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558 results on '"Parker, MJ"'

1. Genomic diagnosis of rare pediatric disease in the United Kingdom and Ireland

Author

Wright, CF, Campbell, P, Eberhardt, RY, Aitken, S, Perrett, D, Brent, S, Danecek, P, Gardner, EJ, Chundru, VK, Lindsay, SJ, Andrews, K, Hampstead, J, Kaplanis, J, Samocha, KE, Middleton, A, Foreman, J, Hobson, RJ, Parker, MJ, Martin, HC, FitzPatrick, DR, Hurles, ME, Firth, HV, and Study, DDD

Subjects
General Medicine, Article
Abstract

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. With the use of clinical and computational approaches to variant classification, a diagnosis was made in approximately 41% of probands (5502 of 13,449), of whom 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.)

Published
2023

2. Predictors of non-use of intrauterine contraception among women aged 18–49 years in a general practice setting in the UK

Author

Walker SH, Newton VL, Hoggart L, and Parker MJ

Subjects
Intrauterine device, intrauterine contraception, intrauterine system, General Practice, United Kingdom, Gynecology and obstetrics, RG1-991
Abstract

Susan H Walker,1 Victoria L Newton,2 Lesley Hoggart,3 Mike J Parker4 1Faculty of Health, Social Care & Education, Anglia Ruskin University, Chelmsford, 2Faculty of Health & Social Care, The Open University, Milton Keynes, 3School of Health, Wellbeing and Social Care, The Open University, Milton Keynes, 4Postgraduate Medical Institute, Anglia Ruskin University, Chelmsford, UK Objectives: Our research examined the barriers to the uptake of intrauterine contraception (IUC) by women in a general practice (GP) setting in the UK. This study reports predictors of non-use of IUC in this context.Design: We used a mixed method Qual/Quant approach in which the initial qualitative research provides a framework for subsequent larger quantitative surveys. Utilizing findings derived from 30 qualitative interviews, a quantitative survey was developed and distributed to a pragmatic sample of 1,195 women, aged 18–49 years, who were recruited through 32 participating GP practices in an area of England, UK. Outcome measures were percentage of attributes or responses in the sample and use or non-use of IUC. Results were analyzed using descriptive statistical analysis and binary logistic regression, using use/non-use as a binary response variable.Results: Attitudinal variables, which were the strongest predictors of non-use of IUC, were an adverse opinion on long-acting aspect of IUC (odds ratio [OR]=8.34), disliking the thought of IUC inside the body (OR=3.138), concerns about IUC causing difficulties becoming pregnant in the future (OR=2.587), concerns about womb damage (OR=2.224), having heard adverse opinions about levonorgestrel-releasing intrauterine system (Mirena®) (OR=2.551), having an adverse opinion of having light, irregular periods (OR=2.382) and, having an adverse opinion of having no periods (OR=2.018).Conclusion: Concerns about the long-acting nature of IUC and persisting concerns about the safety of IUC may act as barriers to its use. Information for women, tailored to specifically address these concerns, is needed.Implications: Clinicians should provide more reassurance and information to potential users of IUC to increase their confidence about the possibility of removing IUC early or on request. They should also specifically seek to alleviate concerns about internal damage, damage to the womb, or damage to future fertility from using the methods. Keywords: intrauterine device, intrauterine contraception, intrauterine system, general ­practice, UK

Published
2016

3. Refining the Primrose syndrome phenotype: A study of five patients with ZBTB20 de novo variants and a review of the literature

Author

Cleaver, RJ, Berg, J, Craft, E, Foster, A, Gibbons, RJ, Hobson, E, Lachlan, K, Naik, S, Sampson, JR, Sharif, S, Smithson, S, Study, Deciphering Developmental Disorders, Parker, MJ, and Tatton-Brown, K

Subjects
Male, medicine.medical_specialty, Genotype, Nerve Tissue Proteins, Corpus callosum, Intellectual Disability, Intellectual disability, Genetics, Humans, Medicine, Missense mutation, Abnormalities, Multiple, Genetic Predisposition to Disease, Child, Ear Diseases, Genetic Association Studies, Genetics (clinical), Exome sequencing, business.industry, Macrocephaly, Calcinosis, Facies, Genetic Variation, Primrose syndrome, medicine.disease, Magnetic Resonance Imaging, Dermatology, Hypotonia, Muscular Atrophy, Phenotype, Genetic Loci, Child, Preschool, Mutation, Female, Sensorineural hearing loss, medicine.symptom, business, Transcription Factors
Abstract

Primrose syndrome is a rare autosomal dominant condition caused by heterozygous missense variants within ZBTB20. Through an exome sequencing approach (as part of the Deciphering Developmental Disorders [DDD] study) we have identified five unrelated individuals with previously unreported, de novo ZBTB20 pathogenic missense variants. All five missense variants targeted the C2H2 zinc finger domains. This genotype-up approach has allowed further refinement of the Primrose syndrome phenotype. Major characteristics (>90% individuals) include an intellectual disability (most frequently in the moderate range), a recognizable facial appearance and brain MRI abnormalities, particularly abnormalities of the corpus callosum. Other frequent clinical associations (in 50-90% individuals) include sensorineural hearing loss (83%), hypotonia (78%), cryptorchidism in males (75%), macrocephaly (72%), behavioral issues (56%), and dysplastic/hypoplastic nails (57%). Based upon these clinical data we discuss our current management of patients with Primrose syndrome.

Published
2019

5. Structural analysis of pathogenic mutations in the DYRK1A gene in patients with developmental disorders

Author

Evers, JMG, Laskowski, RA, Bertolli, M, Clayton-Smith, J, Deshpande, C, Eason, J, Elmslie, F, Flinter, F, Gardiner, C, Hurst, JA, Kingston, H, Kini, U, Lampe, AK, Lim, D, Male, A, Naik, S, Parker, MJ, Price, S, Robert, L, Sarkar, A, Straub, V, Woods, G, Thornton, JM, DDD Study, and Wright, CF

Subjects
0301 basic medicine, Male, DYRK1A, Protein Conformation, Developmental Disabilities, Mutation, Missense, Haploinsufficiency, Biology, Protein Serine-Threonine Kinases, medicine.disease_cause, DYRK1A Gene, 03 medical and health sciences, Structure-Activity Relationship, 0302 clinical medicine, Intellectual Disability, Genetics, medicine, Missense mutation, Humans, Autistic Disorder, Molecular Biology, Gene, Genetics (clinical), Mutation, General Medicine, Articles, Protein-Tyrosine Kinases, Phenotype, Pedigree, 030104 developmental biology, Protein kinase domain, Female, 030217 neurology & neurosurgery
Abstract

Haploinsufficiency in DYRK1A is associated with a recognizable developmental syndrome, though the mechanism of action of pathogenic missense mutations is currently unclear. Here we present 19 de novo mutations in this gene, including five missense mutations, identified by the Deciphering Developmental Disorder study. Protein structural analysis reveals that the missense mutations are either close to the ATP or peptide binding-sites within the kinase domain, or are important for protein stability, suggesting they lead to a loss of the protein’s function mechanism. Furthermore, there is some correlation between the magnitude of the change and the severity of the resultant phenotype. A comparison of the distribution of the pathogenic mutations along the length of DYRK1A with that of natural variants, as found in the ExAC database, confirms that mutations in the N-terminal end of the kinase domain are more disruptive of protein function. In particular, pathogenic mutations occur in significantly closer proximity to the ATP and the substrate peptide than the natural variants. Overall, we suggest that de novo dominant mutations in DYRK1A account for nearly 0.5% of severe developmental disorders due to substantially reduced kinase function.

