Genetic Phenomena Commons^™

Methylation Of Nonessential Genes In Cutaneous Melanoma – Rule Out Hypothesis, Ivan P Gorlov, Kathleen Conway, Sharon N Edmiston, Eloise A Parrish, Honglin Hao, Christopher I Amos, Spiridon Tsavachidis, Olga Y Gorlova, Colin Begg, Eva Hernando, Chao Cheng, Ronglai Shen, Irene Orlow, Li Luo, Marc S Ernstoff, Pei Fen Kuan, David W Ollila, Yihsuan S Tsai, Marianne Berwick, Nancy E Thomas

Faculty, Staff and Students Publications

Differential methylation plays an important role in melanoma development and is associated with survival, progression and response to treatment. However, the mechanisms by which methylation promotes melanoma development are poorly understood. The traditional explanation of selective advantage provided by differential methylation postulates that hypermethylation of regulatory 5'-cytosine-phosphate-guanine-3' dinucleotides (CpGs) downregulates the expression of tumor suppressor genes and therefore promotes tumorigenesis. We believe that other (not necessarily alternative) explanations of the selective advantages of methylation are also possible. Here, we hypothesize that melanoma cells use methylation to shut down transcription of nonessential genes - those not required for cell survival and …

Evaluation Of An Automated Genome Interpretation Model For Rare Disease Routinely Used In A Clinical Genetic Laboratory, Linyan Meng, Ruben Attali, Tomer Talmy, Yakir Regev, Niv Mizrahi, Pola Smirin-Yosef, Liesbeth Vossaert, Christian Taborda, Michael Santana, Ido Machol, Rui Xiao, Hongzheng Dai, Christine Eng, Fan Xia, Shay Tzur

Faculty, Staff and Students Publications

Purpose: The analysis of exome and genome sequencing data for the diagnosis of rare diseases is challenging and time-consuming. In this study, we evaluated an artificial intelligence model, based on machine learning for automating variant prioritization for diagnosing rare genetic diseases in the Baylor Genetics clinical laboratory.

Methods: The automated analysis model was developed using a supervised learning approach based on thousands of manually curated variants. The model was evaluated on 2 cohorts. The model accuracy was determined using a retrospective cohort comprising 180 randomly selected exome cases (57 singletons, 123 trios); all of which were previously diagnosed and solved …

