Medical Genetics Commons^™

A Genomic Approach For Accurate Identification Of Closely Related Species With Next-Generation Sequencing Samples, Nour Al Dain Marzouka, Amira Al-Aamri, Fatima Alshamsi, Mariam Khalili, Sarah El Hajj Chehadeh, Meera S. Mohamed, Yassir Mohammed Eltahir, Rafeek Koliyan, Mohamed Moustafa Abdelhalim, Assem Attia, Mira Mousa, Guan Tay, Habiba Alsafar

Research outputs 2022 to 2026

Accurate species identification from Whole Genome Sequencing (WGS) data remains challenging, particularly for closely related species such as sheep (Ovis aries) and goats (Capra hircus). Through analysis of mapping quality metrics and Kraken2 taxonomic classification of 40 WGS sheep and goat samples, we demonstrate that conventional approaches yield ambiguous results, with overlapping alignment rates and inconclusive taxonomic assignments. We present a robust comparative genomic approach that uses species-specific genomic regions to distinguish these species in WGS samples. We define species-specific regions as those exhibiting distinctive coverage patterns: average coverage when samples are aligned to their matching reference genome but absent/low …

Mtorc2-Nav1.2 Signaling Drives Early Hyperexcitability In Alzheimer’S Disease Mouse Model, Nolan M Dvorak, Jeffrey L Noebels

Faculty, Staff and Students Publications

Hyperexcitability is a biomarker of early-stage Alzheimer’s Disease (AD) and hastens cognitive decline later in its course. Mechanistic target of rapamycin (mTOR) signaling contributes to the slope of this trajectory, as evidenced by early increased brain expression and the rescue of hyperexcitability by genetic deletion of mTOR complex 2 (mTORC2); however, a molecular mechanism directly linking mTOR signaling to membrane hyperexcitability in early-stage AD remains elusive. Here, we show that hyperactive mTOR signaling stimulates the voltage-gated Na+ channel 1.2 (Nav1.2), a previously identified downstream phosphorylation target of mTORC2 and a key regulator of membrane electrogenesis. Augmented Nav1.2 channel function induced …

In-Hospital Mortality Patterns And Readmissions In Patients With Chronic Obstructive Pulmonary Disease: An Analysis Of The Role Of Pulmonary Hypertension, Saad Afzal Khan, Trishna Parikh, Adishwar Rao, Akriti Agrawal, Aarohi Parikh, Farah Kazzaz, Sarah Shin, Harry Karmouty-Quintana, Maulin Patel, Kha Dinh, Bela Patel, Bindu Akkanti

Faculty, Staff and Student Publications

Chronic obstructive pulmonary disease (COPD) may be complicated by pulmonary hypertension (PH). We aimed to understand the impact of PH on in-hospital mortality and quantify the 30-day readmission rate among patients with COPD. For this cross-sectional study, we used the Nationwide Readmissions Database from 2017-2020 to identify adults ≥18 years with COPD. Patients were stratified according to PH diagnosis. Baseline characteristics between groups were compared using the Pearson chi-square test and two-sample t-test. Predictors of in-hospital mortality were determined using multivariate logistic regression analysis adjusted for demographics and confounders. The 30-day readmission rate and prevalence of PH subgroups by baseline …

Genetic Drivers Of Progression In Alzheimer’S Disease Are Distinct From Disease Risk, Celeste E. Cohen, Shane Fernandez, Umran Yaman, Ahmad R. Ehyaei, Eleftheria Kodosaki, Aydan Askarova, Tenielle Porter, Eleanor O’Brien, Paul Maruff, Alexi Nott, John A. Hardy, Simon M. Laws, Dervis A. Salih, Maryam Shoai

Research outputs 2022 to 2026

Background: Recent trials in Alzheimer’s disease (AD) demonstrate encouraging outcomes. These trials target risk mechanisms identified through genetic analysis whilst directly aiming to reduce progression rates. Evidence from other neurodegenerative diseases suggests the genetics of progression is distinct from risk of disease. To expand these initial successes and improve clinical outcomes further we need to understand genetics of progression of disease. These can be deduced through rigorous analysis of meticulously phenotyped longitudinal cohorts. In this study we first looked at known genetic drivers of risk, namely polygenic risk scores for AD and APOE‑ε4, to assess their role in progression. This …

