Search

Your search keyword '"Clowes V"' showing total 33 results
Start Over Author "Clowes V"
33 results on '"Clowes V"'

1. Functional and clinical studies reveal pathophysiological complexity of CLCN4-related neurodevelopmental condition.

Author

Palmer, E.E., Pusch, M., Picollo, A., Forwood, C., Nguyen, M.H., Suckow, V., Gibbons, J., Hoff, A., Sigfrid, L., Megarbane, A., Nizon, M., Cogné, B., Beneteau, C., Alkuraya, F.S., Chedrawi, A., Hashem, M.O., Stamberger, H., Weckhuysen, S., Vanlander, A., Ceulemans, B., Rajagopalan, S., Nunn, K., Arpin, S., Raynaud, M., Motter, C.S., Ward-Melver, C., Janssens, K., Meuwissen, M., Beysen, D., Dikow, N., Grimmel, M., Haack, T.B., Clement, E., McTague, A., Hunt, D., Townshend, S., Ward, M., Richards, L.J., Simons, C., Costain, G., Dupuis, L., Mendoza-Londono, R., Dudding-Byth, T., Boyle, J., Saunders, C., Fleming, E., Chehadeh, S. El, Spitz, M.A., Piton, A., Gerard, B., bi Warde, M.T. A, Rea, G., McKenna, C., Douzgou, S., Banka, S., Akman, C., Bain, J.M., Sands, T.T., Wilson, G.N., Silvertooth, E.J., Miller, L., Lederer, D., Sachdev, R., Macintosh, R., Monestier, O., Karadurmus, D., Collins, F., Carter, M., Rohena, L., Willemsen, M.H., Ockeloen, C.W., Pfundt, R.P., Kroft, S.D., Field, M., Laranjeira, F.E.R., Fortuna, A.M., Soares, A.R., Michaud, V., Naudion, S., Golla, S., Weaver, D.D., Bird, L.M., Friedman, J., Clowes, V., Joss, S., Pölsler, L., Campeau, P.M., Blazo, M., Bijlsma, E.K., Rosenfeld, J.A., Beetz, C., Powis, Z., McWalter, K., Brandt, T., Torti, E., Mathot, M., Mohammad, S.S., Armstrong, R., Kalscheuer, V.M., Palmer, E.E., Pusch, M., Picollo, A., Forwood, C., Nguyen, M.H., Suckow, V., Gibbons, J., Hoff, A., Sigfrid, L., Megarbane, A., Nizon, M., Cogné, B., Beneteau, C., Alkuraya, F.S., Chedrawi, A., Hashem, M.O., Stamberger, H., Weckhuysen, S., Vanlander, A., Ceulemans, B., Rajagopalan, S., Nunn, K., Arpin, S., Raynaud, M., Motter, C.S., Ward-Melver, C., Janssens, K., Meuwissen, M., Beysen, D., Dikow, N., Grimmel, M., Haack, T.B., Clement, E., McTague, A., Hunt, D., Townshend, S., Ward, M., Richards, L.J., Simons, C., Costain, G., Dupuis, L., Mendoza-Londono, R., Dudding-Byth, T., Boyle, J., Saunders, C., Fleming, E., Chehadeh, S. El, Spitz, M.A., Piton, A., Gerard, B., bi Warde, M.T. A, Rea, G., McKenna, C., Douzgou, S., Banka, S., Akman, C., Bain, J.M., Sands, T.T., Wilson, G.N., Silvertooth, E.J., Miller, L., Lederer, D., Sachdev, R., Macintosh, R., Monestier, O., Karadurmus, D., Collins, F., Carter, M., Rohena, L., Willemsen, M.H., Ockeloen, C.W., Pfundt, R.P., Kroft, S.D., Field, M., Laranjeira, F.E.R., Fortuna, A.M., Soares, A.R., Michaud, V., Naudion, S., Golla, S., Weaver, D.D., Bird, L.M., Friedman, J., Clowes, V., Joss, S., Pölsler, L., Campeau, P.M., Blazo, M., Bijlsma, E.K., Rosenfeld, J.A., Beetz, C., Powis, Z., McWalter, K., Brandt, T., Torti, E., Mathot, M., Mohammad, S.S., Armstrong, R., and Kalscheuer, V.M.

Abstract

01 februari 2023, Item does not contain fulltext, Missense and truncating variants in the X-chromosome-linked CLCN4 gene, resulting in reduced or complete loss-of-function (LOF) of the encoded chloride/proton exchanger ClC-4, were recently demonstrated to cause a neurocognitive phenotype in both males and females. Through international clinical matchmaking and interrogation of public variant databases we assembled a database of 90 rare CLCN4 missense variants in 90 families: 41 unique and 18 recurrent variants in 49 families. For 43 families, including 22 males and 33 females, we collated detailed clinical and segregation data. To confirm causality of variants and to obtain insight into disease mechanisms, we investigated the effect on electrophysiological properties of 59 of the variants in Xenopus oocytes using extended voltage and pH ranges. Detailed analyses revealed new pathophysiological mechanisms: 25% (15/59) of variants demonstrated LOF, characterized by a "shift" of the voltage-dependent activation to more positive voltages, and nine variants resulted in a toxic gain-of-function, associated with a disrupted gate allowing inward transport at negative voltages. Functional results were not always in line with in silico pathogenicity scores, highlighting the complexity of pathogenicity assessment for accurate genetic counselling. The complex neurocognitive and psychiatric manifestations of this condition, and hitherto under-recognized impacts on growth, gastrointestinal function, and motor control are discussed. Including published cases, we summarize features in 122 individuals from 67 families with CLCN4-related neurodevelopmental condition and suggest future research directions with the aim of improving the integrated care for individuals with this diagnosis.

Published
2023

2. The phenotypic continuum of ATPLA3-related disorders

Author

Vezyroglou, A, Akilapa, R, Barwick, K, Koene, S, Brownstein, CA, Holder-Espinasse, M, Fry, AE, Nemeth, AH, Tofaris, GK, Hay, E, Hughes, I, Mansour, S, Mordekar, SR, Splitt, M, Turnpenny, PD, Demetriou, D, Koopmann, TT, Ruivenkamp, CAL, Agrawal, PB, Carr, L, Clowes, V, Ghali, N, Holder, SE, Radley, J, Male, A, Sisodiya, SM, Kurian, MA, Cross, JH, and Balasubramanian, M

Abstract

Background and Objectives ATP1A3 is associated with a broad spectrum of predominantly neurologic disorders, which continues to expand beyond the initially defined phenotypes of alternating hemiplegia of childhood, rapid-onset dystonia parkinsonism, and cerebellar ataxia, areflexia, pes cavus, optic atrophy, sensorineural hearing loss syndrome. This phenotypic variability makes it challenging to assess the pathogenicity of an ATP1A3 variant found in an undiagnosed patient. We describe the phenotypic features of individuals carrying a pathogenic/likely pathogenic ATP1A3 variant and perform a literature review of all ATP1A3 variants published thus far in association with human neurologic disease. Our aim is to demonstrate the heterogeneous clinical spectrum of the gene and look for phenotypic overlap between patients that will streamline the diagnostic process. Methods Undiagnosed individuals with ATP1A3 variants were identified within the cohort of the Deciphering Developmental Disorders study with additional cases contributed by collaborators internationally. Detailed clinical data were collected with consent through a questionnaire completed by the referring clinicians. PubMed was searched for publications containing the term “ATP1A3” from 2004 to 2021. Results Twenty-four individuals with a previously undiagnosed neurologic phenotype were found to carry 21 ATP1A3 variants. Eight variants have been previously published. Patients experienced on average 2–3 different types of paroxysmal events. Permanent neurologic features were common including microcephaly (7; 29%), ataxia (13; 54%), dystonia (10; 42%), and hypotonia (7; 29%). All patients had cognitive impairment. Neuropsychiatric diagnoses were reported in 16 (66.6%) individuals. Phenotypes were extremely varied, and most individuals did not fit clinical criteria for previously published phenotypes. On review of the literature, 1,108 individuals have been reported carrying 168 different ATP1A3 variants. The most common variants are associated with well-defined phenotypes, while more rare variants often result in very rare symptom correlations, such as are seen in our study. Combined Annotation-Dependent Depletion (CADD) scores of pathogenic and likely pathogenic variants were significantly higher and variants clustered within 6 regions of constraint. Discussion Our study shows that looking for a combination of paroxysmal events, hyperkinesia, neuropsychiatric symptoms, and cognitive impairment and evaluating the CADD score and variant location can help identify an ATP1A3-related condition, rather than applying diagnostic criteria alone.

