null mice, and caused lack of ESAM expression in …

Bi-Allelic Snapc4 Variants Dysregulate Global Alternative Splicing And Lead To Neuroregression And Progressive Spastic Paraparesis, F Graeme Frost, Marie Morimoto, Prashant Sharma, Lyse Ruaud, Newell Belnap, Daniel G Calame, Yuri Uchiyama, Naomichi Matsumoto, Machteld M Oud, Elise A Ferreira, Vinodh Narayanan, Sampath Rangasamy, Matt Huentelman, Lisa T Emrick, Ikuko Sato-Shirai, Satoko Kumada, Nicole I Wolf, Peter J Steinbach, Yan Huang, Undiagnosed Diseases Network, Barbara N Pusey, Sandrine Passemard, Jonathan Levy, Séverine Drunat, Marie Vincent, Agnès Guet, Emanuele Agolini, Antonio Novelli, Maria Cristina Digilio, Jill A Rosenfeld, Jennifer L Murphy, James R Lupski, Gilbert Vezina, Ellen F Macnamara, David R Adams, Maria T Acosta, Cynthia J Tifft, William A Gahl, May Christine V Malicdan

Faculty, Staff and Students Publications

The vast majority of human genes encode multiple isoforms through alternative splicing, and the temporal and spatial regulation of those isoforms is critical for organismal development and function. The spliceosome, which regulates and executes splicing reactions, is primarily composed of small nuclear ribonucleoproteins (snRNPs) that consist of small nuclear RNAs (snRNAs) and protein subunits. snRNA gene transcription is initiated by the snRNA-activating protein complex (SNAPc). Here, we report ten individuals, from eight families, with bi-allelic, deleterious SNAPC4 variants. SNAPC4 encoded one of the five SNAPc subunits that is critical for DNA binding. Most affected individuals presented with delayed motor development …

Rapid Profiling Of Dna Replication Dynamics Using Mass Spectrometry-Based Analysis Of Nascent Dna, Mohamed E Ashour, Andrea K Byrum, Alice Meroni, Jun Xia, Saurabh Singh, Roberto Galletto, Susan M Rosenberg, Alessandro Vindigni, Nima Mosammaparast

Faculty, Staff and Students Publications

The primary method for probing DNA replication dynamics is DNA fiber analysis, which utilizes thymidine analog incorporation into nascent DNA, followed by immunofluorescent microscopy of DNA fibers. Besides being time-consuming and prone to experimenter bias, it is not suitable for studying DNA replication dynamics in mitochondria or bacteria, nor is it adaptable for higher-throughput analysis. Here, we present mass spectrometry-based analysis of nascent DNA (MS-BAND) as a rapid, unbiased, quantitative alternative to DNA fiber analysis. In this method, incorporation of thymidine analogs is quantified from DNA using triple quadrupole tandem mass spectrometry. MS-BAND accurately detects DNA replication alterations in both …

Renal-Hepatic-Pancreatic Dysplasia Type 2: Perinatal Lethal Condition Or A Multisystemic Disorder With Variable Expressivity, Kathryn Gunther, Essam M Imseis, Joyce P Samuel, Elizabeth A Hillman, Tiina H Ojala, Timo Jahnukainen, Paul R Hillman

Faculty, Staff and Student Publications

BACKGROUND: Renal-hepatic-pancreatic dysplasia type 2 (RHPD2) is a rare condition that has been described in the literature disproportionately in perinatal losses. The main features of liver and kidney involvement are well described, with cardiac malformations and cardiomyopathy adding additional variation to the phenotype. Many patients reported are within larger cohorts of congenital anomalies of kidney and urinary tract (CAKUT) or liver failure, and with minimal phenotypic and clinical course data.

METHODS: An independent series of phenotypes and prognosis was aggregated from the literature. In this literature review, we describe an additional patient with RHPD2, provide a clinical update on the …

Natural History Of Tango2 Deficiency Disorder: Baseline Assessment Of 73 Patients, Christina Y Miyake, Erica J Lay, Claudia Soler-Alfonso, Kevin E Glinton, Kimberly M Houck, Mustafa Tosur, Nancy E Moran, Sara B Stephens, Fernando Scaglia, Taylor S Howard, Jeffrey J Kim, Tam Dam Pham, Santiago O Valdes, Na Li, Chaya N Murali, Lilei Zhang, Maina Kava, Deane Yim, Cheyenne Beach, Gregory Webster, Leonardo Liberman, Christopher M Janson, Prince J Kannankeril, Samantha Baxter, Moriel Singer-Berk, Jordan Wood, Samuel J Mackenzie, Michael Sacher, Lina Ghaloul-Gonzalez, Claudia Pedroza, Shaine A Morris, Saad A Ehsan, Mahshid S Azamian, Seema R Lalani

Faculty, Staff and Students Publications

PURPOSE: TANGO2 deficiency disorder (TDD), an autosomal recessive disease first reported in 2016, is characterized by neurodevelopmental delay, seizures, intermittent ataxia, hypothyroidism, and life-threatening metabolic and cardiac crises. The purpose of this study was to define the natural history of TDD.

METHODS: Data were collected from an ongoing natural history study of patients with TDD enrolled between February 2019 and May 2022. Data were obtained through phone or video based parent interviews and medical record review.

RESULTS: Data were collected from 73 patients (59% male) from 57 unrelated families living in 16 different countries. The median age of participants at …

Machine Learning And Health Care: Potential Benefits And Issues, J Graham Atkinson, Elizabeth G Atkinson

Faculty, Staff and Students Publications

We discuss the potential for machine learning (ML) and artificial intelligence (AI) to improve health care, while detailing caveats and important considerations to ensure unbiased and equitable implementation. If disparities exist in the data used to train ML algorithms, they must be recognized and accounted for, so they do not bias performance accuracy or are not interpreted by the algorithm as simply a lack of need. We pay particular attention to an area in which bias in data composition is particularly striking, that is in large-scale genetics databases, as people of European descent are vastly overrepresented in the existing resources.