Published
2017

6. Different mutations in DEAF1 lead to clinically distinct dominant and recessive forms of intellectual disability

Author

Sa, MJN, Jensik, PJ, Parker, MJ, Lahiri, N, McNeil, EP, Hibbs, K, Kroes, HY, Stumpel, CTRM, Stegmann, APA, Hagerman, RJ, Harrison, RE, Splitt, M, Montgomery, T, Palmer, EE, Sachdev, RK, Mefford, HC, Scott, AA, Martinez-Agosto, JA, Lorenz, R, Orenstein, N, Berg, JN, Cobben, J, Marco, EJ, de Vries, BBA, Vulto-vanSilfhout, AT, Sa, MJN, Jensik, PJ, Parker, MJ, Lahiri, N, McNeil, EP, Hibbs, K, Kroes, HY, Stumpel, CTRM, Stegmann, APA, Hagerman, RJ, Harrison, RE, Splitt, M, Montgomery, T, Palmer, EE, Sachdev, RK, Mefford, HC, Scott, AA, Martinez-Agosto, JA, Lorenz, R, Orenstein, N, Berg, JN, Cobben, J, Marco, EJ, de Vries, BBA, and Vulto-vanSilfhout, AT

Published
2019

7. De novo and biallelic DEAF1 variants cause a phenotypic spectrum

Author

Nabais Sá, MJ, Jensik, PJ, McGee, SR, Parker, MJ, Lahiri, N, McNeil, EP, Kroes, HY, Hagerman, RJ, Harrison, RE, Montgomery, T, Splitt, M, Palmer, EE, Sachdev, RK, Mefford, HC, Scott, AA, Martinez-Agosto, JA, Lorenz, R, Orenstein, N, Berg, JN, Amiel, J, Heron, D, Keren, B, Cobben, JM, Menke, LA, Marco, EJ, Graham, JM, Pierson, TM, Karimiani, EG, Maroofian, R, Manzini, MC, Cauley, ES, Colombo, R, Odent, S, Dubourg, C, Phornphutkul, C, de Brouwer, APM, de Vries, BBA, Vulto-vanSilfhout, AT, Nabais Sá, MJ, Jensik, PJ, McGee, SR, Parker, MJ, Lahiri, N, McNeil, EP, Kroes, HY, Hagerman, RJ, Harrison, RE, Montgomery, T, Splitt, M, Palmer, EE, Sachdev, RK, Mefford, HC, Scott, AA, Martinez-Agosto, JA, Lorenz, R, Orenstein, N, Berg, JN, Amiel, J, Heron, D, Keren, B, Cobben, JM, Menke, LA, Marco, EJ, Graham, JM, Pierson, TM, Karimiani, EG, Maroofian, R, Manzini, MC, Cauley, ES, Colombo, R, Odent, S, Dubourg, C, Phornphutkul, C, de Brouwer, APM, de Vries, BBA, and Vulto-vanSilfhout, AT

Abstract

Purpose: To investigate the effect of different DEAF1 variants on the phenotype of patients with autosomal dominant and recessive inheritance patterns and on DEAF1 activity in vitro. Methods: We assembled a cohort of 23 patients with de novo and biallelic DEAF1 variants, described the genotype–phenotype correlation, and investigated the differential effect of de novo and recessive variants on transcription assays using DEAF1 and Eif4g3 promoter luciferase constructs. Results: The proportion of the most prevalent phenotypic features, including intellectual disability, speech delay, motor delay, autism, sleep disturbances, and a high pain threshold, were not significantly different in patients with biallelic and pathogenic de novo DEAF1 variants. However, microcephaly was exclusively observed in patients with recessive variants (p < 0.0001). Conclusion: We propose that different variants in the DEAF1 gene result in a phenotypic spectrum centered around neurodevelopmental delay. While a pathogenic de novo dominant variant would also incapacitate the product of the wild-type allele and result in a dominant-negative effect, a combination of two recessive variants would result in a partial loss of function. Because the clinical picture can be nonspecific, detailed phenotype information, segregation, and functional analysis are fundamental to determine the pathogenicity of novel variants and to improve the care of these patients.

Published
2019

9. Truncating Variants in NAA15 Are Associated with Variable Levels of Intellectual Disability, Autism Spectrum Disorder, and Congenital Anomalies

Author

Cheng, H, Dharmadhikari, AV, Varland, S, Ma, N, Domingo, D, Kleyner, R, Rope, AF, Yoon, M, Stray-Pedersen, A, Posey, JE, Crews, SR, Eldomery, MK, Akdemir, ZC, Lewis, AM, Sutton, VR, Rosenfeld, JA, Conboy, E, Agre, K, Xia, F, Walkiewicz, M, Longoni, M, High, FA, van Slegtenhorst, MA, Mancini, GMS, Finnila, CR, van Haeringen, A, den Hollander, N, Ruivenkamp, C, Naidu, S, Mahida, S, Palmer, EE, Murray, L, Lim, D, Jayakar, P, Parker, MJ, Giusto, S, Stracuzzi, E, Romano, C, Beighley, JS, Bernier, RA, Küry, S, Nizon, M, Corbett, MA, Shaw, M, Gardner, A, Barnett, C, Armstrong, R, Kassahn, KS, Van Dijck, A, Vandeweyer, G, Kleefstra, T, Schieving, J, Jongmans, MJ, de Vries, BBA, Pfundt, R, Kerr, B, Rojas, SK, Boycott, KM, Person, R, Willaert, R, Eichler, EE, Kooy, RF, Yang, Y, Wu, JC, Lupski, JR, Arnesen, T, Cooper, GM, Chung, WK, Gecz, J, Stessman, HAF, Meng, L, Lyon, GJ, Cheng, H, Dharmadhikari, AV, Varland, S, Ma, N, Domingo, D, Kleyner, R, Rope, AF, Yoon, M, Stray-Pedersen, A, Posey, JE, Crews, SR, Eldomery, MK, Akdemir, ZC, Lewis, AM, Sutton, VR, Rosenfeld, JA, Conboy, E, Agre, K, Xia, F, Walkiewicz, M, Longoni, M, High, FA, van Slegtenhorst, MA, Mancini, GMS, Finnila, CR, van Haeringen, A, den Hollander, N, Ruivenkamp, C, Naidu, S, Mahida, S, Palmer, EE, Murray, L, Lim, D, Jayakar, P, Parker, MJ, Giusto, S, Stracuzzi, E, Romano, C, Beighley, JS, Bernier, RA, Küry, S, Nizon, M, Corbett, MA, Shaw, M, Gardner, A, Barnett, C, Armstrong, R, Kassahn, KS, Van Dijck, A, Vandeweyer, G, Kleefstra, T, Schieving, J, Jongmans, MJ, de Vries, BBA, Pfundt, R, Kerr, B, Rojas, SK, Boycott, KM, Person, R, Willaert, R, Eichler, EE, Kooy, RF, Yang, Y, Wu, JC, Lupski, JR, Arnesen, T, Cooper, GM, Chung, WK, Gecz, J, Stessman, HAF, Meng, L, and Lyon, GJ

Abstract

N-alpha-acetylation is a common co-translational protein modification that is essential for normal cell function in humans. We previously identified the genetic basis of an X-linked infantile lethal Mendelian disorder involving a c.109T>C (p.Ser37Pro) missense variant in NAA10, which encodes the catalytic subunit of the N-terminal acetyltransferase A (NatA) complex. The auxiliary subunit of the NatA complex, NAA15, is the dimeric binding partner for NAA10. Through a genotype-first approach with whole-exome or genome sequencing (WES/WGS) and targeted sequencing analysis, we identified and phenotypically characterized 38 individuals from 33 unrelated families with 25 different de novo or inherited, dominantly acting likely gene disrupting (LGD) variants in NAA15. Clinical features of affected individuals with LGD variants in NAA15 include variable levels of intellectual disability, delayed speech and motor milestones, and autism spectrum disorder. Additionally, mild craniofacial dysmorphology, congenital cardiac anomalies, and seizures are present in some subjects. RNA analysis in cell lines from two individuals showed degradation of the transcripts with LGD variants, probably as a result of nonsense-mediated decay. Functional assays in yeast confirmed a deleterious effect for two of the LGD variants in NAA15. Further supporting a mechanism of haploinsufficiency, individuals with copy-number variant (CNV) deletions involving NAA15 and surrounding genes can present with mild intellectual disability, mild dysmorphic features, motor delays, and decreased growth. We propose that defects in NatA-mediated N-terminal acetylation (NTA) lead to variable levels of neurodevelopmental disorders in humans, supporting the importance of the NatA complex in normal human development.