De Novo Complex Genomic Rearrangement Spanning 2q31.1 In A Proband With Congenital Malformations: Genotype-Phenotype Correlation And Development Of A Cgr Detection Pipeline, Katherine Helle, Jesse D Bengtsson, Mira Gandhi, Christopher M Grochowski, Ming Yin Lun, Neha Sudhir, Shalini N Jhangiani, Fritz J Sedlazeck, Seema R Lalani, Neil A Hanchard, Claudia M B Carvalho

Faculty, Staff and Students Publications

The 2q31 region is commonly associated with pathogenic alleles of the HOXD cluster leading to various clinical phenotypes related to skeletal development. We present a proband with tetralogy of Fallot and multiple congenital anomalies. Genomic variant screening including an in-house CGR detection pipeline pairing genome sequencing (GS) structural variant calls with read-depth data revealed a de novo complex genomic rearrangement (CGR) spanning 2.7 Mb across 2q31 characterized by a series of duplications and triplications including the HOXD gene cluster. The genomic structure was assembled by applying combined methodologies including short-read and long-read GS, and optical genome mapping (OGM). This in-house …

The Association Between Apoe Genotype, Race, And Dementia: An Analysis Of 7 Population-Based Cohort Studies, Natalia Lakomski, Katherine Giorgio, John Stephen, Maxwell Mansolf, Aïcha Soumaré, Alden L Gross, Allison E Aiello, Archana Singh-Manoux, M Arfan Ikram, Catherine Helmer, Claudia L Satizabal, Deborah A Levine, Donald M Lloyd-Jones, Emily M Briceño, Farzaneh A Sorond, Frank J Wolters, Jayandra J Himali, Lenore J Launer, Djass Mbangdadji, David Li, Lihui Zhao, Oscar L Lopez, Stéphanie Debette, Sudha Seshadri, Suzanne E Judd, Timothy M Hughes, Vilmundur Guðnason, Michael Griswold, Paul S De Vries, Alison Fohner, Pamela L Lutsey, Rachel Zmora, Elizabeth A Peterson, Denise Scholtens, Norrina B Allen, Sanaz Sedaghat

Faculty, Staff and Student Publications

Background and objectives: The apolipoprotein E (APOE) haplotypes are known to be associated with dementia, with the ε4 haplotype associated with higher risk. It has been suggested that the APOE ε2 allele serves as a protective factor for dementia. However, data on the effects of the homozygous APOE ε2/ε2 genotype are limited, likely due to the rarity of the APOE ε2/ε2 genotype. Furthermore, the association between APOE genotypes and dementia may differ across self-reported race. We aim to investigate the association between APOE genotypes and dementia overall and across self-reported race, with a focus on the potential protective …

In Vivo Model Of Neurotropic Human Metapneumovirus Infection In Mice Brain, Joanna Yuen, Gage Greening, Eric S. Geanes, Dharitri Betha, Rebecca Mclennan Phd, Todd Bradley

Posters

No abstract provided.

Tau Pathology In Epilepsy: Emerging Mechanisms And Translational Opportunities, Arjune Sen, Xin You Tai, Aristea Galanopoulou, Maria Thom, Eleonora Aronica, Lucy Vivash, Martin Hardmeier, Action Amos, Stephan Rueegg, Matthias Koepp, Yaroslav Winter, Christoph Helmstaedter, Jeffrey L Noebels, Hilal A Lashuel, Terence J O'Brien

Faculty, Staff and Students Publications

The onset of epilepsy in adulthood occurs most commonly after 55 years of age. Given the ageing global population, this disorder represents an increasing burden on healthcare and society. The bidirectional link between epilepsy and dementia is a focus of intense research with underlying tau pathology highlighted as a potential mechanistic link. In this review, we examine the evidence for tau-related neurodegenerative processes in epilepsy beginning with how changes in biochemical and structural properties of the tau protein can lead to abnormal phosphorylation and pathological aggregation. We consider the role of tau in seizure occurrence and cognitive difficulties in experimental …

Single-Nucleotide Rna M6a Mapping In Bovine Preimplantation Development Reveals Site-Specific Regulation Of Rpl12 At Zygotic Genome Activation, Rajan Iyyappan, Yichi Niu, Yang Li, Hao Ming, Kinga Pajdzik, Noah R Rakestraw, Piyush K Jain, Chuan He, Chenghang Zong, Zongliang Jiang