Published
2022

3. A prospective prostate cancer screening programme for men with pathogenic variants in mismatch repair genes (IMPACT): initial results from an international prospective study.

Author

Bancroft E.K., Page E.C., Brook M.N., Thomas S., Taylor N., Pope J., McHugh J., Jones A.-B., Karlsson Q., Merson S., Ong K.R., Hoffman J., Huber C., Maehle L., Grindedal E.M., Stormorken A., Evans D.G., Rothwell J., Lalloo F., Brady A.F., Bartlett M., Snape K., Hanson H., James P., McKinley J., Mascarenhas L., Syngal S., Ukaegbu C., Side L., Thomas T., Barwell J., Teixeira M.R., Izatt L., Suri M., Macrae F.A., Poplawski N., Chen-Shtoyerman R., Ahmed M., Musgrave H., Nicolai N., Greenhalgh L., Brewer C., Pachter N., Spigelman A.D., Azzabi A., Helfand B.T., Halliday D., Buys S., Ramon y Cajal T., Donaldson A., Cooney K.A., Harris M., McGrath J., Davidson R., Taylor A., Cooke P., Myhill K., Hogben M., Aaronson N.K., Ardern-Jones A., Bangma C.H., Castro E., Dearnaley D., Dias A., Dudderidge T., Eccles D.M., Green K., Eyfjord J., Falconer A., Foster C.S., Gronberg H., Hamdy F.C., Johannsson O., Khoo V., Lilja H., Lindeman G.J., Lubinski J., Axcrona K., Mikropoulos C., Mitra A.V., Moynihan C., Ni Raghallaigh H., Rennert G., Collier R., Adams L., Adlard J., Alfonso R., Ali S., Andrew A., Araujo L., Azam N., Ball D., Barker Q., Basevitch A., Benton B., Berlin C., Bermingham N., Biller L., Bloss A., Bradford M., Bradshaw N., Branson A., Brendler C., Brennan M., Bulman B., Burgess L., Cahill D., Callard A., Calvo Verges N., Cardoso M., Carter V., Catanzaro M., Chamberlain A., Chapman C., Chong M., Clark C., Clowes V., Cogley L., Cole T., Compton C., Conner T., Cookson S., Cornford P., Costello P., Coulier L., Davies M., Dechet C., DeSouza B., Devlin G., Douglas F., Douglas E., Dudakia D., Duncan A., Ellery N., Everest S., Freemantle S., Frydenberg M., Fuller D., Gabriel C., Gale M., Garcia L., Gay S., Genova E., George A., Georgiou D., Gisbert A., Gleeson M., Glover W., Gnanapragasam V., Goff S., Goldgar D., Goncalves N., Goodman S., Gorrie J., Gott H., Grant A., Gray C., Griffiths J., Gupwell K., Gurasashvili J., Hanslien E., Haraldsdottir S., Hart R., Hartigan C., Hawkes L., Heaton T., Henderson A., Henrique R., Hilario K., Hill K., Hulick P., Hunt C., Hutchings M., Ibitoye R., Inglehearn T., Ireland J., Islam F., Ismail S., Jacobs C., James D., Jenkins S., Jobson I., Johnstone A., Jones O., Josefsberg Ben-Yehoshua S., Kaemba B., Kaul K., Kemp Z., Kinsella N., Klehm M., Kockelbergh R., Kohut K., Kosicka-Slawinska M., Kulkarni A., Kumar P., Lam J., LeButt M., Leibovici D., Lim R., Limb L., Lomas C., Longmuir M., Lopez C., Magnani T., Maia S., Maiden J., Male A., Manalo M., Martin P., McBride D., McGuire M., McMahon R., McNally C., McVeigh T., Melzer E., Mencias M., Mercer C., Mitchell G., Mora J., Morton C., Moss C., Murphy M., Murphy D., Mzazi S., Nadolski M., Newlin A., Nogueira P., O'Keefe R., O'Toole K., O'Connell S., Ogden C., Okoth L., Oliveira J., Paez E., Palou J., Park L., Patel N., Paulo Souto J., Pearce A., Peixoto A., Perez K., Petelin L., Pichert G., Poile C., Potter A., Preitner N., Purnell H., Quinn E., Radice P., Rankin B., Rees K., Renton C., Richardson K., Risby P., Rogers J., Ruderman M., Ruiz A., Sajoo A., Salvatore N., Sands V., Sanguedolce F., Sattar A., Saunders K., Schofield L., Scott R., Searle A., Sehra R., Selkirk C., Shackleton K., Shanley S., Shaw A., Shevrin D., Shipman H., Sidat Z., Siguake K., Simon K., Smyth C., Snadden L., Solanky N., Solomons J., Sorrentino M., Stayner B., Stephenson R., Stoffel E., Thomas M., Thompson A., Tidey L., Tischkowitz M., Torokwa A., Townshend S., Treherne K., Tricker K., Trinh Q.-D., Tripathi V., Turnbull C., Valdagni R., Van As N., Venne V., Verdon L., Vitellaro M., Vogel K., Walker L., Watford A., Watt C., Weintroub I., Weiss S., Weissman S., Weston M., Wiggins J., Wise G., Woodhouse C., Yesildag P., Youngs A., Yurgelun M., Zollo F., Offman J., Kote-Jarai Z., Eeles R.A., Bancroft E.K., Page E.C., Brook M.N., Thomas S., Taylor N., Pope J., McHugh J., Jones A.-B., Karlsson Q., Merson S., Ong K.R., Hoffman J., Huber C., Maehle L., Grindedal E.M., Stormorken A., Evans D.G., Rothwell J., Lalloo F., Brady A.F., Bartlett M., Snape K., Hanson H., James P., McKinley J., Mascarenhas L., Syngal S., Ukaegbu C., Side L., Thomas T., Barwell J., Teixeira M.R., Izatt L., Suri M., Macrae F.A., Poplawski N., Chen-Shtoyerman R., Ahmed M., Musgrave H., Nicolai N., Greenhalgh L., Brewer C., Pachter N., Spigelman A.D., Azzabi A., Helfand B.T., Halliday D., Buys S., Ramon y Cajal T., Donaldson A., Cooney K.A., Harris M., McGrath J., Davidson R., Taylor A., Cooke P., Myhill K., Hogben M., Aaronson N.K., Ardern-Jones A., Bangma C.H., Castro E., Dearnaley D., Dias A., Dudderidge T., Eccles D.M., Green K., Eyfjord J., Falconer A., Foster C.S., Gronberg H., Hamdy F.C., Johannsson O., Khoo V., Lilja H., Lindeman G.J., Lubinski J., Axcrona K., Mikropoulos C., Mitra A.V., Moynihan C., Ni Raghallaigh H., Rennert G., Collier R., Adams L., Adlard J., Alfonso R., Ali S., Andrew A., Araujo L., Azam N., Ball D., Barker Q., Basevitch A., Benton B., Berlin C., Bermingham N., Biller L., Bloss A., Bradford M., Bradshaw N., Branson A., Brendler C., Brennan M., Bulman B., Burgess L., Cahill D., Callard A., Calvo Verges N., Cardoso M., Carter V., Catanzaro M., Chamberlain A., Chapman C., Chong M., Clark C., Clowes V., Cogley L., Cole T., Compton C., Conner T., Cookson S., Cornford P., Costello P., Coulier L., Davies M., Dechet C., DeSouza B., Devlin G., Douglas F., Douglas E., Dudakia D., Duncan A., Ellery N., Everest S., Freemantle S., Frydenberg M., Fuller D., Gabriel C., Gale M., Garcia L., Gay S., Genova E., George A., Georgiou D., Gisbert A., Gleeson M., Glover W., Gnanapragasam V., Goff S., Goldgar D., Goncalves N., Goodman S., Gorrie J., Gott H., Grant A., Gray C., Griffiths J., Gupwell K., Gurasashvili J., Hanslien E., Haraldsdottir S., Hart R., Hartigan C., Hawkes L., Heaton T., Henderson A., Henrique R., Hilario K., Hill K., Hulick P., Hunt C., Hutchings M., Ibitoye R., Inglehearn T., Ireland J., Islam F., Ismail S., Jacobs C., James D., Jenkins S., Jobson I., Johnstone A., Jones O., Josefsberg Ben-Yehoshua S., Kaemba B., Kaul K., Kemp Z., Kinsella N., Klehm M., Kockelbergh R., Kohut K., Kosicka-Slawinska M., Kulkarni A., Kumar P., Lam J., LeButt M., Leibovici D., Lim R., Limb L., Lomas C., Longmuir M., Lopez C., Magnani T., Maia S., Maiden J., Male A., Manalo M., Martin P., McBride D., McGuire M., McMahon R., McNally C., McVeigh T., Melzer E., Mencias M., Mercer C., Mitchell G., Mora J., Morton C., Moss C., Murphy M., Murphy D., Mzazi S., Nadolski M., Newlin A., Nogueira P., O'Keefe R., O'Toole K., O'Connell S., Ogden C., Okoth L., Oliveira J., Paez E., Palou J., Park L., Patel N., Paulo Souto J., Pearce A., Peixoto A., Perez K., Petelin L., Pichert G., Poile C., Potter A., Preitner N., Purnell H., Quinn E., Radice P., Rankin B., Rees K., Renton C., Richardson K., Risby P., Rogers J., Ruderman M., Ruiz A., Sajoo A., Salvatore N., Sands V., Sanguedolce F., Sattar A., Saunders K., Schofield L., Scott R., Searle A., Sehra R., Selkirk C., Shackleton K., Shanley S., Shaw A., Shevrin D., Shipman H., Sidat Z., Siguake K., Simon K., Smyth C., Snadden L., Solanky N., Solomons J., Sorrentino M., Stayner B., Stephenson R., Stoffel E., Thomas M., Thompson A., Tidey L., Tischkowitz M., Torokwa A., Townshend S., Treherne K., Tricker K., Trinh Q.-D., Tripathi V., Turnbull C., Valdagni R., Van As N., Venne V., Verdon L., Vitellaro M., Vogel K., Walker L., Watford A., Watt C., Weintroub I., Weiss S., Weissman S., Weston M., Wiggins J., Wise G., Woodhouse C., Yesildag P., Youngs A., Yurgelun M., Zollo F., Offman J., Kote-Jarai Z., and Eeles R.A.