Genome-Wide Association Study Of Lung Adenocarcinoma In East Asia And Comparison With A European Population, Jianxin Shi, Kouya Shiraishi, Jiyeon Choi, Keitaro Matsuo, Tzu-Yu Chen, Juncheng Dai, Rayjean J Hung, Kexin Chen, Xiao-Ou Shu, Young Tae Kim, Maria Teresa Landi, Dongxin Lin, Wei Zheng, Zhihua Yin, Baosen Zhou, Bao Song, Jiucun Wang, Wei Jie Seow, Lei Song, I-Shou Chang, Wei Hu, Li-Hsin Chien, Qiuyin Cai, Yun-Chul Hong, Hee Nam Kim, Yi-Long Wu, Maria Pik Wong, Brian Douglas Richardson, Karen M Funderburk, Shilan Li, Tongwu Zhang, Charles Breeze, Zhaoming Wang, Batel Blechter, Bryan A Bassig, Jin Hee Kim, Demetrius Albanes, Jason Y Y Wong, Min-Ho Shin, Lap Ping Chung, Yang Yang, She-Juan An, Hong Zheng, Yasushi Yatabe, Xu-Chao Zhang, Young-Chul Kim, Neil E Caporaso, Jiang Chang, James Chung Man Ho, Michiaki Kubo, Yataro Daigo, Minsun Song, Yukihide Momozawa, Yoichiro Kamatani, Masashi Kobayashi, Kenichi Okubo, Takayuki Honda, Dean H Hosgood, Hideo Kunitoh, Harsh Patel, Shun-Ichi Watanabe, Yohei Miyagi, Haruhiko Nakayama, Shingo Matsumoto, Hidehito Horinouchi, Masahiro Tsuboi, Ryuji Hamamoto, Koichi Goto, Yuichiro Ohe, Atsushi Takahashi, Akiteru Goto, Yoshihiro Minamiya, Megumi Hara, Yuichiro Nishida, Kenji Takeuchi, Kenji Wakai, Koichi Matsuda, Yoshinori Murakami, Kimihiro Shimizu, Hiroyuki Suzuki, Motonobu Saito, Yoichi Ohtaki, Kazumi Tanaka, Tangchun Wu, Fusheng Wei, Hongji Dai, Mitchell J Machiela, Jian Su, Yeul Hong Kim, In-Jae Oh, Victor Ho Fun Lee, Gee-Chen Chang, Ying-Huang Tsai, Kuan-Yu Chen, Ming-Shyan Huang, Wu-Chou Su, Yuh-Min Chen, Adeline Seow, Jae Yong Park, Sun-Seog Kweon, Kun-Chieh Chen, Yu-Tang Gao, Biyun Qian, Chen Wu, Daru Lu, Jianjun Liu, Ann G Schwartz, Richard Houlston, Margaret R Spitz, Ivan P Gorlov, Xifeng Wu, Ping Yang, Stephen Lam, Adonina Tardon, Chu Chen, Stig E Bojesen, Mattias Johansson, Angela Risch, Heike Bickeböller, Bu-Tian Ji, H-Erich Wichmann, David C Christiani, Gadi Rennert, Susanne Arnold, Paul Brennan, James Mckay, John K Field, Sanjay S Shete, Loic Le Marchand, Geoffrey Liu, Angeline Andrew, Lambertus A Kiemeney, Shan Zienolddiny-Narui, Kjell Grankvist, Mikael Johansson, Angela Cox, Fiona Taylor, Jian-Min Yuan, Philip Lazarus, Matthew B Schabath, Melinda C Aldrich, Hyo-Sung Jeon, Shih Sheng Jiang, Jae Sook Sung, Chung-Hsing Chen, Chin-Fu Hsiao, Yoo Jin Jung, Huan Guo, Zhibin Hu, Laurie Burdett, Meredith Yeager, Amy Hutchinson, Belynda Hicks, Jia Liu, Bin Zhu, Sonja I Berndt, Wei Wu, Junwen Wang, Yuqing Li, Jin Eun Choi, Kyong Hwa Park, Sook Whan Sung, Li Liu, Chang Hyun Kang, Wen-Chang Wang, Jun Xu, Peng Guan, Wen Tan, Chong-Jen Yu, Gong Yang, Alan Dart Loon Sihoe, Ying Chen, Yi Young Choi, Jun Suk Kim, Ho-Il Yoon, In Kyu Park, Ping Xu, Qincheng He, Chih-Liang Wang, Hsiao-Han Hung, Roel C H Vermeulen, Iona Cheng, Junjie Wu, Wei-Yen Lim, Fang-Yu Tsai, John K C Chan, Jihua Li, Hongyan Chen, Hsien-Chih Lin, Li Jin, Jie Liu, Norie Sawada, Taiki Yamaji, Kathleen Wyatt, Shengchao A Li, Hongxia Ma, Meng Zhu, Zhehai Wang, Sensen Cheng, Xuelian Li, Yangwu Ren, Ann Chao, Motoki Iwasaki, Junjie Zhu, Gening Jiang, Ke Fei, Guoping Wu, Chih-Yi Chen, Chien-Jen Chen, Pan-Chyr Yang, Jinming Yu, Victoria L Stevens, Joseph F Fraumeni, Nilanjan Chatterjee, Olga Y Gorlova, Chao Agnes Hsiung, Christopher I Amos, Hongbing Shen, Stephen J Chanock, Nathaniel Rothman, Takashi Kohno, Qing Lan

Faculty, Staff and Student Publications

Lung adenocarcinoma is the most common type of lung cancer. Known risk variants explain only a small fraction of lung adenocarcinoma heritability. Here, we conducted a two-stage genome-wide association study of lung adenocarcinoma of East Asian ancestry (21,658 cases and 150,676 controls; 54.5% never-smokers) and identified 12 novel susceptibility variants, bringing the total number to 28 at 25 independent loci. Transcriptome-wide association analyses together with colocalization studies using a Taiwanese lung expression quantitative trait loci dataset (n = 115) identified novel candidate genes, including FADS1 at 11q12 and ELF5 at 11p13. In a multi-ancestry meta-analysis of East Asian and European …

