Genetics and genomics

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Research outputs from the Clinical Genetics (Peninsula Genetics) Service at the RD&E.


Recent Submissions

Now showing 1 - 5 of 345
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    Maternal type 1 diabetes and relative protection against offspring transmission
    (Elsevier, 2023-09-01) Allen, L. A.; Taylor, P. N.; Gillespie, K. M.; Oram, R. A.; Dayan, C. M.
    Type 1 diabetes is around twice as common in the offspring of men with type 1 diabetes than in the offspring of women with type 1 diabetes, but the reasons for this difference are unclear. This Review summarises the evidence on the rate of transmission of type 1 diabetes to the offspring of affected fathers compared with affected mothers. The findings of nine major studies are presented, describing the magnitude of the effect observed and the relative strengths and weaknesses of these studies. This Review also explores possible underlying mechanisms for this effect, such as genetic mechanisms (eg, the selective loss of fetuses with high-risk genes in mothers with type 1 diabetes, preferential transmission of susceptibility genes from fathers, and parent-of-origin effects influencing gene expression), environmental exposures (eg, exposure to maternal hyperglycaemia, exogenous insulin exposure, and transplacental antibody transfer), and maternal microchimerism. Understanding why type 1 diabetes is more common in the offspring of men versus women with type 1 diabetes will help in the identification of individuals at high risk of the disease and can pave the way in the development of interventions that mimic the protective elements of maternal type 1 diabetes to reduce the risk of disease in individuals at high risk.
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    Genomic Diagnosis of Rare Pediatric Disease in the United Kingdom and Ireland
    (Massachusetts Medical Society, 2023-04-01) Wright, C. F.; Campbell, P.; Eberhardt, R. Y.; Aitken, S.; Perrett, D.; Brent, S.; Danecek, P.; Gardner, E. J.; Chundru, V. K.; Lindsay, S. J.; Andrews, K.; Hampstead, J.; Kaplanis, J.; Samocha, K. E.; Middleton, A.; Foreman, J.; Hobson, R. J.; Parker, M. J.; Martin, H. C.; FitzPatrick, D. R.; Hurles, M. E.; Firth, H. V.
    BACKGROUND: Pediatric disorders include a range of highly penetrant, genetically heterogeneous conditions amenable to genomewide diagnostic approaches. Finding a molecular diagnosis is challenging but can have profound lifelong benefits. METHODS: We conducted a large-scale sequencing study involving more than 13,500 families with probands with severe, probably monogenic, difficult-to-diagnose developmental disorders from 24 regional genetics services in the United Kingdom and Ireland. Standardized phenotypic data were collected, and exome sequencing and microarray analyses were performed to investigate novel genetic causes. We developed an iterative variant analysis pipeline and reported candidate variants to clinical teams for validation and diagnostic interpretation to inform communication with families. Multiple regression analyses were performed to evaluate factors affecting the probability of diagnosis. RESULTS: A total of 13,449 probands were included in the analyses. On average, we reported 1.0 candidate variant per parent-offspring trio and 2.5 variants per singleton proband. Using clinical and computational approaches to variant classification, we made a diagnosis in approximately 41% of probands (5502 of 13,449). Of 3599 probands in trios who received a diagnosis by clinical assertion, approximately 76% had a pathogenic de novo variant. Another 22% of probands (2997 of 13,449) had variants of uncertain significance in genes that were strongly linked to monogenic developmental disorders. Recruitment in a parent-offspring trio had the largest effect on the probability of diagnosis (odds ratio, 4.70; 95% confidence interval [CI], 4.16 to 5.31). Probands were less likely to receive a diagnosis if they were born extremely prematurely (i.e., 22 to 27 weeks' gestation; odds ratio, 0.39; 95% CI, 0.22 to 0.68), had in utero exposure to antiepileptic medications (odds ratio, 0.44; 95% CI, 0.29 to 0.67), had mothers with diabetes (odds ratio, 0.52; 95% CI, 0.41 to 0.67), or were of African ancestry (odds ratio, 0.51; 95% CI, 0.31 to 0.78). CONCLUSIONS: Among probands with severe, probably monogenic, difficult-to-diagnose developmental disorders, multimodal analysis of genomewide data had good diagnostic power, even after previous attempts at diagnosis. (Funded by the Health Innovation Challenge Fund and Wellcome Sanger Institute.).
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    Overlapping neurological phenotypes in two extended consanguineous families with novel variants in the CNTNAP1 and ADGRG1 genes
    (Wiley, 2023-05-01) Khan, S.; Umair, M.; Abbas, S.; Ali, U.; Zaman, G.; Ansar, M.; Wang, R.; Zhang, X.; Houlden, H.; Harlalka, G. V.; Gul, A.