Published
2018

10. Prevalence and architecture of de novo mutations in developmental disorders

Author

McRae, JF, Clayton, S, Fitzgerald, TW, Kaplanis, J, Prigmore, E, Rajan, D, Sifrim, A, Aitken, S, Akawi, N, Alvi, M, Ambridge, K, Barrett, DM, Bayzetinova, T, Jones, P, Jones, WD, King, D, Krishnappa, N, Mason, LE, Singh, T, Tivey, AR, Ahmed, M, Anjum, U, Archer, H, Armstrong, R, Awada, J, Balasubramanian, M, Banka, S, Baralle, D, Barnicoat, A, Batstone, P, Baty, D, Bennett, C, Berg, J, Bernhard, B, Bevan, AP, Bitner-Glindzicz, M, Blair, E, Blyth, M, Bohanna, D, Bourdon, L, Bourn, D, Bradley, L, Brady, A, Brent, S, Brewer, C, Brunstrom, K, Bunyan, DJ, Burn, J, Canham, N, Castle, B, Chandler, K, Chatzimichali, E, Cilliers, D, Clarke, A, Clasper, S, Clayton-Smith, J, Clowes, V, Coates, A, Cole, T, Colgiu, I, Collins, A, Collinson, MN, Connell, F, Cooper, N, Cox, H, Cresswell, L, Cross, G, Crow, Y, D’Alessandro, M, Dabir, T, Davidson, R, Davies, S, de Vries, D, Dean, J, Deshpande, C, Devlin, G, Dixit, A, Dobbie, A, Donaldson, A, Donnai, D, Donnelly, D, Donnelly, C, Douglas, A, Douzgou, S, Duncan, A, Eason, J, Ellard, S, Ellis, I, Elmslie, F, Evans, K, Everest, S, Fendick, T, Fisher, R, Flinter, F, Foulds, N, Fry, A, Fryer, A, Gardiner, C, Gaunt, L, Ghali, N, Gibbons, R, Gill, H, Goodship, J, Goudie, D, Gray, E, Green, A, Greene, P, Greenhalgh, L, Gribble, S, Harrison, R, Harrison, L, Harrison, V, Hawkins, R, He, L, Hellens, S, Henderson, A, Hewitt, S, Hildyard, L, Hobson, E, Holden, S, Holder, M, Holder, S, Hollingsworth, G, Homfray, T, Humphreys, M, Hurst, J, Hutton, B, Ingram, S, Irving, M, Islam, L, Jackson, A, Jarvis, J, Jenkins, L, Johnson, D, Jones, E, Josifova, D, Joss, S, Kaemba, B, Kazembe, S, Kelsell, R, Kerr, B, Kingston, H, Kini, U, Kinning, E, Kirby, G, Kirk, C, Kivuva, E, Kraus, A, Kumar, D, Kumar, VKA, Lachlan, K, Lam, W, Lampe, A, Langman, C, Lees, M, Lim, D, Longman, C, Lowther, G, Lynch, SA, Magee, A, Maher, E, Male, A, Mansour, S, Marks, K, Martin, K, Maye, U, McCann, E, McConnell, V, McEntagart, M, McGowan, R, McKay, K, McKee, S, McMullan, DJ, McNerlan, S, McWilliam, C, Mehta, S, Metcalfe, K, Middleton, A, Miedzybrodzka, Z, Miles, E, Mohammed, S, Montgomery, T, Moore, D, Morgan, S, Morton, J, Mugalaasi, H, Murday, V, Murphy, H, Naik, S, Nemeth, A, Nevitt, L, Newbury-Ecob, R, Norman, A, O’Shea, R, Ogilvie, C, Ong, K-R, Park, S-M, Parker, MJ, Patel, C, Paterson, J, Payne, S, Perrett, D, Phipps, J, Pilz, DT, Pollard, M, Pottinger, C, Poulton, J, Pratt, N, Prescott, K, Price, S, Pridham, A, Procter, A, Purnell, H, Quarrell, O, Ragge, N, Rahbari, R, Randall, J, Rankin, J, Raymond, L, Rice, D, Robert, L, Roberts, E, Roberts, J, Roberts, P, Roberts, G, Ross, A, Rosser, E, Saggar, A, Samant, S, Sampson, J, Sandford, R, Sarkar, A, Schweiger, S, Scott, R, Scurr, I, Selby, A, Seller, A, Sequeira, C, Shannon, N, Sharif, S, Shaw-Smith, C, Shearing, E, Shears, D, Sheridan, E, Simonic, I, Singzon, R, Skitt, Z, Smith, A, Smith, K, Smithson, S, Sneddon, L, Splitt, M, Squires, M, Stewart, F, Stewart, H, Straub, V, Suri, M, Sutton, V, Swaminathan, GJ, Sweeney, E, Tatton-Brown, K, Taylor, C, Taylor, R, Tein, M, Temple, IK, Thomson, J, Tischkowitz, M, Tomkins, S, Torokwa, A, Treacy, B, Turner, C, Turnpenny, P, Tysoe, C, Vandersteen, A, Varghese, V, Vasudevan, P, Vijayarangakannan, P, Vogt, J, Wakeling, E, Wallwark, S, Waters, J, Weber, A, Wellesley, D, Whiteford, M, Widaa, S, Wilcox, S, Wilkinson, E, Williams, D, Williams, N, Wilson, L, Woods, G, Wragg, C, Wright, M, Yates, L, Yau, M, Nellåker, C, Parker, M, Firth, HV, Wright, CF, FitzPatrick, DR, Barrett, JC, and Hurles, ME

Subjects
Male, Parents, Heredity, Developmental Disabilities, GRIN2B, POGZ, Autoantigens, SMAD4, CASK, GATAD2B, 0302 clinical medicine, TRIO, SMARCA2, KCNH1, Average Faces, CTNNB1, SCN1A, Young adult, Casein Kinase II, Child, AUTS2, MEF2C, Exome, ADNP, Exome sequencing, EP300, KCNQ2, KCNQ3, EHMT1, CNKSR2, CREBBP, MYT1L, MED13L, CSNK2A1, Protein Phosphatase 2C, PPP2R1A, ZBTB18, CDKL5, WAC, HNRNPU, Cohort, STXBP1, Medical genetics, SYNGAP1, Mi-2 Nucleosome Remodeling and Deacetylase Complex, Sex characteristics, AHDC1, SCN8A, medicine.medical_specialty, SLC6A1, FOXP1, USP9X, Article, ANKRD11, PUF60, BRAF, 03 medical and health sciences, SATB2, SMC1A, Intellectual Disability, BCL11A, GABRB3, IQSEC2, Humans, TBL1XR1, TCF4, MSL3, TCF20, DNM1, EEF1A2, SUV420H1, DYRK1A, SETD5, COL4A3BP, CTCF, CHD2, R1, CHD4, 030104 developmental biology, NAA10, HDAC8, Mutation, KDM5B, CHAMP1, PhenIcons, 030217 neurology & neurosurgery, Transcription Factors, 0301 basic medicine, ZMYND11, PTEN, De novo mutation, Chromosomal Proteins, Non-Histone, PTPN11, ASXL1, Bioinformatics, medicine.disease_cause, ASXL3, Cohort Studies, DEAD-box RNA Helicases, CHD8, Prevalence, QRICH1, KIF1A, Genetics, Sex Characteristics, GNAI1, Multidisciplinary, WDR45, Middle Aged, KMT2A, PPM1D, MECP2, DNA-Binding Proteins, PPP2R5D, Phenotype, PACS1, ras GTPase-Activating Proteins, DDX3X, Female, FOXG1, SET, Myeloid-Lymphoid Leukemia Protein, Developmental Disease, Adult, KANSL1, Adolescent, NFIX, Nerve Tissue Proteins, PURA, Biology, KAT6B, KAT6A, NSD1, PDHA1, ALG13, Young Adult, Seizures, CDC2 Protein Kinase, medicine, Journal Article, QH426, Homeodomain Proteins, ITPR1, DYNC1H1, GNAO1, Histone-Lysine N-Methyltransferase, Sequence Analysis, DNA, ZC4H2, ARID1B, Repressor Proteins, CNOT3, SCN2A, SLC35A2, CDK13
Abstract

Children with severe, undiagnosed developmental disorders (DDs) are enriched for damaging de novo mutations (DNMs) in developmentally important genes. We exome sequenced 4,294 families with children with DDs, and meta-analysed these data with published data on 3,287 children with similar disorders. We show that the most significant factors influencing the diagnostic yield of de novo mutations are the sex of the child, the relatedness of their parents and the age of both father and mother. We identified 95 genes enriched for damaging de novo mutation at genome-wide significance (P < 5 x 10-7), including fourteen genes for which compelling data for causation was previously lacking. The large number of genome-wide significant findings allow us to demonstrate that, at current cost differentials, exome sequencing has much greater power than genome sequencing for novel gene discovery in genetically heterogeneous disorders. We estimate that 42.5% of our cohort likely carry pathogenic de novo single nucleotide variants (SNVs) and indels in coding sequences, with approximately half operating by a loss-of-function mechanism, and the remainder being gain-of-function. We established that most haploinsufficient developmental disorders have already been identified, but that many gain-of-function disorders remain to be discovered. Extrapolating from the DDD cohort to the general population, we estimate that de novo dominant developmental disorders have an average birth prevalence of 1 in 168 to 1 in 377, depending on parental age.