Srsf1 Haploinsufficiency Is Responsible For A Syndromic Developmental Disorder Associated With Intellectual Disability, Elke Bogaert, Aurore Garde, Thierry Gautier, Kathleen Rooney, Yannis Duffourd, Pontus Leblanc, Emma Van Reempts, Frederic Tran Mau-Them, Ingrid M Wentzensen, Kit Sing Au, Kate Richardson, Hope Northrup, Vincent Gatinois, David Geneviève, Raymond J Louie, Michael J Lyons, Lone Walentin Laulund, Charlotte Brasch-Andersen, Trine Maxel Juul, Fatima El It, Nathalie Marle, Patrick Callier, Raissa Relator, Sadegheh Haghshenas, Haley Mcconkey, Jennifer Kerkhof, Claudia Cesario, Antonio Novelli, Nicola Brunetti-Pierri, Michele Pinelli, Perrine Pennamen, Sophie Naudion, Marine Legendre, Cécile Courdier, Aurelien Trimouille, Martine Doco Fenzy, Lynn Pais, Alison Yeung, Kimberly Nugent, Elizabeth R Roeder, Tadahiro Mitani, Jennifer E Posey, Daniel Calame, Hagith Yonath, Jill A Rosenfeld, Luciana Musante, Flavio Faletra, Francesca Montanari, Giovanna Sartor, Alessandra Vancini, Marco Seri, Claude Besmond, Karine Poirier, Laurence Hubert, Dimitri Hemelsoet, Arnold Munnich, James R Lupski, Christophe Philippe, Christel Thauvin-Robinet, Laurence Faivre, Bekim Sadikovic, Jérôme Govin, Bart Dermaut, Antonio Vitobello

Faculty, Staff and Students Publications

SRSF1 (also known as ASF/SF2) is a non-small nuclear ribonucleoprotein (non-snRNP) that belongs to the arginine/serine (R/S) domain family. It recognizes and binds to mRNA, regulating both constitutive and alternative splicing. The complete loss of this proto-oncogene in mice is embryonically lethal. Through international data sharing, we identified 17 individuals (10 females and 7 males) with a neurodevelopmental disorder (NDD) with heterozygous germline SRSF1 variants, mostly de novo, including three frameshift variants, three nonsense variants, seven missense variants, and two microdeletions within region 17q22 encompassing SRSF1. Only in one family, the de novo origin could not be established. All individuals …

Pediatric Symptom Checklist-17: Factor Structure And Uniform Differential Item Functioning Across Gender And Age In Hiv Orphans And Vulnerable Children In Zambia, Nan Li, Mei Tan, Philip E Thuma, Elena L Grigorenko

Faculty, Staff and Students Publications

This study aimed to investigate the psychometric properties of the Pediatric Symptom Checklist-17 (PSC-17) in a sample of children orphaned or made vulnerable (OVC) by HIV in Zambia. Caregivers of 1,076 OVC (55.1% boys; M_age = 12.91 years) completed the PSC-17. Competing models, including confirmatory factor analysis (CFA), hierarchical CFA, bifactor CFA, exploratory structural equation modeling (ESEM), and bifactor ESEM, were tested to evaluate the optimal factor structure of the PSC-17. Results showed that the bifactor ESEM provided the best approximation of the PSC-17 data with a well-defined general psychosocial problems factor explaining 72% of the reliable variance in …

N-Terminal Egfp-Tagging Of Rabbit Apolipoprotein A-I Decreases Expression And Impairs Cholesterol-Efflux Activity, Bradley K Wacker, Lianxiang Bi, Li Liu, Mary G Sorci-Thomas, Philip Ng, Donna J Palmer, Chongren Tang, David A Dichek

Faculty, Staff and Students Publications

No abstract provided.

The Genetic Determinants Of Recurrent Somatic Mutations In 43,693 Blood Genomes, Joshua S. Weinstock, Cecelia A. Laurie, Jai G. Broome, Kent D. Taylor, Xiuqing Guo, Alan R. Shuldiner, Jeffrey R. O'Connell, Ravi Duggirala, Joanne E. Curran, John Blangero

School of Medicine Publications

Nononcogenic somatic mutations are thought to be uncommon and inconsequential. To test this, we analyzed 43,693 National Heart, Lung and Blood Institute Trans-Omics for Precision Medicine blood whole genomes from 37 cohorts and identified 7131 non-missense somatic mutations that are recurrently mutated in at least 50 individuals. These recurrent non-missense somatic mutations (RNMSMs) are not clearly explained by other clonal phenomena such as clonal hematopoiesis. RNMSM prevalence increased with age, with an average 50-year-old having 27 RNMSMs. Inherited germline variation associated with RNMSM acquisition. These variants were found in genes involved in adaptive immune function, proinflammatory cytokine production, and lymphoid …

Genetic Epidemiology Highlights The Role Of Aortic Strain And Distensibility In Cardiovascular Disease, John W Belmont

Faculty, Staff and Students Publications

No abstract provided.