Faculty, Staff and Students Publications

RNA N6-methyladenosine (m6A) is a key regulator of gene expression during early embryogenesis. Using SAC-seq (m6A-selective allyl chemical labeling and sequencing), an antibody-independent m6A profiling method, we generated the first single-nucleotide-resolution m6A map of bovine oocytes and preimplantation embryos. We observed both coordinated and uncoupled relationships between m6A modification and expression of protein-coding and noncoding genes. Integrative analysis of the transcriptome, m6A epitranscriptome, and translatome revealed dynamic m6A remodeling, particularly in ribosomal protein genes. Functional interrogation of a specific m6A site within the RPL12 transcript demonstrated that loss of this modification reduces protein synthesis, disrupts translation-related gene expression, impairs zygotic …

Genetics Of Cerebrotendinous Xanthomatosis, Jennifer Hanson, Penelope E Bonnen

Faculty, Staff and Students Publications

Cerebrotendinous xanthomatosis (CTX) is rare, autosomal recessive inborn error of metabolism caused by biallelic pathogenic variants in CYP27A1, which encodes sterile 27 hydroxylase, a key enzyme in bile acid biosynthesis. Enzyme deficiency results in reduced cholic and chenodeoxycholic acid synthesis with accumulation of cholestanol, bile acid intermediates, and bile alcohols, producing a progressive multisystem disorder characterized by chronic diarrhea, juvenile-onset cataracts, tendons xanthomas, and neurological dysfunction. Although CTX typically begins in childhood, diagnosis is frequently delayed until adulthood, limiting the benefit of effective disease modifying therapy with chenodeoxycholic acid. Since the identification of CYP27A1, more than 200 pathogenic variants have …

Evidence-Based Classification Of Genes Implicated In Skeletal Disorders Using The Clingen Curation Framework, Ryan F Webb, Hannah Mccurry, Amanda Girod, Madeline Hughes, Emma Wilcox, Mayher Patel, Eleanor C Broeren, Kezang C Tshering, Marina Distefano, Lorenzo D Botto, Lindsay C Burrage, Valérie Cormier-Daire, Juan Dong, Nadja Ehmke, Deborah Krakow, Shahida Moosa, Geert Mortier, Sandesh Nagamani, Loren Pena, Pedro A Sanchez-Lara, Andrea Superti-Furga, Sheila Unger, Danita Velasco, Matthew L Warman, Kerry Brown, Deepika D'Cunha Burkardt, Carlos R Ferreira

Faculty, Staff and Students Publications

More than 770 genetic skeletal disorders have been described, most with disease-causing variants reported in 1 of over 550 different genes. The ClinGen Skeletal Disorders Gene Curation Expert Panel was established to determine the strength of the evidence that supports specific gene-disease relationships (GDRs). Such information can assist clinical testing laboratories in choosing genes that should be included on diagnostic panels. Nine genes accounting for the most frequently encountered skeletal dysplasias (COL1A1, COL1A2, COL2A1, FGFR3, SLC26A2, TRPV4, COMP, ALPL, and SOX9) associated in the medical literature with 26 different skeletal disorders were reviewed using a semi-quantitative scoring framework. This framework …

Jak Inhibition In Pnpt1-Related Mitochondrial Interferonopathy: A Case Report And Review Of Mitochondrial-Immune Crosstalk, Dan Ross Brooks, Hyun Yong Koh, Taylor Martin Kerrins, Steven Lang, Emily Bland, Rui Yang, Sarah Kogan Nicholas, Stephanie Jean Sikkink, Stephen Kralik, Christine Eng, Chaya Nautiyal Murali, Seema Lalani, Pilar Lenglet Magoulas, Lisa Emrick, Kristen Sydney Fisher, Fernando Scaglia