Abstract

Background: Lynch syndrome is a rare familial cancer syndrome caused by pathogenic variants in the mismatch repair genes MLH1, MSH2, MSH6, or PMS2, that cause predisposition to various cancers, predominantly colorectal and endometrial cancer. Data are emerging that pathogenic variants in mismatch repair genes increase the risk of early-onset aggressive prostate cancer. The IMPACT study is prospectively assessing prostate-specific antigen (PSA) screening in men with germline mismatch repair pathogenic variants. Here, we report the usefulness of PSA screening, prostate cancer incidence, and tumour characteristics after the first screening round in men with and without these germline pathogenic variants. Method(s): The IMPACT study is an international, prospective study. Men aged 40-69 years without a previous prostate cancer diagnosis and with a known germline pathogenic variant in the MLH1, MSH2, or MSH6 gene, and age-matched male controls who tested negative for a familial pathogenic variant in these genes were recruited from 34 genetic and urology clinics in eight countries, and underwent a baseline PSA screening. Men who had a PSA level higher than 3.0 ng/mL were offered a transrectal, ultrasound-guided, prostate biopsy and a histopathological analysis was done. All participants are undergoing a minimum of 5 years' annual screening. The primary endpoint was to determine the incidence, stage, and pathology of screening-detected prostate cancer in carriers of pathogenic variants compared with non-carrier controls. We used Fisher's exact test to compare the number of cases, cancer incidence, and positive predictive values of the PSA cutoff and biopsy between carriers and non-carriers and the differences between disease types (ie, cancer vs no cancer, clinically significant cancer vs no cancer). We assessed screening outcomes and tumour characteristics by pathogenic variant status. Here we present results from the first round of PSA screening in the IMPACT study. This

Published
2022

4. Quantifying prediction of pathogenicity for within-codon concordance (PM5) using 7541 functional classifications of BRCA1 and MSH2 missense variants