Language: Its Origin And Ongoing Evolution, Ilia Markov, Kseniia Kharitonova, Elena L Grigorenko

Faculty, Staff and Students Publications

With the present paper, we sought to use research findings to illustrate the following thesis: the evolution of language follows the principles of human evolution. We argued that language does not exist for its own sake, it is one of a multitude of skills that developed to achieve a shared communicative goal, and all its features are reflective of this. Ongoing emerging language adaptations strive to better fit the present state of the human species. Theories of language have evolved from a single-modality to multimodal, from human-specific to usage-based and goal-driven. We proposed that language should be viewed as a …

Defects In Lipid Homeostasis Reflect The Function Of Tango2 In Phospholipid And Neutral Lipid Metabolism, Agustin Leonardo Lujan, Ombretta Foresti, Conor Sugden, Nathalie Brouwers, Alex Mateo Farre, Alessio Vignoli, Mahshid Azamian, Alicia Turner, Jose Wojnacki, Vivek Malhotra

Faculty, Staff and Students Publications

We show that TANGO2 in mammalian cells localizes predominantly to mitochondria and partially at mitochondria sites juxtaposed to lipid droplets (LDs) and the endoplasmic reticulum. HepG2 cells and fibroblasts of patients lacking TANGO2 exhibit enlarged LDs. Quantitative lipidomics revealed a marked increase in lysophosphatidic acid (LPA) and a concomitant decrease in its biosynthetic precursor phosphatidic acid (PA). These changes were exacerbated in nutrient-starved cells. Based on our data, we suggest that TANGO2 function is linked to acyl-CoA metabolism, which is necessary for the acylation of LPA to generate PA. The defect in acyl-CoA availability impacts the metabolism of many other …

B-Complex Vitamins For Patients With Tango2-Deficiency Disorder, Sarah E Sandkuhler, Lilei Zhang, Joshua K Meisner, Lina Ghaloul-Gonzalez, Cheyenne M Beach, David Harris, Pascale De Lonlay, Seema R Lalani, Christina Y Miyake, Samuel J Mackenzie

Faculty, Staff and Students Publications

No abstract provided.

Access To Clinically Indicated Genetic Tests For Pediatric Patients With Medicaid: Evidence From Outpatient Genetics Clinics In Texas, Haley Streff, Crescenda L Uhles, Heather Fisher, Rachel Franciskovich, Rebecca O Littlejohn, Amanda Gerard, Julianna Hudnall, Hadley Stevens Smith

Faculty, Staff and Students Publications

Purpose: Little is known about how Medicaid coverage policies affect access to genetic tests for pediatric patients. Building upon and extending a previous analysis of prior authorization requests (PARs), we describe expected coverage of genetic tests submitted to Texas Medicaid and the PAR and diagnostic outcomes of those tests.

Methods: We retrospectively reviewed genetic tests ordered at 3 pediatric outpatient genetics clinics in Texas. We compared Current Procedural Terminology (CPT) codes with the Texas Medicaid fee-for-service schedule (FFSS) to determine whether tests were expected to be covered by Medicaid. We assessed completion and diagnostic yield of commonly ordered tests.

