Jenny Lord
BSc, MSc, PhD
School of Medicine and Population Health
Lecturer in Systems Biology
Full contact details
School of Medicine and Population Health
Room B27
Sheffield Institute for Translational Neuroscience (SITraN)
385a Glossop Road
Sheffield
S10 2HQ
- Profile
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During my PhD and first postdoctoral position I investigated the genetic basis of Alzheimer’s disease using next generation sequencing. I then moved to the Wellcome Sanger Institute, where my research focus was on rare disorders. I led analysis on two projects, investigating the genetic basis of prenatal structural anomalies (Prenatal Assessment of Genomes and Exomes, PAGE) and the prevalence and nature of splicing variants in the Deciphering Developmental Disorders (DDD) cohort. I then moved to The University of Southampton where I focussed on using genome sequencing and RNA-Seq to better understand the splicing process and its disruption in rare disorders.
In 2022 I moved to the University of Sheffield to start my own research group, using computational genetics approaches to investigate the genetic basis of human disorders, with a focus on splicing and non-coding mechanisms of disease.
Career timeline
2022 – Present: Lecturer in Systems Biology, University of Sheffield
2018 – 2022: Senior postdoctoral research fellow, Diana Baralle and Sarah Ennis’ Labs, University of Southampton
2015 – 2018: Postdoctoral research Fellow, Matt Hurles’ Lab, Wellcome Sanger Institute
2014 – 2015: Postdoctoral research associate, Carlos Cruchaga’s Lab, Washington University in St Louis
- Qualifications
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PhD Clinical Chemistry, University of Nottingham
MSc Molecular Diagnostics, University of Nottingham
BSc Human Genetics, University of Nottingham
- Research interests
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I am fascinated by the way the human genome works, and how disruptions to its normal function lead to disease. We are working at a time where generating huge quantities of data is relatively quick and cheap, but making sense of that data is a major challenge. My group uses large datasets (e.g. genome and transcriptome sequencing) to try to better understand how the genome functions in health and disease.
Splicing (removal of introns and joining together of exons in pre-mRNA processing) has been a long standing interest of mine. It is an exceedingly complex process with tight regulation required to make sure our genes are expressed in the right way, at the right place and time. It relies on the interactions of many different factors, and disruption of any of these can interfere with splicing and lead to disease. We aim to use large, mostly publicly available datasets, to get a better understanding of the splicing process, and understand the ways in which its disruption causes neurodevelopmental and neurodegenerative disorders.
The non-protein coding genome was once referred to as “junk DNA”. We now see that it holds many important functions that we are only just beginning to understand. As well as controlling the way protein coding genes are regulated, there are also many non-protein coding genes which themselves fulfil many crucial roles. We aim to use computational approaches and large datasets to improve understanding of how non-protein coding regions of the genome function, and how disruption to those functions leads to disease.
- Publications
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Journal articles
- Palindrome-mediated 16p13.3 triplications cause a recognizable neurodegenerative disorder with ataxia. The American Journal of Human Genetics, 113(1), 221-233. View this article in WRRO
- M6A-dependent RNA condensation underlies FUS autoregulation and can be harnessed for ALS therapy development. Science Advances, 11(30). View this article in WRRO
- Clinical and genetic characterization of a progressive RBL2 associated neurodevelopmental disorder. Brain, 148(4), 1194-1211. View this article in WRRO
- Molecular diagnoses and candidate gene identification in the congenital heart disease cohorts of the 100,000 genomes project. European Journal of Human Genetics, 33, 793-802. View this article in WRRO
- Predicting the impact of rare variants on RNA splicing in CAGI6. Human Genetics, 144(2-3), 243-251. View this article in WRRO
- Identification of diagnostic candidates in Mendelian disorders using an RNA sequencing-centric approach. Genome Medicine, 16. View this article in WRRO
- Non-coding variants are a rare cause of recessive developmental disorders in trans with coding variants. Genetics in Medicine, 26(12). View this article in WRRO
- De novo variants in the RNU4-2 snRNA cause a frequent neurodevelopmental syndrome. Nature, 632, 832-840. View this article in WRRO
- The impact of inversions across 33,924 families with rare disease from a national genome sequencing project. The American Journal of Human Genetics, 111(6), 1140-1164. View this article in WRRO
- Markers of adipose tissue fibrogenesis associate with clinically significant liver fibrosis and are unchanged by synbiotic treatment in patients with NAFLD. Metabolism, 151, 155759-155759.