Faculty, Staff and Students Publications

Biallelic pathogenic variants in PNPT1 cause combined oxidative phosphorylation deficiency 13 (COXPD13) (MIM #614932), linking mitochondrial dysfunction to type I interferon (IFN) activation through cytosolic leakage of mitochondrial double‐stranded RNA (mt‐dsRNA). This mechanism connects mitochondrial disease to interferonopathies such as Aicardi–Goutières syndrome (AGS). We describe a 7‐month‐old female infant with compound heterozygous PNPT1 variants presenting with severe hypotonia, feeding difficulties necessitating gastrostomy, dystonia, and elevated serum lactate. Brain magnetic resonance imaging (MRI) demonstrated marked cerebellar, brainstem, and basal ganglia atrophy, with a lactate peak on MR spectroscopy (consistent with an inverted doublet). Serum immune profiling revealed a mild but elevated …

Author Correction: Plasticity And Language In The Anaesthetized Human Hippocampus, Kalman A Katlowitz, Eric R Cole, Elizabeth A Mickiewicz, Shraddha Shah, Melissa Franch, Joshua A Adkinson, James L Belanger, Raissa K Mathura, Domokos Meszéna, Matthew Mcginley, William Muñoz, Garrett P Banks, Sydney S Cash, Chih-Wei Hsu, Angelique C Paulk, Nicole R Provenza, Andrew J Watrous, Ziv Williams, Alica M Goldman, Vaishnav Krishnan, Atul Maheshwari, Sarah R Heilbronner, Robert Kim, Nuttida Rungratsameetaweemana, Benjamin Y Hayden, Sameer A Sheth

Faculty, Staff and Students Publications

This corrects the article "Plasticity and language in the anaesthetized human hippocampus" in volume 654 on page 714.

Biphasic Sleep Is A Feature Of Sleep Disturbance In Syngap1-Rd, Aida Doucoure, Het Patel, Mark A Abboud, Alice Sperry, Sarah K Wanigatunga, Deana Crocetti, Heather Volk, Adam P Spira, Stewart H Mostofsky, Vaishnav Krishnan, Constance Smith-Hicks

Faculty, Staff and Students Publications

Study objectives: Sleep problems are common in children with SYNGAP1-Related Disorder (SYNGAP1-RD). The use of devices that objectively estimate sleep are complicated by co-occurring sensory disorders in this population. We examined the feasibility and validity of wrist actigraphy to examine sleep and rest-activity rhythms (RAR).

Methods: Data from five children with SYNGAP1-RD and 42 typically developing children were analyzed. All children were asked to wear the Actiwatch-2 for 14 continuous days and caregivers were asked to complete a sleep diary and the Children Sleep Health Questionnaire (CSHQ). Parametric (alpha, beta, acrophase, amplitude, up/down mesor, mesor), nonparametric (intradaily variability, interdaily stability, …

Tusc3 Serves As A Rate-Limiting Gatekeeper Of A Glycan-Mediated Er Triage Checkpoint For Bmp4/Dpp, Antonio Galeone, Emilio Solazzo, Francesco Lavezzari, Seung Yeop Han, Gaia Consonni, Bruna My, Riccardo Rizzo, Giuseppe Gigli, Hamed Jafar-Nejad, Thomas Vaccari

Faculty, Staff and Students Publications

Trimming of the three glucose residues decorating nascent N-glycoproteins is a critical step for their entry into the endoplasmic reticulum quality control (ERQC) and recognition by ER chaperones. However, the functional relevance of the second glucose (G2) and the regulatory step upstream of its removal by glucosidase II (GCS2) remain poorly understood. Here, we report that TUSC3, a component of the oligosaccharyltransferase (OST) complex, regulates G2 to G1 trimming on N-glycosylated bone morphogenetic protein 4 (BMP4) and its Drosophila homolog Dpp to promote their ERQC entry. Loss- and gain-of-function genetic experiments and biochemical assays in mammalian cells and flies indicate …

Mutation Screening For Confirming Suspected Spinal Muscular Atrophy Using Dried Blood Spotted On In-House Cellulose-Based Cards, Yogik Onky Silvana Wijaya, Farda Tsaqouva Ahza, Annisa Naufal Almaszahra, Mawaddah Ar Rochmah, Dian Kesumapramudya Nurputra