Results: …

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 …

Does The Potocki-Lupski Syndrome Convey The Autism Spectrum Disorder Phenotype? Case Report And Scoping Review, Oksana I Talantseva, Galina V Portnova, Raisa S Romanova, Daria A Martynova, Olga V Sysoeva, Elena L Grigorenko

Faculty, Staff and Students Publications

Potocki-Lupski Syndrome (PTLS) is a rare condition associated with a duplication of 17p11.2 that may underlie a wide range of congenital abnormalities and heterogeneous behavioral phenotypes. Along with developmental delay and intellectual disability, autism-specific traits are often reported to be the most common among patients with PTLS. To contribute to the discussion of the role of autism spectrum disorder (ASD) in the PTLS phenotype, we present a case of a female adolescent with a de novo dup(17) (p11.2p11.2) without ASD features, focusing on in-depth clinical, behavioral, and electrophysiological (EEG) evaluations. Among EEG features, we found the atypical peak-slow wave patterns …

Metabolic Individuality: Limitations, Challenges, And Potential For Clinical Utility, Sarah H Elsea, Jennifer E Posey

Faculty, Staff and Students Publications

In Nature Medicine, Surendran and colleagues recently reported the analysis of human plasma metabolomic data for 913 metabolites in ∼20,000 individuals, identifying 2,599 metabolite-genetic variant associations and >400 metabolite signatures comprised of jointly regulated metabolites. This extensive atlas of variant-metabolite relationships reveals novel genomic mechanisms driving metabolic phenotypes.

Solid Organ Transplantation In Methylmalonic Acidemia And Propionic Acidemia: A Points To Consider Statement Of The American College Of Medical Genetics And Genomics (Acmg), Kuntal Sen, Lindsay C Burrage, Kimberly A Chapman, Ilona Ginevic, George V Mazariegos, Brett H Graham, Acmg Therapeutics Committe

Faculty, Staff and Students Publications

No abstract provided.

Biallelic Variants In Ogdh Encoding Oxoglutarate Dehydrogenase Lead To A Neurodevelopmental Disorder Characterized By Global Developmental Delay, Movement Disorder, And Metabolic Abnormalities, Ella F Whittle, Madison Chilian, Ehsan Ghayoor Karimiani, Helga Progri, Daniela Buhas, Melis Kose, Rebecca D Ganetzky, Mehran Beiraghi Toosi, Paria Najarzadeh Torbati, Reza Shervin Badv, Ivan Shelihan, Hui Yang, Houda Zghal Elloumi, Sukyeong Lee, Yalda Jamshidi, Alan M Pittman, Henry Houlden, Erika Ignatius, Shamima Rahman, Reza Maroofian, Wan Hee Yoon, Christopher J Carroll

Faculty, Staff and Students Publications

PURPOSE: This study aimed to establish the genetic cause of a novel autosomal recessive neurodevelopmental disorder characterized by global developmental delay, movement disorder, and metabolic abnormalities.

METHODS: We performed a detailed clinical characterization of 4 unrelated individuals from consanguineous families with a neurodevelopmental disorder. We used exome sequencing or targeted-exome sequencing, cosegregation, in silico protein modeling, and functional analyses of variants in HEK293 cells and Drosophila melanogaster, as well as in proband-derived fibroblast cells.

RESULTS: In the 4 individuals, we identified 3 novel homozygous variants in oxoglutarate dehydrogenase (OGDH) (NM_002541.3), which encodes a subunit of the tricarboxylic acid cycle enzyme …

Biallelic Variants In Hect E3 Paralogs, Hectd4 And Ube3c, Encoding Ubiquitin Ligases Cause Neurodevelopmental Disorders That Overlap With Angelman Syndrome, Eissa A Faqeih, Malak Ali Alghamdi, Marwa A Almahroos, Essa Alharby, Makki Almuntashri, Amnah M Alshangiti, Prouteau Clément, Daniel G Calame, Leila Qebibo, Lydie Burglen, Martine Doco-Fenzy, Mario Mastrangelo, Annalaura Torella, Filippo Manti, Vincenzo Nigro, Ziegler Alban, Ghadeer Saleh Alharbi, Jamil Amjad Hashmi, Rawya Alraddadi, Razan Alamri, Tadahiro Mitani, Barth Magalie, Zeynep Coban-Akdemir, Bilgen Bilge Geckinli, Davut Pehlivan, Antonio Romito, Vasiliki Karageorgou, Javier Martini, Estelle Colin, Dominique Bonneau, Aida Bertoli-Avella, James R Lupski, Annalisa Pastore, Roy W A Peake, Ashraf Dallol, Majid Alfadhel, Naif A M Almontashiri

Faculty, Staff and Students Publications

Purpose: Pathogenic variants in genes encoding ubiquitin E3 ligases are known to cause neurodevelopmental syndromes. Additional neurodevelopmental disorders associated with the other genes encoding E3 ligases are yet to be identified.