Author

Loong, Lucy, primary, Cubuk, Cankut, additional, Choi, Subin, additional, Allen, Sophie, additional, Torr, Beth, additional, Garrett, Alice, additional, Loveday, Chey, additional, Durkie, Miranda, additional, Callaway, Alison, additional, Burghel, George J., additional, Drummond, James, additional, Robinson, Rachel, additional, Berry, Ian R., additional, Wallace, Andrew, additional, Eccles, Diana M., additional, Tischkowitz, Marc, additional, Ellard, Sian, additional, Ware, James S., additional, Hanson, Helen, additional, Turnbull, Clare, additional, Samant, S., additional, Lucassen, A., additional, Znaczko, A., additional, Shaw, A., additional, Ansari, A., additional, Kumar, A., additional, Donaldson, A., additional, Murray, A., additional, Ross, A., additional, Taylor-Beadling, A., additional, Taylor, A., additional, Innes, A., additional, Brady, A., additional, Kulkarni, A., additional, Hogg, A.-C., additional, Bowden, A. Ramsay, additional, Hadonou, A., additional, Coad, B., additional, McIldowie, B., additional, Speight, B., additional, DeSouza, B., additional, Mullaney, B., additional, McKenna, C., additional, Brewer, C., additional, Olimpio, C., additional, Clabby, C., additional, Crosby, C., additional, Jenkins, C., additional, Armstrong, C., additional, Bowles, C., additional, Brooks, C., additional, Byrne, C., additional, Maurer, C., additional, Baralle, D., additional, Chubb, D., additional, Stobo, D., additional, Moore, D., additional, O'Sullivan, D., additional, Donnelly, D., additional, Randhawa, D., additional, Halliday, D., additional, Atkinson, E., additional, Baple, E., additional, Rauter, E., additional, Johnston, E., additional, Woodward, E., additional, Maher, E., additional, Sofianopoulou, E., additional, Petrides, E., additional, Lalloo, F., additional, McRonald, F., additional, Pelz, F., additional, Frayling, I., additional, Evans, G., additional, Corbett, G., additional, Rea, G., additional, Clouston, H., additional, Powell, H., additional, Williamson, H., additional, Carley, H., additional, Thomas, H.J.W., additional, Tomlinson, I., additional, Cook, J., additional, Hoyle, J., additional, Tellez, J., additional, Whitworth, J., additional, Williams, J., additional, Murray, J., additional, Campbell, J., additional, Tolmie, J., additional, Field, J., additional, Mason, J., additional, Burn, J., additional, Bruty, J., additional, Callaway, J., additional, Grant, J., additional, Del Rey Jimenez, J., additional, Pagan, J., additional, VanCampen, J., additional, Barwell, J., additional, Monahan, K., additional, Tatton-Brown, K., additional, Ong, K.-R., additional, Murphy, K., additional, Andrews, K., additional, Mokretar, K., additional, Cadoo, K., additional, Smith, K., additional, Baker, K., additional, Brown, K., additional, Reay, K., additional, McKay Bounford, K., additional, Bradshaw, K., additional, Russell, K., additional, Stone, K., additional, Snape, K., additional, Crookes, L., additional, Reed, L., additional, Taggart, L., additional, Yarram, L., additional, Cobbold, L., additional, Walker, L., additional, Hawkes, L., additional, Busby, L., additional, Izatt, L., additional, Kiely, L., additional, Hughes, L., additional, Side, L., additional, Sarkies, L., additional, Greenhalgh, K.-L., additional, Shanmugasundaram, M., additional, Duff, M., additional, Bartlett, M., additional, Watson, M., additional, Owens, M., additional, Bradford, M., additional, Huxley, M., additional, Slean, M., additional, Ryten, M., additional, Smith, M., additional, Ahmed, M., additional, Roberts, N., additional, O'Brien, C., additional, Middleton, O., additional, Tarpey, P., additional, Logan, P., additional, Dean, P., additional, May, P., additional, Brace, P., additional, Tredwell, R., additional, Harrison, R., additional, Hart, R., additional, Kirk, R., additional, Martin, R., additional, Nyanhete, R., additional, Wright, R., additional, Davidson, R., additional, Cleaver, R., additional, Talukdar, S., additional, Butler, S., additional, Sampson, J., additional, Ribeiro, S., additional, Dell, S., additional, Mackenzie, S., additional, Hegarty, S., additional, Albaba, S., additional, McKee, S., additional, Palmer-Smith, S., additional, Heggarty, S., additional, MacParland, S., additional, Greville-Heygate, S., additional, Daniels, S., additional, Prapa, S., additional, Abbs, S., additional, Tennant, S., additional, Hardy, S., additional, MacMahon, S., additional, McVeigh, T., additional, Foo, T., additional, Bedenham, T., additional, Cranston, T., additional, McDevitt, T., additional, Clowes, V., additional, Tripathi, V., additional, McConnell, V., additional, Woodwaer, N., additional, Wallis, Y., additional, Kemp, Z., additional, Mullan, G., additional, Pierson, L., additional, Rainey, L., additional, Joyce, C., additional, Timbs, A., additional, Reuther, A.-M., additional, Frugtniet, B., additional, Husher, C., additional, Lawn, C., additional, Corbett, C., additional, Nocera-Jijon, D., additional, Reay, D., additional, Cross, E., additional, Ryan, F., additional, Lindsay, H., additional, Oliver, J., additional, Dring, J., additional, Spiers, J., additional, Harper, J., additional, Ciucias, K., additional, Connolly, L., additional, Tsang, M., additional, Brown, R., additional, Shepherd, S., additional, Begum, S., additional, Tadiso, T., additional, Linton-Willoughby, T., additional, Heppell, H., additional, Sahan, K., additional, Worrillow, L., additional, Allen, Z., additional, Barlett, M., additional, Watt, C., additional, and Hegarty, M., additional

Published
2022
Full Text
View/download PDF

5. Targeted prostate cancer screening in men with mutations in BRCA1 and BRCA2 detects aggressive prostate cancer: preliminary analysis of the results of the IMPACT study

Author

Mitra, Anita V., Bancroft, Elizabeth K., Barbachano, Yolanda, Page, Elizabeth C., Foster, C. S., Jameson, C., Mitchell, G., Lindeman, G. J., Stapleton, A., Suthers, G., Evans, D. G., Cruger, D., Blanco, I., Mercer, C., Kirk, J., Maehle, L., Hodgson, S., Walker, L., Izatt, L., Douglas, F., Tucker, K., Dorkins, H., Clowes, V., Male, A., Donaldson, A., Brewer, C., Doherty, R., Bulman, B., Osther, P. J., Salinas, M., Eccles, D., Axcrona, K., Jobson, I., Newcombe, B., Cybulski, C., Rubinstein, W. S., Buys, S., Townshend, S., Friedman, E., Domchek, S., Ramon y Cajal, T., Spigelman, A., Teo, S. H., Nicolai, N., Aaronson, N., Ardern-Jones, A., Bangma, C., Dearnaley, D., Eyfjord, J., Falconer, A., Grönberg, H., Hamdy, F., Johannsson, O., Khoo, V., Kote-Jarai, Z., Lilja, H., Lubinski, J., Melia, J., Moynihan, C., Peock, S., Rennert, G., Schröder, F., Sibley, P., Suri, M., Wilson, P., Bignon, Y. J., Strom, S., Tischkowitz, M., Liljegren, A., Ilencikova, D., Abele, A., Kyriacou, K., van Asperen, C., Kiemeney, L., Easton, D. F., and Eeles, Rosalind A.

