Genetics and genomics
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Research outputs from the Clinical Genetics (Peninsula Genetics) Service at the RD&E.
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Item A de novo TLR7 gain-of-function mutation causing severe monogenic lupus in an infant(American Society for Clinical Investigation, 2024-05-01) Stremenova Spegarova, J.; Sinnappurajar, P.; Al Julandani, D.; Navickas, R.; Griffin, H.; Ahuja, M.; Grainger, A.; Livingstone, K.; Rice, G. I.; Sutherland, F.; Hayes, C.; Parke, S.; Pang, L.; Roderick, M. R.; Slatter, M.; Crow, Y.; Ramanan, A. V.; Hambleton, S.Item Investigating the role of common cis-regulatory variants in modifying penetrance of putatively damaging, inherited variants in severe neurodevelopmental disorders(Nature, 2024-04-01) Wigdor, E. M.; Samocha, K. E.; Eberhardt, R. Y.; Chundru, V. K.; Firth, H. V.; Wright, C. F.; Hurles, M. E.; Martin, H. C.Recent work has revealed an important role for rare, incompletely penetrant inherited coding variants in neurodevelopmental disorders (NDDs). Additionally, we have previously shown that common variants contribute to risk for rare NDDs. Here, we investigate whether common variants exert their effects by modifying gene expression, using multi-cis-expression quantitative trait loci (cis-eQTL) prediction models. We first performed a transcriptome-wide association study for NDDs using 6987 probands from the Deciphering Developmental Disorders (DDD) study and 9720 controls, and found one gene, RAB2A, that passed multiple testing correction (p = 6.7 × 10(-7)). We then investigated whether cis-eQTLs modify the penetrance of putatively damaging, rare coding variants inherited by NDD probands from their unaffected parents in a set of 1700 trios. We found no evidence that unaffected parents transmitting putatively damaging coding variants had higher genetically-predicted expression of the variant-harboring gene than their child. In probands carrying putatively damaging variants in constrained genes, the genetically-predicted expression of these genes in blood was lower than in controls (p = 2.7 × 10(-3)). However, results for proband-control comparisons were inconsistent across different sets of genes, variant filters and tissues. We find limited evidence that common cis-eQTLs modify penetrance of rare coding variants in a large cohort of NDD probands.Item Exploring the benefits, harms and costs of genomic newborn screening for rare diseases(Nature, 2024-06-01) Baple, E. L.; Scott, R. H.; Banka, S.; Buchanan, J.; Fish, L.; Wynn, S.; Wilkinson, D.; Ellard, S.; MacArthur, D. G.; Stark, Z.Item Development of a clinical calculator to aid the identification of MODY in pediatric patients at the time of diabetes diagnosis(Nature, 2024-05-01) Shields, B. M.; Carlsson, A.; Patel, K.; Knupp, J.; Kaur, A.; Johnston, D.; Colclough, K.; Larsson, H. E.; Forsander, G.; Samuelsson, U.; Hattersley, A.; Ludvigsson, J.Maturity Onset Diabetes of the Young (MODY) is a young-onset, monogenic form of diabetes without needing insulin treatment. Diagnostic testing is expensive. To aid decisions on who to test, we aimed to develop a MODY probability calculator for paediatric cases at the time of diabetes diagnosis, when the existing MODY calculator" cannot be used. Firth logistic regression models were developed on data from 3541 paediatric patients from the Swedish 'Better Diabetes Diagnosis' (BDD) population study (n = 46 (1.3%) MODY (HNF1A, HNF4A, GCK)). Model performance was compared to using islet autoantibody testing. HbA1c, parent with diabetes, and absence of polyuria were significant independent predictors of MODY. The model showed excellent discrimination (c-statistic = 0.963) and calibrated well (Brier score = 0.01). MODY probability > 1.3% (ie. above background prevalence) had similar performance to being negative for all 3 antibodies (positive predictive value (PPV) = 10% v 11% respectively i.e. ~ 1 in 10 positive test rate). Probability > 1.3% and negative for 3 islet autoantibodies narrowed down to 4% of the cohort, and detected 96% of MODY cases (PPV = 31%). This MODY calculator for paediatric patients at time of diabetes diagnosis will help target genetic testing to those most likely to benefit, to get the right diagnosis."Item Genetic modifiers of rare variants in monogenic developmental disorder loci(Nature, 2024-05-01) Kingdom, R.; Beaumont, R. N.; Wood, A. R.; Weedon, M. N.; Wright, C. F.Rare damaging variants in a large number of genes are known to cause monogenic developmental disorders (DDs) and have also been shown to cause milder subclinical phenotypes in population cohorts. Here, we show that carrying multiple (2-5) rare damaging variants across 599 dominant DD genes has an additive adverse effect on numerous cognitive and socioeconomic traits in UK Biobank, which can be partially counterbalanced by a higher educational attainment polygenic score (EA-PGS). Phenotypic deviators from expected EA-PGS could be partly explained by the enrichment or depletion of rare DD variants. Among carriers of rare DD variants, those with a DD-related clinical diagnosis had a substantially lower EA-PGS and more severe phenotype than those without a clinical diagnosis. Our results suggest that the overall burden of both rare and common variants can modify the expressivity of a phenotype, which may then influence whether an individual reaches the threshold for clinical disease.