Published
2017

11. Genetic and phenotypic dissection of 1q43q44 microdeletion syndrome and neurodevelopmental phenotypes associated with mutations in ZBTB18 and HNRNPU

Author

Depienne, C, Nava, C, Keren, B, Heide, S, Rastetter, A, Passemard, S, Chantot-Bastaraud, S, Moutard, M-L, Agrawal, PB, VanNoy, G, Stoler, JM, Amor, DJ, de Villemeur, TB, Doummar, D, Alby, C, Cormier-Daire, V, Garel, C, Marzin, P, Scheidecker, S, de Saint-Martin, A, Hirsch, E, Korff, C, Bottani, A, Faivre, L, Verloes, A, Orzechowski, C, Burglen, L, Leheup, B, Roume, J, Andrieux, J, Sheth, F, Datar, C, Parker, MJ, Pasquier, L, Odent, S, Naudion, S, Delrue, M-A, Le Caignec, C, Vincent, M, Isidor, B, Renaldo, F, Stewart, F, Toutain, A, Koehler, U, Hackl, B, von Stulpnagel, C, Kluger, G, Moller, RS, Pal, D, Jonson, T, Soller, M, Verbeek, NE, van Haelst, MM, de Kovel, C, Koeleman, B, Monroe, G, van Haaften, G, Study, DDD, Attie-Bitach, T, Boutaud, L, Heron, D, Mignot, C, Depienne, C, Nava, C, Keren, B, Heide, S, Rastetter, A, Passemard, S, Chantot-Bastaraud, S, Moutard, M-L, Agrawal, PB, VanNoy, G, Stoler, JM, Amor, DJ, de Villemeur, TB, Doummar, D, Alby, C, Cormier-Daire, V, Garel, C, Marzin, P, Scheidecker, S, de Saint-Martin, A, Hirsch, E, Korff, C, Bottani, A, Faivre, L, Verloes, A, Orzechowski, C, Burglen, L, Leheup, B, Roume, J, Andrieux, J, Sheth, F, Datar, C, Parker, MJ, Pasquier, L, Odent, S, Naudion, S, Delrue, M-A, Le Caignec, C, Vincent, M, Isidor, B, Renaldo, F, Stewart, F, Toutain, A, Koehler, U, Hackl, B, von Stulpnagel, C, Kluger, G, Moller, RS, Pal, D, Jonson, T, Soller, M, Verbeek, NE, van Haelst, MM, de Kovel, C, Koeleman, B, Monroe, G, van Haaften, G, Study, DDD, Attie-Bitach, T, Boutaud, L, Heron, D, and Mignot, C

Abstract

Subtelomeric 1q43q44 microdeletions cause a syndrome associating intellectual disability, microcephaly, seizures and anomalies of the corpus callosum. Despite several previous studies assessing genotype-phenotype correlations, the contribution of genes located in this region to the specific features of this syndrome remains uncertain. Among those, three genes, AKT3, HNRNPU and ZBTB18 are highly expressed in the brain and point mutations in these genes have been recently identified in children with neurodevelopmental phenotypes. In this study, we report the clinical and molecular data from 17 patients with 1q43q44 microdeletions, four with ZBTB18 mutations and seven with HNRNPU mutations, and review additional data from 37 previously published patients with 1q43q44 microdeletions. We compare clinical data of patients with 1q43q44 microdeletions with those of patients with point mutations in HNRNPU and ZBTB18 to assess the contribution of each gene as well as the possibility of epistasis between genes. Our study demonstrates that AKT3 haploinsufficiency is the main driver for microcephaly, whereas HNRNPU alteration mostly drives epilepsy and determines the degree of intellectual disability. ZBTB18 deletions or mutations are associated with variable corpus callosum anomalies with an incomplete penetrance. ZBTB18 may also contribute to microcephaly and HNRNPU to thin corpus callosum, but with a lower penetrance. Co-deletion of contiguous genes has additive effects. Our results confirm and refine the complex genotype-phenotype correlations existing in the 1qter microdeletion syndrome and define more precisely the neurodevelopmental phenotypes associated with genetic alterations of AKT3, ZBTB18 and HNRNPU in humans.

Published
2017

12. Genetic heterogeneity in Cornelia de Lange syndrome (CdLS) and CdLS-like phenotypes with observed and predicted levels of mosaicism

Author

Ansari, M, Poke, G, Ferry, Q, Williamson, K, Aldridge, R, Meynert, AM, Bengani, H, Chan, CY, Kayserili, H, Avci, S, Hennekam, RC, Lampe, AK, Redeker, E, Homfray, T, Ross, A, Falkenberg Smeland, M, Mansour, S, Parker, MJ, Cook, JA, Splitt, M, Fisher, RB, Fryer, A, Magee, AC, Wilkie, A, Barnicoat, A, Brady, AF, Cooper, NS, Mercer, C, Deshpande, C, Bennett, CP, Pilz, DT, Ruddy, D, Cilliers, D, Johnson, DS, Josifova, D, Rosser, E, Thompson, EM, Wakeling, E, Kinning, E, Stewart, F, Flinter, F, Girisha, KM, Cox, H, Firth, HV, Kingston, H, Wee, JS, Hurst, JA, Clayton-Smith, J, Tolmie, J, Vogt, J, Tatton-Brown, K, Chandler, K, Prescott, K, Wilson, L, Behnam, M, McEntagart, M, Davidson, R, Lynch, SA, Sisodiya, S, Mehta, SG, McKee, SA, Mohammed, S, Holden, S, Park, SM, Holder, SE, Harrison, V, McConnell, V, Lam, WK, Green, AJ, Donnai, D, Bitner-Glindzicz, M, Donnelly, DE, Nellåker, C, Taylor, MS, FitzPatrick, DR, ANS - Amsterdam Neuroscience, APH - Amsterdam Public Health, Human Genetics, ACS - Amsterdam Cardiovascular Sciences, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, and Other Research

Subjects
Genetic Heterogeneity, Copy-number, Phenotype, Mosaicism, De Lange Syndrome, Face, Mutation, Genotype-Phenotype Correlations, Humans, Molecular genetics, Clinical genetics, Genetic Association Studies
Abstract

BACKGROUND: Cornelia de Lange syndrome (CdLS) is a multisystem disorder with distinctive facial appearance, intellectual disability and growth failure as prominent features. Most individuals with typical CdLS have de novo heterozygous loss-of-function mutations in NIPBL with mosaic individuals representing a significant proportion. Mutations in other cohesin components, SMC1A, SMC3, HDAC8 and RAD21 cause less typical CdLS.METHODS: We screened 163 affected individuals for coding region mutations in the known genes, 90 for genomic rearrangements, 19 for deep intronic variants in NIPBL and 5 had whole-exome sequencing.RESULTS: Pathogenic mutations [including mosaic changes] were identified in: NIPBL 46 [3] (28.2%); SMC1A 5 [1] (3.1%); SMC3 5 [1] (3.1%); HDAC8 6 [0] (3.6%) and RAD21 1 [0] (0.6%). One individual had a de novo 1.3 Mb deletion of 1p36.3. Another had a 520 kb duplication of 12q13.13 encompassing ESPL1, encoding separase, an enzyme that cleaves the cohesin ring. Three de novo mutations were identified in ANKRD11 demonstrating a phenotypic overlap with KBG syndrome. To estimate the number of undetected mosaic cases we used recursive partitioning to identify discriminating features in the NIPBL-positive subgroup. Filtering of the mutation-negative group on these features classified at least 18% as ‘NIPBL-like’. A computer composition of the average face of this NIPBL-like subgroup was also more typical in appearance than that of all others in the mutation-negative group supporting the existence of undetected mosaic cases.CONCLUSIONS: Future diagnostic testing in ‘mutation-negative’ CdLS thus merits deeper sequencing of multiple DNA samples derived from different tissues.