Published
2011
Full Text
View/download PDF

6. Psychosocial impact of undergoing prostate cancer screening for men with BRCA1 or BRCA2 mutations

Author

Bancroft, EK, Saya, S, Page, EC, Myhill, K, Thomas, S, Pope, J, Chamberlain, A, Hart, R, Glover, W, Cook, J, Rosario, DJ, Helfand, BT, Selkirk, CH, Davidson, R, Longmuir, M, Eccles, DM, Gadea, N, Brewer, C, Barwell, J, Salinas, M, Greenhalgh, L, Tischkowitz, M, Henderson, A, Evans, DG, Buys, SS, Eeles, RA, Aaronson, NK, Eeles, R, Bancroft, E, Page, E, Kote-Jarai, Z, Ardern-Jones, A, Bangma, C, Castro, E, Dearnaley, D, Falconer, A, Foster, C, Gronberg, H, Hamdy, FC, Johannsson, OT, Khoo, V, Eccles, D, Lilja, H, Evans, G, Eyfjord, J, Lubinski, J, Maehle, L, Mikropoulos, C, Millner, A, Mitra, A, Offman, J, Moynihan, C, Rennert, G, Suri, M, Dias, A, Taylor, N, D'Mello, L, James, P, Mitchell, G, Shanley, S, Richardson, K, McKinley, J, Petelin, L, Murphy, M, Mascarenhas, L, Murphy, D, Lam, J, Taylor, L, Miller, C, Stapleton, A, Chong, M, Suthers, G, Poplawski, N, Tucker, K, Andrews, L, Duffy, J, Millard, R, Ward, R, Williams, R, Stricker, P, Kirk, J, Bowman, M, Patel, M, Harris, M, O'Connell, S, Hunt, C, Smyth, C, Frydenberg, M, Lindeman, G, Shackleton, K, Morton, C, Susman, R, McGaughran, J, Boon, M, Pachter, N, Townshend, S, Schofield, L, Nicholls, C, Spigelman, A, Gleeson, M, Amor, D, Burke, J, Patterson, B, Swindle, P, Scott, R, Foulkes, W, Boshari, T, Aprikian, A, Jensen, T, Bojeson, A, Osther, P, Skytte, A-B, Cruger, D, Tondering, MK, Gerdes, A-M, Schmutzler, R, Rhiem, K, Wihler, P, Kast, K, Griebsch, C, Johannsson, O, Stefansdottir, V, Murthy, V, Sarin, R, Awatagiri, K, Ghonge, S, Kowtal, P, Mulgund, G, Gallagher, D, Bambury, R, Farrell, M, Gallagher, F, Kiernan, I, Friedman, E, Chen-Shtoyerman, R, Basevitch, A, Leibovici, D, Melzer, E, Ben-Yehoshua, SJ, Nicolai, N, Radice, P, Valdagni, R, Magnani, T, Gay, S, Teo, SH, Tan, HM, Yoon, S-Y, Thong, MK, Vasen, H, Ringleberg, J, van Asperen, C, Kiemeney, B, van Zelst-Stams, W, Ausems, MGEM, van der Luijt, RB, van Os, T, Ruijs, MWG, Adank, MA, Oldenburg, RA, Helderman-van den Enden, APTJM, Caanen, BAH, Oosterwijk, JC, Moller, P, Brennhovd, B, Medvik, H, Hanslien, E, Grindedal, EM, Cybulski, C, Wokolorczyk, D, Teixeira, M, Maia, S, Peixoto, A, Henrique, R, Oliveira, J, Goncalves, N, Araujo, L, Seixas, M, Souto, JP, Nogueira, P, Copakova, L, Zgajnar, J, Krajc, M, Vrecar, A, Capella, G, Ramon y Cajal, T, Fisas, D, Mora, J, Esquena, S, Balmana, J, Morote, J, Liljegren, A, Hjalm-Eriksson, M, Ekdahl, K-J, Carlsson, S, George, A, Kemp, Z, Wiggins, J, Moss, C, Van As, N, Thompson, A, Ogden, C, Woodhouse, C, Kumar, P, Bulman, B, Rothwell, J, Tricker, K, Wise, G, Mercer, C, McBride, D, Costello, P, Pearce, A, Torokwa, A, Paterson, J, Clowes, V, Taylor, A, Newcombe, B, Walker, L, Halliday, D, Stayner, B, Fleming-Brown, D, Snape, K, Hanson, H, Hodgson, S, Brice, G, Homfray, T, Hammond, C, Kohut, K, Anjum, U, Dearing, A, Mencias, M, Potter, A, Renton, C, Searle, A, Hill, K, Goodman, S, Garcia, L, Devlin, G, Everest, S, Nadolski, M, Douglas, F, Jobson, I, Paez, E, Donaldson, A, Tomkins, S, Langman, C, Jacobs, C, Pichert, G, Shaw, A, Kulkarni, A, Tripathi, V, Rose, S, Compton, C, Watson, M, Reinholtz, C, Brady, A, Dorkins, H, Melville, A, Kosicka-Slawinska, M, Cummings, C, Kiesel, V, Bartlett, M, Randhawa, K, Ellery, N, Side, L, Male, A, Simon, K, Rees, K, Tidey, L, Gurasashvili, J, Nevitt, L, Ingram, S, Howell, A, Rosario, D, Catto, J, Howson, J, Ong, K-R, Chapman, C, Cole, T, Heaton, T, Hoffman, J, Burgess, L, Huber, C, Islam, F, Watt, C, Duncan, A, Kockelbergh, R, Mzazi, S, Dineen, A, Sattar, A, Kaemba, B, Sidat, Z, Patel, N, Siguake, K, Birt, A, Poultney, U, Umez-Eronini, N, Mom, J, Sutton, V, Cornford, P, Bermingham, N, Yesildag, P, Treherne, K, Griffiths, J, Cogley, L, Gott, H, Rubinstein, WS, Hulick, P, McGuire, M, Shevrin, D, Kaul, K, Weissman, S, Newlin, A, Vogel, K, Weiss, S, Hook, N, Buys, S, Goldgar, D, Conner, T, Venne, V, Stephenson, R, Dechet, C, Domchek, S, Powers, J, Rustgi, N, Strom, S, Arun, B, Davis, JW, Yamamura, Y, Obeid, E, Giri, V, Gross, L, Bealin, L, Cooney, K, Stoffel, E, Okoth, L, Bancroft, EK, Saya, S, Page, EC, Myhill, K, Thomas, S, Pope, J, Chamberlain, A, Hart, R, Glover, W, Cook, J, Rosario, DJ, Helfand, BT, Selkirk, CH, Davidson, R, Longmuir, M, Eccles, DM, Gadea, N, Brewer, C, Barwell, J, Salinas, M, Greenhalgh, L, Tischkowitz, M, Henderson, A, Evans, DG, Buys, SS, Eeles, RA, Aaronson, NK, Eeles, R, Bancroft, E, Page, E, Kote-Jarai, Z, Ardern-Jones, A, Bangma, C, Castro, E, Dearnaley, D, Falconer, A, Foster, C, Gronberg, H, Hamdy, FC, Johannsson, OT, Khoo, V, Eccles, D, Lilja, H, Evans, G, Eyfjord, J, Lubinski, J, Maehle, L, Mikropoulos, C, Millner, A, Mitra, A, Offman, J, Moynihan, C, Rennert, G, Suri, M, Dias, A, Taylor, N, D'Mello, L, James, P, Mitchell, G, Shanley, S, Richardson, K, McKinley, J, Petelin, L, Murphy, M, Mascarenhas, L, Murphy, D, Lam, J, Taylor, L, Miller, C, Stapleton, A, Chong, M, Suthers, G, Poplawski, N, Tucker, K, Andrews, L, Duffy, J, Millard, R, Ward, R, Williams, R, Stricker, P, Kirk, J, Bowman, M, Patel, M, Harris, M, O'Connell, S, Hunt, C, Smyth, C, Frydenberg, M, Lindeman, G, Shackleton, K, Morton, C, Susman, R, McGaughran, J, Boon, M, Pachter, N, Townshend, S, Schofield, L, Nicholls, C, Spigelman, A, Gleeson, M, Amor, D, Burke, J, Patterson, B, Swindle, P, Scott, R, Foulkes, W, Boshari, T, Aprikian, A, Jensen, T, Bojeson, A, Osther, P, Skytte, A-B, Cruger, D, Tondering, MK, Gerdes, A-M, Schmutzler, R, Rhiem, K, Wihler, P, Kast, K, Griebsch, C, Johannsson, O, Stefansdottir, V, Murthy, V, Sarin, R, Awatagiri, K, Ghonge, S, Kowtal, P, Mulgund, G, Gallagher, D, Bambury, R, Farrell, M, Gallagher, F, Kiernan, I, Friedman, E, Chen-Shtoyerman, R, Basevitch, A, Leibovici, D, Melzer, E, Ben-Yehoshua, SJ, Nicolai, N, Radice, P, Valdagni, R, Magnani, T, Gay, S, Teo, SH, Tan, HM, Yoon, S-Y, Thong, MK, Vasen, H, Ringleberg, J, van Asperen, C, Kiemeney, B, van Zelst-Stams, W, Ausems, MGEM, van der Luijt, RB, van Os, T, Ruijs, MWG, Adank, MA, Oldenburg, RA, Helderman-van den Enden, APTJM, Caanen, BAH, Oosterwijk, JC, Moller, P, Brennhovd, B, Medvik, H, Hanslien, E, Grindedal, EM, Cybulski, C, Wokolorczyk, D, Teixeira, M, Maia, S, Peixoto, A, Henrique, R, Oliveira, J, Goncalves, N, Araujo, L, Seixas, M, Souto, JP, Nogueira, P, Copakova, L, Zgajnar, J, Krajc, M, Vrecar, A, Capella, G, Ramon y Cajal, T, Fisas, D, Mora, J, Esquena, S, Balmana, J, Morote, J, Liljegren, A, Hjalm-Eriksson, M, Ekdahl, K-J, Carlsson, S, George, A, Kemp, Z, Wiggins, J, Moss, C, Van As, N, Thompson, A, Ogden, C, Woodhouse, C, Kumar, P, Bulman, B, Rothwell, J, Tricker, K, Wise, G, Mercer, C, McBride, D, Costello, P, Pearce, A, Torokwa, A, Paterson, J, Clowes, V, Taylor, A, Newcombe, B, Walker, L, Halliday, D, Stayner, B, Fleming-Brown, D, Snape, K, Hanson, H, Hodgson, S, Brice, G, Homfray, T, Hammond, C, Kohut, K, Anjum, U, Dearing, A, Mencias, M, Potter, A, Renton, C, Searle, A, Hill, K, Goodman, S, Garcia, L, Devlin, G, Everest, S, Nadolski, M, Douglas, F, Jobson, I, Paez, E, Donaldson, A, Tomkins, S, Langman, C, Jacobs, C, Pichert, G, Shaw, A, Kulkarni, A, Tripathi, V, Rose, S, Compton, C, Watson, M, Reinholtz, C, Brady, A, Dorkins, H, Melville, A, Kosicka-Slawinska, M, Cummings, C, Kiesel, V, Bartlett, M, Randhawa, K, Ellery, N, Side, L, Male, A, Simon, K, Rees, K, Tidey, L, Gurasashvili, J, Nevitt, L, Ingram, S, Howell, A, Rosario, D, Catto, J, Howson, J, Ong, K-R, Chapman, C, Cole, T, Heaton, T, Hoffman, J, Burgess, L, Huber, C, Islam, F, Watt, C, Duncan, A, Kockelbergh, R, Mzazi, S, Dineen, A, Sattar, A, Kaemba, B, Sidat, Z, Patel, N, Siguake, K, Birt, A, Poultney, U, Umez-Eronini, N, Mom, J, Sutton, V, Cornford, P, Bermingham, N, Yesildag, P, Treherne, K, Griffiths, J, Cogley, L, Gott, H, Rubinstein, WS, Hulick, P, McGuire, M, Shevrin, D, Kaul, K, Weissman, S, Newlin, A, Vogel, K, Weiss, S, Hook, N, Buys, S, Goldgar, D, Conner, T, Venne, V, Stephenson, R, Dechet, C, Domchek, S, Powers, J, Rustgi, N, Strom, S, Arun, B, Davis, JW, Yamamura, Y, Obeid, E, Giri, V, Gross, L, Bealin, L, Cooney, K, Stoffel, E, and Okoth, L

