Molecular Genetics

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Research outputs from the Molecular Genetics department at the RD&E. The Molecular Genetics Laboratory is in the RILD Building at the RD&E and is co-located with University of Exeter Medical School researchers in genetics, genomics and epigenetics. For more information, please visit their website:


Recent Submissions

Now showing 1 - 5 of 194
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    Barriers and facilitators to clinical behaviour change by primary care practitioners: a theory-informed systematic review of reviews using the Theoretical Domains Framework and Behaviour Change Wheel
    (BioMed Central, 2022-08-30) Mather, M.; Pettigrew, L. M.; Navaratnam, S.
    BACKGROUND: Understanding the barriers and facilitators to behaviour change by primary care practitioners (PCPs) is vital to inform the design and implementation of successful Behaviour Change Interventions (BCIs), embed evidence-based medicine into routine clinical practice, and improve quality of care and population health outcomes. METHODS: A theory-led systematic review of reviews examining barriers and facilitators to clinical behaviour change by PCPs in high-income primary care contexts using PRISMA. Embase, MEDLINE, PsychInfo, HMIC and Cochrane Library were searched. Content and framework analysis was used to map reported barriers and facilitators to the Theoretical Domains Framework (TDF) and describe emergent themes. Intervention functions and policy categories to change behaviour associated with these domains were identified using the COM-B Model and Behaviour Change Wheel (BCW). RESULTS: Four thousand three hundred eighty-eight reviews were identified. Nineteen were included. The average quality score was 7.5/11. Reviews infrequently used theory to structure their methods or interpret their findings. Barriers and facilitators most frequently identified as important were principally related to 'Knowledge', 'Environmental context and resources' and 'Social influences' TDF domains. These fall under the 'Capability' and 'Opportunity' domains of COM-B, and are linked with interventions related to education, training, restriction, environmental restructuring and enablement. From this, three key areas for policy change include guidelines, regulation and legislation. Factors least frequently identified as important were related to 'Motivation' and other psychological aspects of 'Capability' of COM-B. Based on this, BCW intervention functions of persuasion, incentivisation, coercion and modelling may be perceived as less relevant by PCPs to change behaviour. CONCLUSIONS: PCPs commonly perceive barriers and facilitators to behaviour change related to the 'Capability' and 'Opportunity' domains of COM-B. PCPs may lack insight into the role that 'Motivation' and aspects of psychological 'Capability' have in behaviour change and/or that research methods have been inadequate to capture their function. Future research should apply theory-based frameworks and appropriate design methods to explore these factors. With no 'one size fits all' intervention, these findings provide general, transferable insights into how to approach changing clinical behaviour by PCPs, based on their own views on the barriers and facilitators to behaviour change. SYSTEMATIC REVIEW REGISTRATION: A protocol was submitted to the London School of Hygiene and Tropical Medicine via the Ethics and CARE form submission on 16.4.2020, ref number 21478 (available on request). The project was not registered on PROSPERO.
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    Fetal alleles predisposing to metabolically favourable adiposity are associated with higher birth weight
    (Oxford University Press, 2021-12-13) Thompson, W. D.; Beaumont, R. N.; Kuang, A.; Warrington, N. M.; Ji, Y.; Tyrrell, J.; Wood, A. R.; Scholtens, D.; Knight, B. A.; Evans, D. M.; Lowe, B. L.; Santorelli, G.; Azad, R.; Mason, D.; Hattersley, A. T.; Frayling, T. M.; Yaghootkar, H.; Borges, M. C.; Lawlor, D. A.; Freathy, R. M.