Published
2014

13. Prevention of pulmonary embolism and deep vein thrombosis with low dose aspirin: Pulmonary Embolism Prevention (PEP) trial

Author

O'Brien, J, Duncan, H, Kirsh, G, Allen, V, King, P, Hargraves, R, Mendes, L, Perera, T, Catto, P, Schofield, S, Ploschke, H, Hefner, T, Churchland, M, Woolnough, S, Wuttke, R, Manning, M, Jeffries, T, Hensley, L, Bath, P, Bainbridge, D, Guinane, F, McMahon, L, Zavattaro, D, Wilson, D, Blake, K, Morton, J, Sharman, D, Locke, R, Ghabrial, J, McNeil, S, Rehfisch, P, van der Merwe, S, Einoder, B, Douglas, D, Ashwell, J, Morrissey, A, Brown, A, Simm, R, Fisch, G, Crawford, W, Everding, T, Tanham, D, Hooper, J, Aldana, C, Goldwasser, M, Mibus, M, Rowden, N, Mills, J, Johnson, P, Stilwell, J, Williams, R, Stevenson, T, Zwar, J, Bauze, R, Nyunt, B, Russell, R, Day, G, Cameron, M, Clements, P, Beck, T, Ellis, A, Phipps, S, Quaill, W, Skirving, A, McGuiness, M, Gray, P, Rankin, J, Wood, D, Senior, J, Courtenay, B, Green, M, Harris, I, Rush, J, Kilgour, M, Davies, J, Newcombe, J, Lewis, C, Leitl, S, Chilcott, R, Pianta, R, Aguila, A, Hawe, C, Nade, S, Smith, M, Robertson, P, Rothwell, A, May, S, Williams, S, Shamy, S, Martin, G, Steele, V, Jeffery, K, Kelman, I, McKillan, J, Dayaram, P, Culling, J, Lawson, D, Winfield, P, Kuzel, R, Milburn, C, Palmer, N, Pitts, A, Lamb, G, Prodan, L, Gray, H, Walker, K, Smith, K, Newton, C, Atkinson, D, Fail, B, Panting, A, Menzies, J, Watkiss, A, Outhred, J, Clay, D, Lander, R, Fou, R, Clarke, DS, Murrell, T, Rolleston, B, Keyworth, S, Medlicott, P, Woods, T, Dawe, C, Waldron, R, Taine, W, Le Roy, L, Smith, A, Cowley, G, Campbell, C, Maxwell, R, Elvy, M, Thurston, A, Newth, S, Cousins, L, Sanderson, M, MacMillan, C, Golele, R, Walters, J, Kruger, S, Ramsden, T, Joseph, H, Gantz, D, Steyn, S, Hadjichristofis, S, Nojoko, L, Snowdowne, R, Botha, M, Knebel, R, Sernbo, I, Ferris, B, Tello, E, Nevelos, A, Dunn, C, Warwick, D, Sudhakar, J, Tuite, JD, Francis, J, Wallace, ME, Jordan, A, Baird, P, Fowler, W, Ainscow, DAP, Harrison, A, Butler-Manuel, A, Broome, G, Swailes, P, Stahl, TJ, Randall, AM, Forester, AJ, Hucker, J, Redden, J, Logan, L, Howard, PW, Brownlee, D, Angus, P, Boyce, A, Porter, BB, Arbid, M, Youll, J, Ogden, AS, MacDowell, C, Beverly, M, Ramdeholl, P, Nelson, I, Howlett, I, Weeber, A, Peacock, A, Hubbard, MJS, Flanagan, M, Crawshaw, C, Kinninmonth, A, Campbell, T, Tibrewal, S, Lennox, CME, Clifford, I, Gillham, N, Hunt, M, Bulstrode, C, Handley, R, Iyer, V, Lawton, J, Robbins, J, Harper, WM, Davison, J, Hope, P, Smallbones, K, Jones, W, Ratnam, KR, Upton, J, Hirst, P, Knox, S, Sadique, T, Khan, M, Umar, M, Anderson, J, Frank, J, Briggs, P, Sanderson, P, McBride, D, Leese, K, Bayliss, NC, El-Deen, M, Banan, H, Parker, MJ, Minhas, H, Best, A, Blakeway, C, Salter, T, Foy, MA, Pollitt, A, Blayney, JDM, Davis, S, Parnell, E, Ko, C, Grover, ML, Howells, S, Williams, D, Saunders, C, Brenkel, I, Mani, G, Grizzle, M, Henderson, A, Board, T, Chadwick, CJ, Overton, M, Hodkinson, S, Macdonald, DA, Lewis, V, McDonald, RJM, Adamson, J, Bradley, J, Hodgson, E, Plewes, JL, Clarke, D, Hullin, M, Smith, J, Lemon, GJ, Greatrex, K, Miles, C, Bannister, G, Dare, J, Carden, DG, Aughton, J, Stirrat, A, Fishburn, J, Ebizie, AO, Mason, M, Irvine, G, Facey, T, Spratt, C, Kanagavel, N, Gerrard, T, Reissis, N, Tzanetos, P, Stefanotti, M, Greiss, M, Wright, V, Rahmaty, A, Archer, J, Bedford, A, Taylor, D, Griffith, M, Evans, J, Heron, K, Livingstone, B, O'Dwyer, K, Wheatley, D, Campbell, P, Dixon, P, McSweeney, L, Shanahan, MDG, Griffith, I, MacMahon, S, Rodgers, A, Collins, R, Prentice, C, Norton, R, Ockleford, P, Rutland, M, Dickinson, J, Gregg, P, Macdonald, D, Mollan, RAB, Douglas, J, Beaumont, D, Broad, J, Clark, T, Henderson, M, McCulloch, A, Neal, B, Prasad, R, Walker, N, Wood, M, Beighton, A, Bell, P, Farrell, B, Murch, K, Sharpe, N, Gordon, G, Doughty, R, Ratnasabapathy, Y, Danesh, J, Sleight, P, Peto, R, Simes, J, Keech, A, and Tri, PEP

Subjects
medicine.medical_specialty, Hip fracture, Aspirin, business.industry, Deep vein, medicine.medical_treatment, Hazard ratio, General Medicine, Placebo, medicine.disease, Thrombosis, Arthroplasty, Surgery, Pulmonary embolism, medicine.anatomical_structure, Anesthesia, medicine, business, medicine.drug
Abstract

Summary Background Previous trials of antiplatelet therapy for the prevention of venous thromboembolism have individually been inconclusive, but a meta-analysis of their results indicated reductions in the risks of deep-vein thrombosis and of pulmonary embolism in various high-risk groups. The aim of this large randomised placebo-controlled trial was to confirm or refute these apparent benefits. Methods During 1992–1998, 148 hospitals in Australia, New Zealand, South Africa, Sweden and the UK randomised 13 356 patients undergoing surgery for hip fracture, and 22 hospitals in New Zealand randomised a further 4088 patients undergoing elective arthroplasty. Study treatment was 160 mg daily aspirin or placebo, started preoperatively and continued for 35 days. Patients received any other thromboprophylaxis thought necessary. Follow-up was of mortality and of in-hospital morbidity up to day 35. Findings Among the patients with hip fracture, allocation to aspirin produced proportional reductions in pulmonary embolism of 43% (95% CI 18–60; p=0·002) and in symptomatic deep-vein thrombosis of 29% (3–48; p=0·03). Pulmonary embolism or deep-vein thrombosis was confirmed in 105 (1·6%) of 6679 patients assigned aspirin compared with 165 (2·5%) of 6677 assigned placebo, which represents an absolute reduction of 9 (SE 2) per 1000 and a proportional reduction of 36% (19–50; p=0·0003). Similar proportional effects were seen in all major subgroups, including patients receiving subcutaneous heparin. Aspirin prevented 4 (1) fatal pulmonary emboli per 1000 patients (18 aspirin-group vs 43 placebo-group deaths), representing a proportional reduction of 58% (27–76; p=0·002), with no apparent effect on deaths from any other vascular cause (hazard ratio 1·04 [95% CI 0·86–1·26]) or non-vascular cause (1·01 [0·84–1·23]). Deaths due to bleeding were few (13 aspirin vs 15 placebo), but there was an excess of 6 (3) postoperative transfused bleeding episodes per 1000 patients assigned aspirin (p=0·04). Among electivearthroplasty patients, rates of venous thromboembolism were lower, but the proportional effects of aspirin were compatible with those among patients with hip fracture.