Abstract

OBJECTIVES: To report the baseline results of a longitudinal psychosocial study that forms part of the IMPACT study, a multi-national investigation of targeted prostate cancer (PCa) screening among men with a known pathogenic germline mutation in the BRCA1 or BRCA2 genes. PARTICPANTS AND METHODS: Men enrolled in the IMPACT study were invited to complete a questionnaire at collaborating sites prior to each annual screening visit. The questionnaire included sociodemographic characteristics and the following measures: the Hospital Anxiety and Depression Scale (HADS), Impact of Event Scale (IES), 36-item short-form health survey (SF-36), Memorial Anxiety Scale for Prostate Cancer, Cancer Worry Scale-Revised, risk perception and knowledge. The results of the baseline questionnaire are presented. RESULTS: A total of 432 men completed questionnaires: 98 and 160 had mutations in BRCA1 and BRCA2 genes, respectively, and 174 were controls (familial mutation negative). Participants' perception of PCa risk was influenced by genetic status. Knowledge levels were high and unrelated to genetic status. Mean scores for the HADS and SF-36 were within reported general population norms and mean IES scores were within normal range. IES mean intrusion and avoidance scores were significantly higher in BRCA1/BRCA2 carriers than in controls and were higher in men with increased PCa risk perception. At the multivariate level, risk perception contributed more significantly to variance in IES scores than genetic status. CONCLUSION: This is the first study to report the psychosocial profile of men with BRCA1/BRCA2 mutations undergoing PCa screening. No clinically concerning levels of general or cancer-specific distress or poor quality of life were detected in the cohort as a whole. A small subset of participants reported higher levels of distress, suggesting the need for healthcare professionals offering PCa screening to identify these risk factors and offer additional information and support t

Published
2019

7. Quantifying prediction of pathogenicity for within-codon concordance (PM5) using 7541 functional classifications of BRCA1and MSH2missense variants

Author

Loong, Lucy, Cubuk, Cankut, Choi, Subin, Allen, Sophie, Torr, Beth, Garrett, Alice, Loveday, Chey, Durkie, Miranda, Callaway, Alison, Burghel, George J., Drummond, James, Robinson, Rachel, Berry, Ian R., Wallace, Andrew, Eccles, Diana M., Tischkowitz, Marc, Ellard, Sian, Ware, James S., Hanson, Helen, Turnbull, Clare, Samant, S., Lucassen, A., Znaczko, A., Shaw, A., Ansari, A., Kumar, A., Donaldson, A., Murray, A., Ross, A., Taylor-Beadling, A., Taylor, A., Innes, A., Brady, A., Kulkarni, A., Hogg, A.-C., Bowden, A. Ramsay, Hadonou, A., Coad, B., McIldowie, B., Speight, B., DeSouza, B., Mullaney, B., McKenna, C., Brewer, C., Olimpio, C., Clabby, C., Crosby, C., Jenkins, C., Armstrong, C., Bowles, C., Brooks, C., Byrne, C., Maurer, C., Baralle, D., Chubb, D., Stobo, D., Moore, D., O'Sullivan, D., Donnelly, D., Randhawa, D., Halliday, D., Atkinson, E., Baple, E., Rauter, E., Johnston, E., Woodward, E., Maher, E., Sofianopoulou, E., Petrides, E., Lalloo, F., McRonald, F., Pelz, F., Frayling, I., Evans, G., Corbett, G., Rea, G., Clouston, H., Powell, H., Williamson, H., Carley, H., Thomas, H.J.W., Tomlinson, I., Cook, J., Hoyle, J., Tellez, J., Whitworth, J., Williams, J., Murray, J., Campbell, J., Tolmie, J., Field, J., Mason, J., Burn, J., Bruty, J., Callaway, J., Grant, J., Del Rey Jimenez, J., Pagan, J., VanCampen, J., Barwell, J., Monahan, K., Tatton-Brown, K., Ong, K.-R., Murphy, K., Andrews, K., Mokretar, K., Cadoo, K., Smith, K., Baker, K., Brown, K., Reay, K., McKay Bounford, K., Bradshaw, K., Russell, K., Stone, K., Snape, K., Crookes, L., Reed, L., Taggart, L., Yarram, L., Cobbold, L., Walker, L., Walker, L., Hawkes, L., Busby, L., Izatt, L., Kiely, L., Hughes, L., Side, L., Sarkies, L., Greenhalgh, K.-L., Shanmugasundaram, M., Duff, M., Bartlett, M., Watson, M., Owens, M., Bradford, M., Huxley, M., Slean, M., Ryten, M., Smith, M., Ahmed, M., Roberts, N., O'Brien, C., Middleton, O., Tarpey, P., Logan, P., Dean, P., May, P., Brace, P., Tredwell, R., Harrison, R., Hart, R., Kirk, R., Martin, R., Nyanhete, R., Wright, R., Martin, R., Davidson, R., Cleaver, R., Talukdar, S., Butler, S., Sampson, J., Ribeiro, S., Dell, S., Mackenzie, S., Hegarty, S., Albaba, S., McKee, S., Palmer-Smith, S., Heggarty, S., MacParland, S., Greville-Heygate, S., Daniels, S., Prapa, S., Abbs, S., Tennant, S., Hardy, S., MacMahon, S., McVeigh, T., Foo, T., Bedenham, T., Cranston, T., McDevitt, T., Clowes, V., Tripathi, V., McConnell, V., Woodwaer, N., Wallis, Y., Kemp, Z., Mullan, G., Pierson, L., Rainey, L., Joyce, C., Timbs, A., Reuther, A.-M., Frugtniet, B., DeSouza, B., Husher, C., Lawn, C., Corbett, C., Nocera-Jijon, D., Reay, D., Cross, E., Ryan, F., Lindsay, H., Oliver, J., Dring, J., Spiers, J., Harper, J., Ciucias, K., Connolly, L., Tsang, M., Brown, R., Shepherd, S., Begum, S., Daniels, S., Tadiso, T., Linton-Willoughby, T., Heppell, H., Sahan, K., Worrillow, L., Allen, Z., Barlett, M., Watt, C., and Hegarty, M.