- Blood gene expression predicts intensive care unit admission in hospitalised patients with COVID-19. Frontiers in Immunology, 13. View this article in WRRO
- Microtubule modification defects underlie cilium degeneration in cell models of retinitis pigmentosa associated with pre-mRNA splicing factor mutations. Frontiers in Genetics, 13. View this article in WRRO
- A systematic analysis of splicing variants identifies new diagnoses in the 100,000 Genomes Project. Genome Medicine, 14(1). View this article in WRRO
- Recommendations for clinical interpretation of variants found in non-coding regions of the genome. Genome Medicine, 14(1). View this article in WRRO
- Uncovering the burden of hidden ciliopathies in the 100 000 Genomes Project: a reverse phenotyping approach. Journal of Medical Genetics, 59, 1151-1164. View this article in WRRO
- CI-SpliceAI—Improving machine learning predictions of disease causing splicing variants using curated alternative splice sites. PLOS ONE, 17(6). View this article in WRRO
- Evaluating the immune response in treatment-naive hospitalised patients with influenza and COVID-19. Frontiers in Immunology, 13. View this article in WRRO
- Fetal central nervous system anomalies: When should we offer exome sequencing?. Prenatal Diagnosis, 42(6), 736-743.
- Molecular diagnoses in the congenital malformations caused by ciliopathies cohort of the 100,000 Genomes Project. Journal of Medical Genetics, 59(8), 737-747.
- Fetal hydrops and the Incremental yield of Next‐generation sequencing over standard prenatal Diagnostic testing (
FIND ) study: prospective cohort study and meta‐analysis. Ultrasound in Obstetrics & Gynecology, 58(4), 509-518.
- Whole genome sequencing in the diagnosis of primary ciliary dyskinesia. BMC Medical Genomics, 14(1).
- Early outcomes and complications following cardiac surgery in patients testing positive for coronavirus disease 2019: An international cohort study. The Journal of Thoracic and Cardiovascular Surgery, 162(2), e355-e372. View this article in WRRO
- Correction: Janus-faced EPHB4-associated disorders: novel pathogenic variants and unreported intrafamilial overlapping phenotypes. Genetics in Medicine, 23(7), 1376-1377.
- Janus-faced EPHB4-associated disorders: novel pathogenic variants and unreported intrafamilial overlapping phenotypes. Genetics in Medicine, 23(7), 1315-1324.
- A CRISPR and high-content imaging assay compliant with ACMG/AMP guidelines for clinical variant interpretation in ciliopathies. Human Genetics, 140(4), 593-607.
- Evidence for 28 genetic disorders discovered by combining healthcare and research data. Nature, 586(7831), 757-762. View this article in WRRO
- Blood RNA analysis can increase clinical diagnostic rate and resolve variants of uncertain significance. Genetics in Medicine, 22(6), 1005-1014. View this article in WRRO
- Correction: Blood RNA analysis can increase clinical diagnostic rate and resolve variants of uncertain significance.. Genet Med, 22(6), 1129.
- Splicing in the pathogenesis, diagnosis and treatment of ciliopathies. Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms, 1862(11-12), 194433-194433.
- Author Correction: Genetic meta-analysis of diagnosed Alzheimer’s disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing. Nature Genetics, 51(9), 1423-1424.
- Prenatal Exome Sequencing Analysis in Fetal Structural Anomalies Detected by Ultrasonography (PAGE): A Cohort Study. Obstetrical & Gynecological Survey, 74(7), 394-396.
- Genetic meta-analysis of diagnosed Alzheimer’s disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing. Nature Genetics, 51(3), 414-430.
- Prenatal exome sequencing analysis in fetal structural anomalies detected by ultrasonography (PAGE): a cohort study. The Lancet, 393(10173), 747-757.
- Pathogenicity and selective constraint on variation near splice sites. Genome Research, 29(2), 159-170.
- Molecular autopsy by trio exome sequencing (ES) and postmortem examination in fetuses and neonates with prenatally identified structural anomalies. Genetics in Medicine, 21(5), 1065-1073.
- Mendelian adult-onset leukodystrophy genes in Alzheimer's disease: critical influence of CSF1R and NOTCH3. Neurobiology of Aging, 66, 179.e17-179.e29.
- Making new genetic diagnoses with old data: iterative reanalysis and reporting from genome-wide data in 1,133 families with developmental disorders. Genetics in Medicine, 20(10), 1216-1223.
- Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease. Nature Genetics, 49(9), 1373-1384.
- ABCA7 p.G215S as potential protective factor for Alzheimer's disease. Neurobiology of Aging, 46, 235.e1-235.e9.
- A potential endophenotype for Alzheimer's disease: cerebrospinal fluid clusterin. Neurobiology of Aging, 37, 208.e1-208.e9.
- Discovery of four recessive developmental disorders using probabilistic genotype and phenotype matching among 4,125 families. Nature Genetics, 47(11), 1363-1369. View this article in WRRO
- The epigenetic landscape of Alzheimer's disease. Nature Neuroscience, 17(9), 1138-1140.
- Investigating the role of rare coding variability in Mendelian dementia genes ( APP , PSEN1 , PSEN2 , GRN , MAPT , and PRNP ) in late-onset Alzheimer's disease. Neurobiology of Aging, 35(12), 2881.e1-2881.e6.
- Exome sequencing identifies 2 novel presenilin 1 mutations (p.L166V and p.S230R) in British early-onset Alzheimer's disease. Neurobiology of Aging, 35(10), 2422.e13-2422.e16.