Makara Journal of Science

Early and accurate diagnosis for spinal muscular atrophy (SMA) has gained relevance in an era of emerging therapies to improve patient outcomes. While screening of dried blood spots (DBS) effectively detects deletion-type SMA, non-deletion cases are often missed. Mutation screening from DBS is needed to address this gap. Here, we aimed to evaluate the feasibility of an in-house, cellulose-based card for direct Sanger sequencing for variant hunting, avoiding DNA extraction and offering an alternative to commercial cards. As a proof of concept, sequences obtained from DBSs of 23 healthy individuals were compared with sequences derived from isolated genomic DNA (gDNA). …

The Effect Of Hunger On The Likelihood Of Glucose Excursions In Adults With Overweight Or Obesity: Continuous Glucose Monitoring And Ecological Momentary Assessment Observational Study, Byunggul Lim, Phrashiah Githinji, Yue Liao, Jacob Szeszulski, Alexandra L Macmillan Uribe, Rebecca A Seguin-Fowler, Jane Anderson, Chad D Rethorst

Faculty, Staff and Students Publications

Background: Maintaining stable glucose levels is important for metabolic health. Glucose excursions (GEs), which are marked increases in glucose following food intake, have been associated with a higher risk for cardiovascular disease and metabolic dysfunction. Individuals with overweight or obesity who do not have diabetes may still show impaired glucose regulation, as reflected in increased glucose variability. Hunger, as a real-time physiological cue, may be associated with subsequent glucose changes and represents a potential target for just-in-time adaptive interventions.

Objective: This study aimed to investigate the temporal relationship between self-reported hunger and subsequent glucose dynamics, including the likelihood of GE …

In Vivo Orf Overexpression Screening Identifies Ccn4 As A Regulator Of Glioblastoma Growth Validated Across Multiple Models, Pushan Dasgupta

Faculty, Staff and Students Publications

Despite current multimodal therapies for glioblastoma (GBM), its prognosis remains grim. Thus, a tremendous need exists to identify new genetic drivers that may serve as potential therapeutic targets in glioblastoma (GBM). We describe an in vivo overexpression screening strategy to identify drivers of glioblastoma where we have leveraged TCGA datasets to conduct a functional genomics screen of prioritized open reading frames (ORFs) that are overexpressed and/or amplified in GBM. To interrogate these potential drivers within a more relevant physiological context, the screening was accomplished in vivo in an orthotopic patient-derived glioma stem-like cell (GSC) model. Among 5 positive "hits" from …

Development And Preliminary Validation Of Orca-Pd, An Online Rapid Cognitive Assessment For Parkinson Disease: Mixed Methods Study, Avigail Lithwick Algon, Sarah Brisman, Chi-Ying R Lin, William Saban

Faculty, Staff and Students Publications

Background: Traditional in-person neuropsychological tests for Parkinson disease (PD) lack accessibility, scalability, and PD specificity. Mobility impairments hinder access to in-person assessments, and long waiting times for expert evaluation limit scalability. Common tools for cognitive screening, such as the Montreal Cognitive Assessment, are generic and not specific to PD.

Objective: The goal of this study was to address these challenges by leveraging the internet. This study aimed to develop a sensitive tool to detect cognitive impairments in early- to mid-stage PD in an accessible and scalable manner.

Methods: We developed the Online Rapid Cognitive Assessment for Parkinson's Disease (ORCA-PD), a …

Cytosine Base Editing Of Lpa In Transgenic Mice Averts Large Deletions, Marcel A Chuecos, So Hyun Park, Madhvi M Bhakta, Usosa Too-Chiobi, Daniel Betancourth, Mingming Cao, Marco De Giorgi, Christopher J Walkey, Anjana Tiwari, Biana Godin, Julia M Assini, Donna J Palmer, Philip Ng, Michael B Boffa, Marlys L Koschinsky, Gang Bao, William R Lagor

Faculty, Staff and Students Publications

Lipoprotein(a) (Lp(a)) is a genetically determined causal risk factor for cardiovascular disease, with approximately 20% of the population exhibiting elevated levels. While there are promising drugs in development, there are currently no approved therapies specifically designed to lower Lp(a) levels. For high-risk individuals with extreme levels of Lp(a), liver-directed genome editing could be an effective one-time solution. Genome editing approaches such as CRISPR and TALENs can reduce Lp(a) in LPA-transgenic mouse models, but they frequently induce large and potentially harmful genomic deletions. Here, we report the first application of TadA-derived cytosine base editing (CBE), delivered via helper-dependent adenovirus (HDAdV) and …