Abstract

Conditions and thresholds applied for evidence weighting of within-codon concordance (PM5) for pathogenicity vary widely between laboratories and expert groups. Because of the sparseness of available clinical classifications, there is little evidence for variation in practice.

Published
2022
Full Text
View/download PDF

8. Comprehensive cancer-predisposition gene testing in an adult multiple primary tumor series shows a broad range of deleterious variants and atypical tumor phenotypes

Author

Whitworth, J, Smith, PS, Martin, J-E, West, H, Luchetti, A, Rodger, F, Clark, G, Carss, K, Stephens, J, Stirrups, K, Penkett, C, Mapeta, R, Ashford, S, Megy, K, Shakeel, H, Ahmed, M, Adlard, J, Barwell, J, Brewer, C, Casey, RT, Armstrong, R, Cole, T, Evans, DG, Fostira, F, Greenhalgh, L, Hanson, H, Henderson, A, Hoffman, J, Izatt, L, Kumar, A, Kwong, A, Lalloo, F, Ong, KR, Paterson, J, Park, S-M, Chen-Shtoyerman, R, Searle, C, Side, L, Skytte, A-B, Snape, K, Woodward, ER, Tischkowitz, MD, Maher, ER, Aitman, T, Alachkar, H, Ali, S, Allen, L, Allsup, D, Ambegaonkar, G, Anderson, J, Antrobus, R, Arno, G, Arumugakani, G, Astle, W, Attwood, A, Austin, S, Bacchelli, C, Bakchoul, T, Bariana, TK, Baxendale, H, Bennett, D, Bethune, C, Bibi, S, Bitner-Glindzicz, M, Bleda, M, Boggard, H, Bolton-Maggs, P, Booth, C, Bradley, JR, Brady, A, Brown, M, Browning, M, Bryson, C, Burns, S, Calleja, P, Canham, N, Carmichael, J, Caulfield, M, Chalmers, E, Chandra, A, Chinnery, P, Chitre, M, Church, C, Clement, E, Clements-Brod, N, Clowes, V, Coghlan, G, Collins, P, Cookson, V, Cooper, N, Corris, P, Creaser-Myers, A, Dacosta, R, Daugherty, L, Davies, S, Davis, J, De Vries, M, Deegan, P, Deevi, SVV, Deshpande, C, Devlin, L, Dewhurst, E, Dixon, P, Doffinger, R, Dormand, N, Drewe, E, Edgar, D, Egner, W, Erber, WN, Erwood, M, Everington, T, Favier, R, Firth, H, Fletcher, D, Flinter, F, Frary, A, Freson, K, Furie, B, Furnell, A, Gale, D, Gardham, A, Gattens, M, Ghali, N, Ghataorhe, PK, Ghurye, R, Gibbs, S, Gilmour, K, Gissen, P, Goddard, S, Gomez, K, Gordins, P, Graf, S, Gräf, S, Greene, D, Greenhalgh, A, Greinacher, A, Grigoriadou, S, Grozeva, D, Hackett, S, Hadinnapola, C, Hague, R, Haimel, M, Halmagyi, C, Hammerton, T, Hart, D, Hayman, G, Heemskerk, JWM, Henderson, R, Hensiek, A, Henskens, Y, Herwadkar, A, Holden, S, Holder, M, Holder, S, Hu, F, Veld, A, Huissoon, A, Humbert, M, Hurst, J, James, R, Jolles, S, Josifova, D, Kazmi, R, Keeling, D, Kelleher, P, Kelly, AM, Kennedy, F, Kiely, D, Kingston, N, Koziell, A, Krishnakumar, D, Kuijpers, TW, Kuijpers, T, Kumararatne, D, Kurian, M, Laffan, MA, Lambert, MP, Allen, HL, Lango-Allen, H, Lawrie, A, Lear, S, Lees, M, Lentaigne, C, Liesner, R, Linger, R, Longhurst, H, Lorenzo, L, Louka, E, Machado, R, Ross, RM, Maclaren, R, Maher, E, Maimaris, J, Mangles, S, Manson, A, Markus, HS, Martin, J, Masati, L, Mathias, M, Matser, V, Maw, A, McDermott, E, McJannet, C, Meacham, S, Meehan, S, Mehta, S, Michaelides, M, Millar, CM, Moledina, S, Moore, A, Morrell, N, Mumford, A, Murng, S, Murphy, E, Nejentsev, S, Noorani, S, Nurden, P, Oksenhendler, E, Othman, S, Ouwehand, WH, Papadia, S, Parker, A, Pasi, J, Patch, C, Payne, J, Peacock, A, Peerlinck, K, Penkett, CJ, Pepke-Zaba, J, Perry, D, Perry, DJ, Pollock, V, Polwarth, G, Ponsford, M, Qasim, W, Quinti, I, Rankin, S, Rankin, J, Raymond, FL, Rayner-Matthews, P, Rehnstrom, K, Reid, E, Rhodes, CJ, Richards, M, Richardson, S, Richter, A, Roberts, I, Rondina, M, Rosser, E, Roughley, C, Roy, N, Rue-Albrecht, K, Samarghitean, C, Sanchis-Juan, A, Sandford, R, Santra, S, Sargur, R, Savic, S, Schotte, G, Schulman, S, Schulze, H, Scott, R, Scully, M, Seneviratne, S, Sewell, C, Shamardina, O, Shipley, D, Simeoni, I, Sivapalaratnam, S, Smith, KGC, Sohal, A, Southgate, L, Staines, S, Staples, E, Stark, H, Stauss, H, Stein, P, Stock, S, Suntharalingam, J, Talks, K, Tan, Y, Thachil, J, Thaventhiran, J, Thomas, E, Thomas, M, Thompson, D, Thrasher, A, Tischkowitz, M, Titterton, C, Toh, C-H, Toshner, M, Treacy, C, Trembath, R, Tuna, S, Turek, W, Turro, E, Van Geet, C, Veltman, M, Vogt, J, Von Ziegenweldt, J, Noordegraaf, AV, Wakeling, E, Wanjiku, I, Warner, TQ, Wassmer, E, Watkins, H, Watt, C, Webster, N, Welch, S, Westbury, S, Wharton, J, Whitehorn, D, Wilkins, M, Willcocks, L, Williamson, C, Woods, G, Wort, J, Yeatman, N, Yong, P, Young, T, and Yu, P