Published
2000

14. Large-scale discovery of novel genetic causes of developmental disorders

Author

Fitzgerald, TW, Gerety, SS, Jones, WD, van Kogelenberg, M, King, DA, McRae, J, Morley, KI, Parthiban, V, Al-Turki, S, Ambridge, K, Barrett, DM, Bayzetinova, T, Clayton, S, Coomber, EL, Gribble, S, Jones, P, Krishnappa, N, Mason, LE, Middleton, A, Miller, R, Prigmore, E, Rajan, D, Sifrim, A, Tivey, AR, Ahmed, M, Akawi, N, Andrews, R, Anjum, U, Archer, H, Armstrong, R, Balasubramanian, M, Banerjee, R, Baralle, D, Batstone, P, Baty, D, Bennett, C, Berg, J, Bernhard, B, Bevan, AP, Blair, E, Blyth, M, Bohanna, D, Bourdon, L, Bourn, D, Brady, A, Bragin, E, Brewer, C, Brueton, L, Brunstrom, K, Bumpstead, SJ, Bunyan, DJ, Burn, J, Burton, J, Canham, N, Castle, B, Chandler, K, Clasper, S, Clayton-Smith, J, Cole, T, Collins, A, Collinson, MN, Connell, F, Cooper, N, Cox, H, Cresswell, L, Cross, G, Crow, Y, D'Alessandro, M, Dabir, T, Davidson, R, Davies, S, Dean, J, Deshpande, C, Devlin, G, Dixit, A, Dominiczak, A, Donnelly, C, Donnelly, D, Douglas, A, Duncan, A, Eason, J, Edkins, S, Ellard, S, Ellis, P, Elmslie, F, Evans, K, Everest, S, Fendick, T, Fisher, R, Flinter, F, Foulds, N, Fryer, A, Fu, B, Gardiner, C, Gaunt, L, Ghali, N, Gibbons, R, Pereira, SLG, Goodship, J, Goudie, D, Gray, E, Greene, P, Greenhalgh, L, Harrison, L, Hawkins, R, Hellens, S, Henderson, A, Hobson, E, Holden, S, Holder, S, Hollingsworth, G, Homfray, T, Humphreys, M, Hurst, J, Ingram, S, Irving, M, Jarvis, J, Jenkins, L, Johnson, D, Jones, D, Jones, E, Josifova, D, Joss, S, Kaemba, B, Kazembe, S, Kerr, B, Kini, U, Kinning, E, Kirby, G, Kirk, C, Kivuva, E, Kraus, A, Kumar, D, Lachlan, K, Lam, W, Lampe, A, Langman, C, Lees, M, Lim, D, Lowther, G, Lynch, SA, Magee, A, Maher, E, Mansour, S, Marks, K, Martin, K, Maye, U, McCann, E, McConnell, V, McEntagart, M, McGowan, R, McKay, K, McKee, S, McMullan, DJ, McNerlan, S, Mehta, S, Metcalfe, K, Miles, E, Mohammed, S, Montgomery, T, Moore, D, Morgan, S, Morris, A, Morton, J, Mugalaasi, H, Murday, V, Nevitt, L, Newbury-Ecob, R, Norman, A, O'Shea, R, Ogilvie, C, Park, S, Parker, MJ, Patel, C, Paterson, J, Payne, S, Phipps, J, Pilz, DT, Porteous, D, Pratt, N, Prescott, K, Price, S, Pridham, A, Procter, A, Purnell, H, Ragge, N, Rankin, J, Raymond, L, Rice, D, Robert, L, Roberts, E, Roberts, G, Roberts, J, Roberts, P, Ross, A, Rosser, E, Saggar, A, Samant, S, Sandford, R, Sarkar, A, Schweier, S, Scott, C, Scott, R, Selby, A, Seller, A, Sequeira, C, Shannon, N, Shanrif, S, Shaw-Smith, C, Shearing, E, Shears, D, Simonic, I, Simpkin, D, Singzon, R, Skitt, Z, Smith, A, Smith, B, Smith, K, Smithson, S, Sneddon, L, Splitt, M, Squires, M, Stewart, F, Stewart, H, Suri, M, Sutton, V, Swaminathan, GJ, Sweeney, E, Tatton-Brown, K, Taylor, C, Taylor, R, Tein, M, Temple, IK, Thomson, J, Tolmie, J, Torokwa, A, Treacy, B, Turner, C, Turnpenny, P, Tysoe, C, Vandersteen, A, Vasudevan, P, Vogt, J, Wakeling, E, Walker, D, Waters, J, Weber, A, Wellesley, D, Whiteford, M, Widaa, S, Wilcox, S, Williams, D, Williams, N, Woods, G, Wragg, C, Wright, M, Yang, F, Yau, M, Carter, NP, Parker, M, Firth, HV, FitzPatrick, DR, Wright, CF, Barrett, JC, Hurles, ME, Fitzgerald, TW, Gerety, SS, Jones, WD, van Kogelenberg, M, King, DA, McRae, J, Morley, KI, Parthiban, V, Al-Turki, S, Ambridge, K, Barrett, DM, Bayzetinova, T, Clayton, S, Coomber, EL, Gribble, S, Jones, P, Krishnappa, N, Mason, LE, Middleton, A, Miller, R, Prigmore, E, Rajan, D, Sifrim, A, Tivey, AR, Ahmed, M, Akawi, N, Andrews, R, Anjum, U, Archer, H, Armstrong, R, Balasubramanian, M, Banerjee, R, Baralle, D, Batstone, P, Baty, D, Bennett, C, Berg, J, Bernhard, B, Bevan, AP, Blair, E, Blyth, M, Bohanna, D, Bourdon, L, Bourn, D, Brady, A, Bragin, E, Brewer, C, Brueton, L, Brunstrom, K, Bumpstead, SJ, Bunyan, DJ, Burn, J, Burton, J, Canham, N, Castle, B, Chandler, K, Clasper, S, Clayton-Smith, J, Cole, T, Collins, A, Collinson, MN, Connell, F, Cooper, N, Cox, H, Cresswell, L, Cross, G, Crow, Y, D'Alessandro, M, Dabir, T, Davidson, R, Davies, S, Dean, J, Deshpande, C, Devlin, G, Dixit, A, Dominiczak, A, Donnelly, C, Donnelly, D, Douglas, A, Duncan, A, Eason, J, Edkins, S, Ellard, S, Ellis, P, Elmslie, F, Evans, K, Everest, S, Fendick, T, Fisher, R, Flinter, F, Foulds, N, Fryer, A, Fu, B, Gardiner, C, Gaunt, L, Ghali, N, Gibbons, R, Pereira, SLG, Goodship, J, Goudie, D, Gray, E, Greene, P, Greenhalgh, L, Harrison, L, Hawkins, R, Hellens, S, Henderson, A, Hobson, E, Holden, S, Holder, S, Hollingsworth, G, Homfray, T, Humphreys, M, Hurst, J, Ingram, S, Irving, M, Jarvis, J, Jenkins, L, Johnson, D, Jones, D, Jones, E, Josifova, D, Joss, S, Kaemba, B, Kazembe, S, Kerr, B, Kini, U, Kinning, E, Kirby, G, Kirk, C, Kivuva, E, Kraus, A, Kumar, D, Lachlan, K, Lam, W, Lampe, A, Langman, C, Lees, M, Lim, D, Lowther, G, Lynch, SA, Magee, A, Maher, E, Mansour, S, Marks, K, Martin, K, Maye, U, McCann, E, McConnell, V, McEntagart, M, McGowan, R, McKay, K, McKee, S, McMullan, DJ, McNerlan, S, Mehta, S, Metcalfe, K, Miles, E, Mohammed, S, Montgomery, T, Moore, D, Morgan, S, Morris, A, Morton, J, Mugalaasi, H, Murday, V, Nevitt, L, Newbury-Ecob, R, Norman, A, O'Shea, R, Ogilvie, C, Park, S, Parker, MJ, Patel, C, Paterson, J, Payne, S, Phipps, J, Pilz, DT, Porteous, D, Pratt, N, Prescott, K, Price, S, Pridham, A, Procter, A, Purnell, H, Ragge, N, Rankin, J, Raymond, L, Rice, D, Robert, L, Roberts, E, Roberts, G, Roberts, J, Roberts, P, Ross, A, Rosser, E, Saggar, A, Samant, S, Sandford, R, Sarkar, A, Schweier, S, Scott, C, Scott, R, Selby, A, Seller, A, Sequeira, C, Shannon, N, Shanrif, S, Shaw-Smith, C, Shearing, E, Shears, D, Simonic, I, Simpkin, D, Singzon, R, Skitt, Z, Smith, A, Smith, B, Smith, K, Smithson, S, Sneddon, L, Splitt, M, Squires, M, Stewart, F, Stewart, H, Suri, M, Sutton, V, Swaminathan, GJ, Sweeney, E, Tatton-Brown, K, Taylor, C, Taylor, R, Tein, M, Temple, IK, Thomson, J, Tolmie, J, Torokwa, A, Treacy, B, Turner, C, Turnpenny, P, Tysoe, C, Vandersteen, A, Vasudevan, P, Vogt, J, Wakeling, E, Walker, D, Waters, J, Weber, A, Wellesley, D, Whiteford, M, Widaa, S, Wilcox, S, Williams, D, Williams, N, Woods, G, Wragg, C, Wright, M, Yang, F, Yau, M, Carter, NP, Parker, M, Firth, HV, FitzPatrick, DR, Wright, CF, Barrett, JC, and Hurles, ME