Methods: Chromosomal analysis and exome sequencing were used to identify the genetic causes in 10 patients from 7 unrelated families with syndromic neurodevelopmental, seizure, and movement disorders and neurobehavioral phenotypes.

Results: In total, 4 patients were found to have 3 different homozygous loss-of-function (LoF) variants, and 3 patients had 4 compound heterozygous missense variants in the candidate E3 ligase gene, HECTD4, that were rare, absent from controls as homozygous, …

Exploring Genetic And Neural Risk Of Specific Reading Disability Within A Nuclear Twin Family Case Study: A Translational Clinical Application, Tina Thomas, Griffin Litwin, David J Francis, Elena L Grigorenko

Faculty, Staff and Students Publications

Imaging and genetic studies have characterized biological risk factors contributing to specific reading disability (SRD). The current study aimed to apply this literature to a family of twins discordant for SRD and an older sibling with reading difficulty. Intraclass correlations were used to understand the similarity of imaging phenotypes between pairs. Reading-related genes and brain region phenotypes, including asymmetry indices representing the relative size of left compared to right hemispheric structures, were descriptively examined. SNPs that corresponded between the SRD siblings and not the typically developing (TD) siblings were in genes ZNF385D, LPHN3, CNTNAP2, FGF18, NOP9 …

Brain Monoamine Vesicular Transport Disease Caused By Homozygous Slc18a2 Variants: A Study In 42 Affected Individuals, Ken Saida, Reza Maroofian, Toru Sengoku, Tadahiro Mitani, Alistair T Pagnamenta, Dana Marafi, Maha S Zaki, Thomas J O'Brien, Ehsan Ghayoor Karimiani, Rauan Kaiyrzhanov, Marina Takizawa, Sachiko Ohori, Huey Yin Leong, Gulsen Akay, Hamid Galehdari, Mina Zamani, Ratna Romy, Christopher J Carroll, Mehran Beiraghi Toosi, Farah Ashrafzadeh, Shima Imannezhad, Hadis Malek, Najmeh Ahangari, Hoda Tomoum, Vykuntaraju K Gowda, Varunvenkat M Srinivasan, David Murphy, Natalia Dominik, Hasnaa M Elbendary, Karima Rafat, Sanem Yilmaz, Seda Kanmaz, Mine Serin, Deepa Krishnakumar, Alice Gardham, Anna Maw, Tekki Sreenivasa Rao, Sarah Alsubhi, Myriam Srour, Daniela Buhas, Tamison Jewett, Rachel E Goldberg, Hanan Shamseldin, Eirik Frengen, Doriana Misceo, Petter Strømme, José Ricardo Magliocco Ceroni, Chong Ae Kim, Gozde Yesil, Esma Sengenc, Serhat Guler, Mariam Hull, Mered Parnes, Dilek Aktas, Banu Anlar, Yavuz Bayram, Davut Pehlivan, Jennifer E Posey, Shahryar Alavi, Seyed Ali Madani Manshadi, Hamad Alzaidan, Mohammad Al-Owain, Lama Alabdi, Ferdous Abdulwahab, Futoshi Sekiguchi, Kohei Hamanaka, Atsushi Fujita, Yuri Uchiyama, Takeshi Mizuguchi, Satoko Miyatake, Noriko Miyake, Reem M Elshafie, Kamran Salayev, Ulviyya Guliyeva, Fowzan S Alkuraya, Joseph G Gleeson, Kristin G Monaghan, Katherine G Langley, Hui Yang, Mahsa Motavaf, Saeid Safari, Mozhgan Alipour, Kazuhiro Ogata, André E X Brown, James R Lupski, Henry Houlden, Naomichi Matsumoto

Faculty, Staff and Students Publications

Purpose: Brain monoamine vesicular transport disease is an infantile-onset movement disorder that mimics cerebral palsy. In 2013, the homozygous SLC18A2 variant, p.Pro387Leu, was first reported as a cause of this rare disorder, and dopamine agonists were efficient for treating affected individuals from a single large family. To date, only 6 variants have been reported. In this study, we evaluated genotype-phenotype correlations in individuals with biallelic SLC18A2 variants.