    BACKGROUND: Higher birthweight is associated with higher adult BMI. Alleles that predispose to greater adult adiposity might act in fetal life to increase fetal growth and birthweight. Whether there are fetal effects of recently identified adult metabolically favourable adiposity alleles on birthweight is unknown. Aim We aimed to test the effect on birthweight of fetal genetic predisposition to higher metabolically favourable adult adiposity and compare that with the effect of fetal genetic predisposition to higher adult BMI. METHODS: We used published GWAS data (n = upto 406 063) to estimate fetal effects on birthweight (adjusting for maternal genotype) of alleles known to raise metabolically favourable adult adiposity or BMI. We combined summary data across SNPs with random effects meta-analyses. We performed weighted linear regression of SNP-birthweight effects against SNP-adult adiposity effects to test for a dose-dependent association. RESULTS: Fetal genetic predisposition to higher metabolically favourable adult adiposity and higher adult BMI were both associated with higher birthweight (3grams per effect allele (95%CI, 1 to 5) averaged over 14 SNPs; p = 0.002; 0.5grams per effect allele (95%CI, 0 to 1) averaged over 76 SNPs; p = 0.042, respectively). SNPs with greater effects on metabolically favourable adiposity tended to have greater effects on birthweight (R2 = 0.2912, p = 0.027). There was no dose-dependent association for BMI (R2 = -0.0019, p = 0.602). CONCLUSIONS: Fetal genetic predisposition to both higher adult metabolically favourable adiposity and BMI is associated with birthweight. Fetal effects of metabolically favourable adiposity-raising alleles on birthweight are modestly proportional to their effects on future adiposity, but those of BMI-raising alleles are not.
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    Non-coding region variants upstream of MEF2C cause severe developmental disorder through three distinct loss-of-function mechanisms
    (Cell Press, 2021-05-21) Wright, C. F.; Quaife, N. M.; Ramos-Hernández, L.; Danecek, P.; Ferla, M. P.; Samocha, K. E.; Kaplanis, J.; Gardner, E. J.; Eberhardt, R. Y.; Chao, K. R.; Karczewski, K. J.; Morales, J.; Gallone, G.; Balasubramanian, M.; Banka, S.; Gompertz, L.; Kerr, B.; Kirby, A.; Lynch, S. A.; Morton, J. E. V.; Pinz, H.; Sansbury, F. H.; Stewart, H.; Zuccarelli, B. D.; Cook, S. A.; Taylor, J. C.; Juusola, J.; Retterer, K.; Firth, H. V.; Hurles, M. E.; Lara-Pezzi, E.; Barton, P. J. R.; Whiffin, N.
    Clinical genetic testing of protein-coding regions identifies a likely causative variant in only around half of developmental disorder (DD) cases. The contribution of regulatory variation in non-coding regions to rare disease, including DD, remains very poorly understood. We screened 9,858 probands from the Deciphering Developmental Disorders (DDD) study for de novo mutations in the 5' untranslated regions (5' UTRs) of genes within which variants have previously been shown to cause DD through a dominant haploinsufficient mechanism. We identified four single-nucleotide variants and two copy-number variants upstream of MEF2C in a total of ten individual probands. We developed multiple bespoke and orthogonal experimental approaches to demonstrate that these variants cause DD through three distinct loss-of-function mechanisms, disrupting transcription, translation, and/or protein function. These non-coding region variants represent 23% of likely diagnoses identified in MEF2C in the DDD cohort, but these would all be missed in standard clinical genetics approaches. Nonetheless, these variants are readily detectable in exome sequence data, with 30.7% of 5' UTR bases across all genes well covered in the DDD dataset. Our analyses show that non-coding variants upstream of genes within which coding variants are known to cause DD are an important cause of severe disease and demonstrate that analyzing 5' UTRs can increase diagnostic yield. We also show how non-coding variants can help inform both the disease-causing mechanism underlying protein-coding variants and dosage tolerance of the gene.
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    S-nitrosothiols, and other products of nitrate metabolism, are increased in multiple human blood compartments following ingestion of beetroot juice
    (Elsevier, 2021-07-01) Abu-Alghayth, M.; Vanhatalo, A.; Wylie, L. J.; McDonagh, S. T.; Thompson, C.; Kadach, S.; Kerr, P.; Smallwood, M. J.; Jones, A. M.; Winyard, P. G.