Abstract

Despite three decades of successful, predominantly phenotype-driven discovery of the genetic causes of monogenic disorders, up to half of children with severe developmental disorders of probable genetic origin remain without a genetic diagnosis. Particularly challenging are those disorders rare enough to have eluded recognition as a discrete clinical entity, those with highly variable clinical manifestations, and those that are difficult to distinguish from other, very similar, disorders. Here we demonstrate the power of using an unbiased genotype-driven approach to identify subsets of patients with similar disorders. By studying 1,133 children with severe, undiagnosed developmental disorders, and their parents, using a combination of exome sequencing and array-based detection of chromosomal rearrangements, we discovered 12 novel genes associated with developmental disorders. These newly implicated genes increase by 10% (from 28% to 31%) the proportion of children that could be diagnosed. Clustering of missense mutations in six of these newly implicated genes suggests that normal development is being perturbed by an activating or dominant-negative mechanism. Our findings demonstrate the value of adopting a comprehensive strategy, both genome-wide and nationwide, to elucidate the underlying causes of rare genetic disorders.

Published
2015

15. International network of cancer genome projects

Author

Hudson, TJ, Anderson, W, Aretz, A, Barker, AD, Bell, C, Bernabe, RR, Bhan, MK, Calvo, F, Eerola, I, Gerhard, DS, Guttmacher, A, Guyer, M, Hemsley, FM, Jennings, JL, Kerr, D, Klatt, P, Kolar, P, Kusuda, J, Lane, DP, Laplace, F, Lu, Y, Nettekoven, G, Ozenberger, B, Peterson, J, Rao, TS, Remacle, J, Schafer, AJ, Shibata, T, Stratton, MR, Vockley, JG, Watanabe, K, Yang, H, Yuen, MMF, Knoppers, M, Bobrow, M, Cambon-Thomsen, A, Dressler, LG, Dyke, SOM, Joly, Y, Kato, K, Kennedy, KL, Nicolas, P, Parker, MJ, Rial-Sebbag, E, Romeo-Casabona, CM, Shaw, KM, Wallace, S, Wiesner, GL, Zeps, N, Lichter, P, Biankin, AV, Chabannon, C, Chin, L, Clement, B, de Alava, E, Degos, F, Ferguson, ML, Geary, P, Hayes, DN, Johns, AL, Nakagawa, H, Penny, R, Piris, MA, Sarin, R, Scarpa, A, van de Vijver, M, Futreal, PA, Aburatani, H, Bayes, M, Bowtell, DDL, Campbell, PJ, Estivill, X, Grimmond, SM, Gut, I, Hirst, M, Lopez-Otin, C, Majumder, P, Marra, M, Ning, Z, Puente, XS, Ruan, Y, Stunnenberg, HG, Swerdlow, H, Velculescu, VE, Wilson, RK, Xue, HH, Yang, L, Spellman, PT, Bader, GD, Boutros, PC, Flicek, P, Getz, G, Guigo, R, Guo, G, Haussler, D, Heath, S, Hubbard, TJ, Jiang, T, Jones, SM, Li, Q, Lopez-Bigas, N, Luo, R, Pearson, JV, Quesada, V, Raphael, BJ, Sander, C, Speed, TP, Stuart, JM, Teague, JW, Totoki, Y, Tsunoda, T, Valencia, A, Wheeler, DA, Wu, H, Zhao, S, Zhou, G, Stein, LD, Lathrop, M, Ouellette, BFF, Thomas, G, Yoshida, T, Axton, M, Gunter, C, McPherson, JD, Miller, LJ, Kasprzyk, A, Zhang, J, Haider, SA, Wang, J, Yung, CK, Cross, A, Liang, Y, Gnaneshan, S, Guberman, J, Hsu, J, Chalmers, DRC, Hasel, KW, Kaan, TSH, Knoppers, BM, Lowrance, WW, Masui, T, Rodriguez, LL, Vergely, C, Cloonan, N, Defazio, A, Eshleman, JR, Etemadmoghadam, D, Gardiner, BA, Kench, JG, Sutherland, RL, Tempero, MA, Waddell, NJ, Wilson, PJ, Gallinger, S, Tsao, M-S, Shaw, PA, Petersen, GM, Mukhopadhyay, D, DePinho, RA, Thayer, S, Muthuswamy, L, Shazand, K, Beck, T, Sam, M, Timms, L, Ballin, V, Ji, J, Zhang, X, Chen, F, Hu, X, Yang, Q, Tian, G, Zhang, L, Xing, X, Li, X, Zhu, Z, Yu, Y, Yu, J, Tost, J, Brennan, P, Holcatova, I, Zaridze, D, Brazma, A, Egevad, L, Prokhortchouk, E, Banks, RE, Uhlen, M, Viksna, J, Ponten, F, Skryabin, K, Birney, E, Borg, A, Borresen-Dale, A-L, Caldas, C, Foekens, JA, Martin, S, Reis-Filho, JS, Richardson, AL, Sotiriou, C, van't Veer, L, Birnbaum, D, Blanche, H, Boucher, P, Boyault, S, Masson-Jacquemier, JD, Pauporte, I, Pivot, X, Vincent-Salomon, A, Tabone, E, Theillet, C, Treilleux, I, Bioulac-Sage, P, Decaens, T, Franco, D, Gut, M, Samuel, D, Zucman-Rossi, J, Eils, R, Brors, B, Korbel, JO, Korshunov, A, Landgraf, P, Lehrach, H, Pfister, S, Radlwimmer, B, Reifenberger, G, Taylor, MD, von Kalle, C, Majumder, PP, Pederzoli, P, Lawlor, RT, Delledonne, M, Bardelli, A, Gress, T, Klimstra, D, Zamboni, G, Nakamura, Y, Miyano, S, Fujimoto, A, Campo, E, de Sanjose, S, Montserrat, E, Gonzalez-Diaz, M, Jares, P, Himmelbaue, H, Bea, S, Aparicio, S, Easton, DF, Collins, FS, Compton, CC, Lander, ES, Burke, W, Green, AR, Hamilton, SR, Kallioniemi, OP, Ley, TJ, Liu, ET, Wainwright, BJ, Hudson, TJ, Anderson, W, Aretz, A, Barker, AD, Bell, C, Bernabe, RR, Bhan, MK, Calvo, F, Eerola, I, Gerhard, DS, Guttmacher, A, Guyer, M, Hemsley, FM, Jennings, JL, Kerr, D, Klatt, P, Kolar, P, Kusuda, J, Lane, DP, Laplace, F, Lu, Y, Nettekoven, G, Ozenberger, B, Peterson, J, Rao, TS, Remacle, J, Schafer, AJ, Shibata, T, Stratton, MR, Vockley, JG, Watanabe, K, Yang, H, Yuen, MMF, Knoppers, M, Bobrow, M, Cambon-Thomsen, A, Dressler, LG, Dyke, SOM, Joly, Y, Kato, K, Kennedy, KL, Nicolas, P, Parker, MJ, Rial-Sebbag, E, Romeo-Casabona, CM, Shaw, KM, Wallace, S, Wiesner, GL, Zeps, N, Lichter, P, Biankin, AV, Chabannon, C, Chin, L, Clement, B, de Alava, E, Degos, F, Ferguson, ML, Geary, P, Hayes, DN, Johns, AL, Nakagawa, H, Penny, R, Piris, MA, Sarin, R, Scarpa, A, van de Vijver, M, Futreal, PA, Aburatani, H, Bayes, M, Bowtell, DDL, Campbell, PJ, Estivill, X, Grimmond, SM, Gut, I, Hirst, M, Lopez-Otin, C, Majumder, P, Marra, M, Ning, Z, Puente, XS, Ruan, Y, Stunnenberg, HG, Swerdlow, H, Velculescu, VE, Wilson, RK, Xue, HH, Yang, L, Spellman, PT, Bader, GD, Boutros, PC, Flicek, P, Getz, G, Guigo, R, Guo, G, Haussler, D, Heath, S, Hubbard, TJ, Jiang, T, Jones, SM, Li, Q, Lopez-Bigas, N, Luo, R, Pearson, JV, Quesada, V, Raphael, BJ, Sander, C, Speed, TP, Stuart, JM, Teague, JW, Totoki, Y, Tsunoda, T, Valencia, A, Wheeler, DA, Wu, H, Zhao, S, Zhou, G, Stein, LD, Lathrop, M, Ouellette, BFF, Thomas, G, Yoshida, T, Axton, M, Gunter, C, McPherson, JD, Miller, LJ, Kasprzyk, A, Zhang, J, Haider, SA, Wang, J, Yung, CK, Cross, A, Liang, Y, Gnaneshan, S, Guberman, J, Hsu, J, Chalmers, DRC, Hasel, KW, Kaan, TSH, Knoppers, BM, Lowrance, WW, Masui, T, Rodriguez, LL, Vergely, C, Cloonan, N, Defazio, A, Eshleman, JR, Etemadmoghadam, D, Gardiner, BA, Kench, JG, Sutherland, RL, Tempero, MA, Waddell, NJ, Wilson, PJ, Gallinger, S, Tsao, M-S, Shaw, PA, Petersen, GM, Mukhopadhyay, D, DePinho, RA, Thayer, S, Muthuswamy, L, Shazand, K, Beck, T, Sam, M, Timms, L, Ballin, V, Ji, J, Zhang, X, Chen, F, Hu, X, Yang, Q, Tian, G, Zhang, L, Xing, X, Li, X, Zhu, Z, Yu, Y, Yu, J, Tost, J, Brennan, P, Holcatova, I, Zaridze, D, Brazma, A, Egevad, L, Prokhortchouk, E, Banks, RE, Uhlen, M, Viksna, J, Ponten, F, Skryabin, K, Birney, E, Borg, A, Borresen-Dale, A-L, Caldas, C, Foekens, JA, Martin, S, Reis-Filho, JS, Richardson, AL, Sotiriou, C, van't Veer, L, Birnbaum, D, Blanche, H, Boucher, P, Boyault, S, Masson-Jacquemier, JD, Pauporte, I, Pivot, X, Vincent-Salomon, A, Tabone, E, Theillet, C, Treilleux, I, Bioulac-Sage, P, Decaens, T, Franco, D, Gut, M, Samuel, D, Zucman-Rossi, J, Eils, R, Brors, B, Korbel, JO, Korshunov, A, Landgraf, P, Lehrach, H, Pfister, S, Radlwimmer, B, Reifenberger, G, Taylor, MD, von Kalle, C, Majumder, PP, Pederzoli, P, Lawlor, RT, Delledonne, M, Bardelli, A, Gress, T, Klimstra, D, Zamboni, G, Nakamura, Y, Miyano, S, Fujimoto, A, Campo, E, de Sanjose, S, Montserrat, E, Gonzalez-Diaz, M, Jares, P, Himmelbaue, H, Bea, S, Aparicio, S, Easton, DF, Collins, FS, Compton, CC, Lander, ES, Burke, W, Green, AR, Hamilton, SR, Kallioniemi, OP, Ley, TJ, Liu, ET, and Wainwright, BJ