Methods: A total of 42 affected individuals with homozygous SLC18A2 variant alleles were identified. We evaluated genotype-phenotype correlations and the missense variants in the affected individuals based on the structural modeling of rat …

Genetics In Medicine Open To Us All, Bo Yuan

Faculty, Staff and Students Publications

No abstract provided.

The Role Of Neural And Genetic Processes In Learning To Read And Specific Reading Disabilities: Implications For Instruction, Jessica A Church, Elena L Grigorenko, Jack M Fletcher

Faculty, Staff and Students Publications

To learn to read, the brain must repurpose neural systems for oral language and visual processing to mediate written language. We begin with a description of computational models for how alphabetic written language is processed. Next, we explain the roles of a dorsal sublexical system in the brain that relates print and speech, a ventral lexical system that develops the visual expertise for rapid orthographic processing at the word level, and the role of cognitive control networks that regulate attentional processes as children read. We then use studies of children, adult illiterates learning to read, and studies of poor readers …

Editorial: Insights In Neurogenomics: 2022, Aayushi Gandhi, Sarah H Elsea

Faculty, Staff and Students Publications

No abstract provided.

Editorial: Neurogenetic Disorders: From The Tests To The Clinic, Shanshan Mao, Chunyu Li, Bo Yuan, Lan Yu, Huifang Shang

Faculty, Staff and Students Publications

No abstract provided.

The Global Prevalence Of Autism Spectrum Disorder: A Three-Level Meta-Analysis, Oksana I Talantseva, Raisa S Romanova, Ekaterina M Shurdova, Tatiana A Dolgorukova, Polina S Sologub, Olga S Titova, Daria F Kleeva, Elena L Grigorenko

Faculty, Staff and Students Publications

Autism spectrum disorder (ASD) is one the most disabling developmental disorders, imposing an extremely high economic burden. Obtaining as accurate prevalence estimates as possible is crucial to guide governments in planning policies for identification and intervention for individuals with ASD and their relatives. The precision of prevalence estimates can be heightened by summative analyses of the data collected around the world. To that end, we conducted a three-level mixed-effects meta-analysis. A systematic search of the Web of Science, PubMed, EMBASE, and PsycINFO databases from 2000 up to 13 July 2020 was performed, and reference lists of previous reviews and existing …

Truvari: Refined Structural Variant Comparison Preserves Allelic Diversity, Adam C English, Vipin K Menon, Richard A Gibbs, Ginger A Metcalf, Fritz J Sedlazeck

Faculty, Staff and Students Publications

The fundamental challenge of multi-sample structural variant (SV) analysis such as merging and benchmarking is identifying when two SVs are the same. Common approaches for comparing SVs were developed alongside technologies which produce ill-defined boundaries. As SV detection becomes more exact, algorithms to preserve this refined signal are needed. Here, we present Truvari-an SV comparison, annotation, and analysis toolkit-and demonstrate the effect of SV comparison choices by building population-level VCFs from 36 haplotype-resolved long-read assemblies. We observe over-merging from other SV merging approaches which cause up to a 2.2× inflation of allele frequency, relative to Truvari.

Deciphering The Mechanism And Function Of Hsp100 Unfoldases From Protein Structure, Grace Lee, Rebecca S Kim, Sang Bum Lee, Sukyeong Lee, Francis T F Tsai

Faculty, Staff and Students Publications

Hsp100 chaperones, also known as Clp proteins, constitute a family of ring-forming ATPases that differ in 3D structure and cellular function from other stress-inducible molecular chaperones. While the vast majority of ATP-dependent molecular chaperones promote the folding of either the nascent chain or a newly imported polypeptide to reach its native conformation, Hsp100 chaperones harness metabolic energy to perform the reverse and facilitate the unfolding of a misfolded polypeptide or protein aggregate. It is now known that inside cells and organelles, different Hsp100 members are involved in rescuing stress-damaged proteins from a previously aggregated state or in recycling polypeptides marked …

Mechanisms Of Irf2bpl-Related Disorders And Identification Of A Potential Therapeutic Strategy, Shrestha Sinha Ray, Debdeep Dutta, Cassandra Dennys, Samantha Powers, Florence Roussel, Pawel Lisowski, Petar Glažar, Xiaojin Zhang, Pipasha Biswas, Joseph R Caporale, Nikolaus Rajewsky, Marc Bickle, Nicolas Wein, Hugo J Bellen, Shibi Likhite, Paul C Marcogliese, Kathrin C Meyer