    BACKGROUND: Population diversity is important and rare disease isolates can frequently reveal novel homozygous or biallelic mutations that lead to expanded clinical heterogeneity, with diverse clinical presentations. METHODS: The present study describes two consanguineous families with a total of seven affected individuals suffering from a clinically similar severe syndromic neurological disorder, with abnormal development and central nervous system (CNS) and peripheral nervous system (PNS) abnormalities. Whole exome sequencing (WES) and Sanger sequencing followed by 3D protein modeling was performed to identify the disease-causing gene. RNA was extracted from the fresh blood of both families affected and healthy individuals. RESULTS: The families were clinically assessed in the field in different regions of Khyber Pakhtunkhwa. Magnetic resonance imagining was obtained in the probands and blood was collected for DNA extraction and WES was performed. Sanger sequencing confirmed a homozygous, likely pathogenic mutation (GRCh38: chr17:42684199G>C; (NM_003632.3): c.333G>C);(NP_003623.1): p.(Trp111Cys) in the CNTNAP1 gene in family A, previously associated with Congenital Hypo myelinating Neuropathy 3 (CHN3; OMIM # 618186) and a novel nonsense variant in family B, (GRCh38: chr16: 57654086C>T; NC_000016.10 (NM_001370440.1): c.721C>T); (NP_001357369.1): p.(Gln241Ter) in the ADGRG1 gene previously associated with bilateral frontoparietal polymicrogyria (OMIM # 606854); both families have extended CNS and PNS clinical manifestations. In addition, 3D protein modeling was performed for the missense variant, p.(Trp111Cys), identified in the CNTNAP1, suggesting extensive secondary structure changes that might lead to improper function or downstream signaling. No RNA expression was observed in both families affected and healthy individuals hence showing that these genes are not expressed in blood. CONCLUSIONS: In the present study, two novel biallelic variants in the CNTNAP1 and ADGRG1 genes in two different consanguineous families with a clinical overlap in the phenotype were identified. Thus, the clinical and mutation spectrum is expanded to provide further evidence that CNTNAP1 and ADGRG1 are very important for widespread neurological development.
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    Penetrance of pathogenic genetic variants associated with premature ovarian insufficiency
    (Nature, 2023-07-01) Shekari, S.; Stankovic, S.; Gardner, E. J.; Hawkes, G.; Kentistou, K. A.; Beaumont, R. N.; Mörseburg, A.; Wood, A. R.; Prague, J. K.; Mishra, G. D.; Day, F. R.; Baptista, J.; Wright, C. F.; Weedon, M. N.; Hoffmann, E. R.; Ruth, K. S.; Ong, K. K.; Perry, J. R. B.; Murray, A.
    Premature ovarian insufficiency (POI) affects 1% of women and is a leading cause of infertility. It is often considered to be a monogenic disorder, with pathogenic variants in ~100 genes described in the literature. We sought to systematically evaluate the penetrance of variants in these genes using exome sequence data in 104,733 women from the UK Biobank, 2,231 (1.14%) of whom reported at natural menopause under the age of 40 years. We found limited evidence to support any previously reported autosomal dominant effect. For nearly all heterozygous effects on previously reported POI genes, we ruled out even modest penetrance, with 99.9% (13,699 out of 13,708) of all protein-truncating variants found in reproductively healthy women. We found evidence of haploinsufficiency effects in several genes, including TWNK (1.54 years earlier menopause, P = 1.59 × 10(-6)) and SOHLH2 (3.48 years earlier menopause, P = 1.03 × 10(-4)). Collectively, our results suggest that, for the vast majority of women, POI is not caused by autosomal dominant variants either in genes previously reported or currently evaluated in clinical diagnostic panels. Our findings, plus previous studies, suggest that most POI cases are likely oligogenic or polygenic in nature, which has important implications for future clinical genetic studies, and genetic counseling for families affected by POI.
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    Genetic analysis of blood molecular phenotypes reveals common properties in the regulatory networks affecting complex traits
    (Nature, 2023-08-01) Brown, A. A.; Fernandez-Tajes, J. J.; Hong, M. G.; Brorsson, C. A.; Koivula, R. W.; Davtian, D.; Dupuis, T.; Sartori, A.; Michalettou, T. D.; Forgie, I. M.; Adam, J.; Allin, K. H.; Caiazzo, R.; Cederberg, H.; De Masi, F.; Elders, P. J. M.; Giordano, G. N.; Haid, M.; Hansen, T.; Hansen, T. H.; Hattersley, A. T.; Heggie, A. J.; Howald, C.; Jones, A. G.; Kokkola, T.; Laakso, M.; Mahajan, A.; Mari, A.; McDonald, T. J.; McEvoy, D.; Mourby, M.; Musholt, P. B.; Nilsson, B.; Pattou, F.; Penet, D.; Raverdy, V.; Ridderstråle, M.; Romano, L.; Rutters, F.; Sharma, S.; Teare, H.; t Hart, L.; Tsirigos, K. D.; Vangipurapu, J.; Vestergaard, H.; Brunak, S.; Franks, P. W.; Frost, G.; Grallert, H.; Jablonka, B.; McCarthy, M. I.; Pavo, I.; Pedersen, O.; Ruetten, H.; Walker, M.; Adamski, J.; Schwenk, J. M.; Pearson, E. R.; Dermitzakis, E. T.; Viñuela, A.
    We evaluate the shared genetic regulation of mRNA molecules, proteins and metabolites derived from whole blood from 3029 human donors. We find abundant allelic heterogeneity, where multiple variants regulate a particular molecular phenotype, and pleiotropy, where a single variant associates with multiple molecular phenotypes over multiple genomic regions. The highest proportion of share genetic regulation is detected between gene expression and proteins (66.6%), with a further median shared genetic associations across 49 different tissues of 78.3% and 62.4% between plasma proteins and gene expression. We represent the genetic and molecular associations in networks including 2828 known GWAS variants, showing that GWAS variants are more often connected to gene expression in trans than other molecular phenotypes in the network. Our work provides a roadmap to understanding molecular networks and deriving the underlying mechanism of action of GWAS variants using different molecular phenotypes in an accessible tissue.