Abstract

The International Cancer Genome Consortium (ICGC) was launched to coordinate large-scale cancer genome studies in tumours from 50 different cancer types and/or subtypes that are of clinical and societal importance across the globe. Systematic studies of more than 25,000 cancer genomes at the genomic, epigenomic and transcriptomic levels will reveal the repertoire of oncogenic mutations, uncover traces of the mutagenic influences, define clinically relevant subtypes for prognosis and therapeutic management, and enable the development of new cancer therapies.

Published
2010

17. Cutting-out of the dynamic hip screw related to its position

Author

Parker Mj

Subjects
Orthodontics, Dynamic hip screw, Osteosynthesis, business.industry, Hip Fractures, Bone Screws, Dentistry, Femur Head, Lower limb, Bone screws, Radiography, Position (vector), Fracture Fixation, Medicine, Humans, Orthopedics and Sports Medicine, Surgery, Femur, business
Published
1992

47. Iron supplementation for anemia after hip fracture surgery: a randomized trial of 300 patients.

Author

Parker MJ and Parker, Martyn J

Abstract

Background: Anemia as a consequence of surgery is often treated with iron therapy. The evidence base for this practice is limited. To determine if oral iron therapy is beneficial for the treatment of anemia after surgery for the treatment of a hip fracture, we undertook a prospective, randomized controlled trial.Methods: Three hundred patients with a hemoglobin level of <110 g/L after treatment for a hip fracture were randomized to receive either a twenty-eight-day course of ferrous sulfate therapy or no iron therapy. Hemoglobin levels were measured at six weeks after surgery. The length of the hospital stay and the mortality rate at one year were compared between groups.Results: The mean rise in hemoglobin levels six weeks after discharge from the hospital was 21 g/L in the iron group, compared with 18 g/L in the no-iron group (p = 0.07). There was no significant difference between the two groups with regard to the length of hospital stay or the mortality rate. Seventeen percent of the patients who were allocated to iron therapy reported adverse effects of the medication.Conclusions: The present study demonstrated that iron therapy had no clinically relevant benefit when used to treat anemia associated with a hip fracture. [ABSTRACT FROM AUTHOR]

Published
2010
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49. Incidence of fracture-healing complications after femoral neck fractures.

Author

Parker MJ, Raghavan R, Gurusamy K, Parker, Martyn J, Raghavan, Roshan, and Gurusamy, Kurinchi

Abstract

What is the relationship between the age or gender of the patient and the incidence of fracture-healing complications after internal fixation of intracapsular fractures? We aimed to determine the association between the age of the patient and fracture nonunion and also to establish if the gender of the patient had any influence on the occurrence of fracture nonunion. We prospectively studied 1133 patients with intracapsular fractures of the femoral neck treated by internal fixation. The overall incidence of nonunion was 19.3%. Fracture nonunion was less common for undisplaced fractures than for displaced fractures (48 of 565 [8.5%] versus 171 of 568 [30.1%]) and in men than in women (35 of 271 [12.9%] versus 184 of 862 [21.3%]). The incidence of nonunion progressively increased with age from one of 17 (5.9%) in patients younger than 40 years to 84 of 337 (24.9%) in patients in their 70s. For patients in their 80s, the incidence of nonunion began to decrease, but if patients who died within 1 year after injury were excluded, the incidence continued to increase. Our study showed an increased risk for intracapsular hip fractures developing nonunion with older age and in females. [ABSTRACT FROM AUTHOR]

Published
2007

50. Modern methods of treating hip fractures.

Author

Parker MJ and Gurusamy K

Abstract

Contemporary surgical and anaesthetic methods should enable almost all hip fractures to be treated surgically. Many of the implants used for the internal fixation of hip fractures or the arthroplasties for replacement of the hip joint have been in use for over 50 years. Marked improvements in surgical technique have led to lower fracture and surgical complications. Undisplaced intracapsular fractures and displaced fractures in the younger patient are best treated by internal fixation. For the elderly with a displaced intracapsular fracture then hemiarthroplasty is generally used. There is insufficient evidence that total hip replacements or bipolar hemiarthroplasties have any advantage over the more traditional designs. For trochanteric fractures the sliding hip screw remains the implant of choice, although the newer intramedullary nails are valuable for more specific fracture types and their use will become more common. Following surgery almost all patients should be allowed to mobilize without any restrictions on weight bearing or hip movements. [ABSTRACT FROM AUTHOR]

Published
2005
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