Faculty, Staff and Students Publications

The recently discovered neurological disorder NEDAMSS is caused by heterozygous truncations in the transcriptional regulator IRF2BPL. Here, we reprogram patient skin fibroblasts to astrocytes and neurons to study mechanisms of this newly described disease. While full-length IRF2BPL primarily localizes to the nucleus, truncated patient variants sequester the wild-type protein to the cytoplasm and cause aggregation. Moreover, patient astrocytes fail to support neuronal survival in coculture and exhibit aberrant mitochondria and respiratory dysfunction. Treatment with the small molecule copper ATSM (CuATSM) rescues neuronal survival and restores mitochondrial function. Importantly, the in vitro findings are recapitulated in vivo, where co-expression of full-length …

Exome Sequencing Efficacy And Phenotypic Expansions Involving Esophageal Atresia/Tracheoesophageal Fistula Plus, Mary R Sy, Jaynee Chauhan, Katrina Prescott, Aliza Imam, Alison Kraus, Ana Beleza, Lee Salkeld, Saraswati Hosdurga, Michael Parker, Pradeep Vasudevan, Lily Islam, Himanshu Goel, Nicole Bain, Soo-Mi Park, Shehla Mohammed, Klaus Dieterich, Charles Coutton, Véronique Satre, Gaëlle Vieville, Alan Donaldson, Claire Beneteau, Jamal Ghoumid, Kris Van Den Bogaert, Anneleen Boogaerts, Elise Boudry, Clémence Vanlerberghe, Florence Petit, Laura Bernardini, Barbara Torres, Teresa Mattina, Diana Carli, Giorgia Mandrile, Michele Pinelli, Nicola Brunetti-Pierri, Katherine Neas, Rachel Beddow, Pernille M Tørring, Flavio Faletra, Beatrice Spedicati, Paolo Gasparini, Alessandro Mussa, Giovanni Battista Ferrero, Anne Lampe, Wayne Lam, Weimin Bi, Carlos A Bacino, Akela Kuwahara, Jeffrey O Bush, Xiaonan Zhao, Pamela N Luna, Chad A Shaw, Jill A Rosenfeld, Daryl A Scott

Faculty, Staff and Students Publications

Esophageal atresia/tracheoesophageal fistula (EA/TEF) is a life-threatening birth defect that often occurs with other major birth defects (EA/TEF+). Despite advances in genetic testing, a molecular diagnosis can only be made in a minority of EA/TEF+ cases. Here, we analyzed clinical exome sequencing data and data from the DECIPHER database to determine the efficacy of exome sequencing in cases of EA/TEF+ and to identify phenotypic expansions involving EA/TEF. Among 67 individuals with EA/TEF+ referred for clinical exome sequencing, a definitive or probable diagnosis was made in 11 cases for an efficacy rate of 16% (11/67). This efficacy rate is significantly lower …

Long Read Sequencing And Expression Studies Of Ahdc1 Deletions In Xia-Gibbs Syndrome Reveal A Novel Genetic Regulatory Mechanism, Varuna Chander, Medhat Mahmoud, Jianhong Hu, Zain Dardas, Christopher M Grochowski, Moez Dawood, Michael M Khayat, He Li, Shoudong Li, Shalini Jhangiani, Viktoriya Korchina, Hua Shen, George Weissenberger, Qingchang Meng, Marie-Claude Gingras, Donna M Muzny, Harsha Doddapaneni, Jennifer E Posey, James R Lupski, Aniko Sabo, David R Murdock, Fritz J Sedlazeck, Richard A Gibbs

Faculty, Staff and Students Publications

Xia-Gibbs syndrome (XGS; MIM# 615829) is a rare mendelian disorder characterized by Development Delay (DD), intellectual disability (ID), and hypotonia. Individuals with XGS typically harbor de novo protein-truncating mutations in the AT-Hook DNA binding motif containing 1 (AHDC1) gene, although some missense mutations can also cause XGS. Large de novo heterozygous deletions that encompass the AHDC1 gene have also been ascribed as diagnostic for the disorder, without substantial evidence to support their pathogenicity. We analyzed 19 individuals with large contiguous deletions involving AHDC1, along with other genes. One individual bore the smallest known contiguous AHDC1 deletion (∼350 Kb), encompassing eight …