- Missense variant in TREML2 protects against Alzheimer's disease. Neurobiology of Aging, 35(6), 1510.e19-1510.e26.
- Rare coding variants in the phospholipase D3 gene confer risk for Alzheimer’s disease. Nature, 505(7484), 550-554.
- Next generation sequencing of CLU, PICALM and CR1: pitfalls and potential solutions.. Int J Mol Epidemiol Genet, 3(4), 262-275.
- Systematic identification of disease-causing promoter and untranslated region variants in 8040 undiagnosed individuals with rare disease. Genome Medicine, 17(1).
- Comparison of in silico strategies to prioritize rare genomic variants impacting RNA splicing for the diagnosis of genomic disorders. Scientific Reports, 11(1).
- Splicing in the Diagnosis of Rare Disease: Advances and Challenges. Frontiers in Genetics, 12.
- Caspase-8, association with Alzheimer’s Disease and functional analysis of rare variants. PLOS ONE, 12(10), e0185777-e0185777.
- Influence of Coding Variability in APP-Aβ Metabolism Genes in Sporadic Alzheimer’s Disease. PLOS ONE, 11(6), e0150079-e0150079.
- Genetic studies of plasma analytes identify novel potential biomarkers for several complex traits. Scientific Reports, 6(1).
- Identification of rare variants in Alzheimer’s disease. Frontiers in Genetics, 5.
Conference proceedings
- De novo variants in the non-coding spliceosomal snRNA gene RNU4-2 are a frequent cause of syndromic neurodevelopmental disorders. EUROPEAN JOURNAL OF HUMAN GENETICS, Vol. 32 (pp 854-854)
- Analysis of RNAseq from over 5000 individuals in the 100,000 Genomes Project identifies new potential diagnoses for patients with rare disease. EUROPEAN JOURNAL OF HUMAN GENETICS, Vol. 32 (pp 847-847)
- RNA-seq identifies diagnostically relevant splicing abnormalities in patients without candidate variants. EUROPEAN JOURNAL OF HUMAN GENETICS, Vol. 32 (pp 616-617)
- Analysis of RNAseq from 4400 individuals in the 100,000 Genomes Project identifies new potential diagnoses. EUROPEAN JOURNAL OF HUMAN GENETICS, Vol. 32 (pp 3-4)
- Assessment of variants of unknown significance using RNA sequencing to improve diagnostic yield. EUROPEAN JOURNAL OF HUMAN GENETICS, Vol. 32 (pp 634-634)
- Recommendations for clinical interpretation of variants in non-coding regions of the genome. EUROPEAN JOURNAL OF HUMAN GENETICS, Vol. 31 (pp 284-285)
- Blood RNA-seq in diagnostic genomic medicine. EUROPEAN JOURNAL OF HUMAN GENETICS, Vol. 31 (pp 580-580)
- A systematic analysis of splicing variants identifies new diagnoses in the 100,000 Genomes Project. EUROPEAN JOURNAL OF HUMAN GENETICS, Vol. 31 (pp 58-58)
- Primary ciliary dyskinesia and non-CF bronchiectasis in the 100,000 Genomes Project. Paediatric respiratory epidemiology (pp 3503-3503)
- Exome sequencing of 406 parental/fetal trios with structural abnormalities revealed by ultrasound in the UK Prenatal Assessment of Genomes and Exomes (PAGE) project. EUROPEAN JOURNAL OF HUMAN GENETICS, Vol. 26 (pp 82-82)
Preprints
- Biallelic variants in
RNU2-2
cause a remarkably frequent developmental epileptic encephalopathy, openRxiv.
- FUS post-transcriptional splicing is autoregulated via RNA condensation with therapeutic potential for ALS-FUS, openRxiv.
- De novovariants in the non-coding spliceosomal snRNA geneRNU4-2are a frequent cause of syndromic neurodevelopmental disorders, Cold Spring Harbor Laboratory.
- Systematic identification of disease-causing promoter and untranslated region variants in 8,040 undiagnosed individuals with rare disease, openRxiv.
- RNA-sequencing first approach generates new diagnostic candidates in Mendelian disorders, openRxiv.
- Predicting the impact of rare variants on RNA splicing in CAGI6, openRxiv.
- Distinct immune responses in patients infected with influenza or SARS-CoV-2, and in COVID-19 survivors, characterised by transcriptomic and cellular abundance differences in blood, openRxiv.
- High-throughput
PRPF31
variant characterisation pipeline consistent with ACMG/AMP clinical variant interpretation guidelines, openRxiv.
- Pathogenicity and selective constraint on variation near splice sites, openRxiv.
- Palindrome-mediated 16p13.3 triplications cause a recognizable neurodegenerative disorder with ataxia. The American Journal of Human Genetics, 113(1), 221-233. View this article in WRRO
- Teaching activities
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I am the program lead for the MSc in Translational Neuroscience, and lead several modules across this course and the MSc in Advanced Cell and Gene Therapies.