    Ingested inorganic nitrate (NO(3)?) has multiple effects in the human body including vasodilation, inhibition of platelet aggregation, and improved skeletal muscle function. The functional effects of oral NO(3)? involve the in vivo reduction of NO(3)? to nitrite (NO(2)?) and thence to nitric oxide (NO). However, the potential involvement of S-nitrosothiol (RSNO) formation is unclear. We hypothesised that the RSNO concentration ([RSNO]) in red blood cells (RBCs) and plasma is increased by NO(3)?-rich beetroot juice ingestion. In healthy human volunteers, we tested the effect of dietary supplementation with NO(3)?-rich beetroot juice (BR) or NO(3)?-depleted beetroot juice (placebo; PL) on [RSNO], [NO(3)?] and [NO(2)?] in RBCs, whole blood and plasma, as measured by ozone-based chemiluminescence. The median basal [RSNO] in plasma samples (n = 22) was 10 (5-13) nM (interquartile range in brackets). In comparison, the median values for basal [RSNO] in the corresponding RBC preparations (n = 19) and whole blood samples (n = 19) were higher (p < 0.001) than in plasma, being 40 (30-60) nM and 35 (25-80) nM, respectively. The median RBC [RSNO] in a separate cohort of healthy subjects (n = 5) was increased to 110 (93-125) nM after ingesting BR (12.8 mmol NO(3)?) compared to a corresponding baseline value of 25 (21-31) nM (Mann-Whitney test, p < 0.01). The median plasma [RSNO] in another cohort of healthy subjects (n = 14) was increased almost ten-fold to 104 (58-151) nM after BR supplementation (7 × 6.4 mmol of NO(3)? over two days, p < 0.01) compared to PL. In conclusion, RBC and plasma [RSNO] are increased by BR ingestion. In addition to NO(2)?, RSNO may be involved in dietary NO(3)? metabolism/actions.
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    Recurrent TTN metatranscript-only c.39974-11T>G splice variant associated with autosomal recessive arthrogryposis multiplex congenita and myopathy
    (Wiley, 2020-02-01) Bryen, S. J.; Ewans, L. J.; Pinner, J.; MacLennan, S. C.; Donkervoort, S.; Castro, D.; Töpf, A.; O'Grady, G.; Cummings, B.; Chao, K. R.; Weisburd, B.; Francioli, L.; Faiz, F.; Bournazos, A. M.; Hu, Y.; Grosmann, C.; Malicki, D. M.; Doyle, H.; Witting, N.; Vissing, J.; Claeys, K. G.; Urankar, K.; Beleza-Meireles, A.; Baptista, J.; Ellard, S.; Savarese, M.; Johari, M.; Vihola, A.; Udd, B.; Majumdar, A.; Straub, V.; Bönnemann, C. G.; MacArthur, D. G.; Davis, M. R.; Cooper, S. T.
    We present eight families with arthrogryposis multiplex congenita and myopathy bearing a TTN intron 213 extended splice-site variant (NM_001267550.1:c.39974-11T>G), inherited in trans with a second pathogenic TTN variant. Muscle-derived RNA studies of three individuals confirmed mis-splicing induced by the c.39974-11T>G variant; in-frame exon 214 skipping or use of a cryptic 3' splice-site effecting a frameshift. Confounding interpretation of pathogenicity is the absence of exons 213-217 within the described skeletal muscle TTN N2A isoform. However, RNA-sequencing from 365 adult human gastrocnemius samples revealed that 56% specimens predominantly include exons 213-217 in TTN transcripts (inclusion rate ?66%). Further, RNA-sequencing of five fetal muscle samples confirmed that 4/5 specimens predominantly include exons 213-217 (fifth sample inclusion rate 57%). Contractures improved significantly with age for four individuals, which may be linked to decreased expression of pathogenic fetal transcripts. Our study extends emerging evidence supporting a vital developmental role for TTN isoforms containing metatranscript-only exons.