Abstract

Multiple primary tumors (MPTs) affect a substantial proportion of cancer survivors and can result from various causes, including inherited predisposition. Currently, germline genetic testing of MPT-affected individuals for variants in cancer-predisposition genes (CPGs) is mostly targeted by tumor type. We ascertained pre-assessed MPT individuals (with at least two primary tumors by age 60 years or at least three by 70 years) from genetics centers and performed whole-genome sequencing (WGS) on 460 individuals from 440 families. Despite previous negative genetic assessment and molecular investigations, pathogenic variants in moderate- and high-risk CPGs were detected in 67/440 (15.2%) probands. WGS detected variants that would not be (or were not) detected by targeted resequencing strategies, including low-frequency structural variants (6/440 [1.4%] probands). In most individuals with a germline variant assessed as pathogenic or likely pathogenic (P/LP), at least one of their tumor types was characteristic of variants in the relevant CPG. However, in 29 probands (42.2% of those with a P/LP variant), the tumor phenotype appeared discordant. The frequency of individuals with truncating or splice-site CPG variants and at least one discordant tumor type was significantly higher than in a control population (χ2 = 43.642; p ≤ 0.0001). 2/67 (3%) probands with P/LP variants had evidence of multiple inherited neoplasia allele syndrome (MINAS) with deleterious variants in two CPGs. Together with variant detection rates from a previous series of similarly ascertained MPT-affected individuals, the present results suggest that first-line comprehensive CPG analysis in an MPT cohort referred to clinical genetics services would detect a deleterious variant in about a third of individuals.

Published
2018

9. Publisher Correction: Telomerecat: A ploidy-agnostic method for estimating telomere length from whole genome sequencing data

Author

Farmery, JHR, Smith, ML, Lynch, AG, Huissoon, A, Furnell, A, Mead, A, Levine, AP, Manzur, A, Thrasher, A, Greenhalgh, A, Parker, A, Sanchis-Juan, A, Richter, A, Gardham, A, Lawrie, A, Sohal, A, Creaser-Myers, A, Frary, A, Greinacher, A, Themistocleous, A, Peacock, AJ, Marshall, A, Mumford, A, Rice, A, Webster, A, Brady, A, Koziell, A, Manson, A, Chandra, A, Hensiek, A, In't Veld, AH, Maw, A, Kelly, AM, Moore, A, Noordegraaf, AV, Attwood, A, Herwadkar, A, Ghofrani, A, Houweling, AC, Girerd, B, Furie, B, Treacy, CM, Millar, CM, Sewell, C, Roughley, C, Titterton, C, Williamson, C, Hadinnapola, C, Deshpande, C, Toh, C-H, Bacchelli, C, Patch, C, Van Geet, C, Babbs, C, Bryson, C, Penkett, CJ, Rhodes, CJ, Watt, C, Bethune, C, Booth, C, Lentaigne, C, McJannet, C, Church, C, French, C, Samarghitean, C, Halmagyi, C, Gale, D, Greene, D, Hart, D, Allsup, D, Bennett, D, Edgar, D, Kiely, DG, Gosal, D, Perry, DJ, Keeling, D, Montani, D, Shipley, D, Whitehorn, D, Fletcher, D, Krishnakumar, D, Grozeva, D, Kumararatne, D, Thompson, D, Josifova, D, Maher, E, Wong, EKS, Murphy, E, Dewhurst, E, Louka, E, Rosser, E, Chalmers, E, Colby, E, Drewe, E, McDermott, E, Thomas, E, Staples, E, Clement, E, Matthews, E, Wakeling, E, Oksenhendler, E, Turro, E, Reid, E, Wassmer, E, Raymond, FL, Hu, F, Kennedy, F, Soubrier, F, Flinter, F, Kovacs, G, Polwarth, G, Ambegaonkar, G, Arno, G, Hudson, G, Woods, G, Coghlan, G, Hayman, G, Arumugakani, G, Schotte, G, Cook, HT, Alachkar, H, Allen, HL, Lango-Allen, H, Stark, H, Stauss, H, Schulze, H, Boggard, HJ, Baxendale, H, Dolling, H, Firth, H, Gall, H, Watson, H, Longhurst, H, Markus, HS, Watkins, H, Simeoni, I, Emmerson, I, Roberts, I, Quinti, I, Wanjiku, I, Gibbs, JSR, Thaventhiran, J, Whitworth, J, Hurst, J, Collins, J, Suntharalingam, J, Payne, J, Thachil, J, Martin, JM, Martin, J, Carmichael, J, Maimaris, J, Paterson, J, Pepke-Zaba, J, Heemskerk, JWM, Gebhart, J, Davis, J, Pasi, J, Bradley, JR, Wharton, J, Stephens, J, Rankin, J, Anderson, J, Vogt, J, Von Ziegenweldt, J, Rehnstrom, K, Megy, K, Talks, K, Peerlinck, K, Yates, K, Freson, K, Stirrups, K, Gomez, K, Smith, KGC, Carss, K, Rue-Albrecht, K, Gilmour, K, Masati, L, Scelsi, L, Southgate, L, Ranganathan, L, Ginsberg, L, Devlin, L, Willcocks, L, Ormondroyd, L, Lorenzo, L, Harper, L, Allen, L, Daugherty, L, Chitre, M, Kurian, M, Humbert, M, Tischkowitz, M, Bitner-Glindzicz, M, Erwood, M, Scully, M, Veltman, M, Caulfield, M, Layton, M, McCarthy, M, Ponsford, M, Toshner, M, Bleda, M, Wilkins, M, Mathias, M, Reilly, M, Afzal, M, Brown, M, Rondina, M, Stubbs, M, Haimel, M, Lees, M, Laffan, MA, Browning, M, Gattens, M, Richards, M, Michaelides, M, Lambert, MP, Makris, M, De Vries, M, Mahdi-Rogers, M, Saleem, M, Thomas, M, Holder, M, Eyries, M, Clements-Brod, N, Canham, N, Dormand, N, Van Zuydam, N, Kingston, N, Ghali, N, Cooper, N, Morrell, NW, Yeatman, N, Roy, N, Shamardina, O, Alavijeh, OS, Gresele, P, Nurden, P, Chinnery, P, Deegan, P, Yong, P, Yu-Wai-Man, P, Corris, PA, Calleja, P, Gissen, P, Bolton-Maggs, P, Rayner-Matthews, P, Ghataorhe, PK, Gordins, P, Stein, P, Collins, P, Dixon, P, Kelleher, P, Ancliff, P, Yu, P, Tait, RC, Linger, R, Doffinger, R, Machado, R, Kazmi, R, Sargur, R, Favier, R, Tan, R, Liesner, R, Antrobus, R, Sandford, R, Scott, R, Trembath, R, Horvath, R, Hadden, R, MackenzieRoss, RV, Henderson, R, MacLaren, R, James, R, Ghurye, R, DaCosta, R, Hague, R, Mapeta, R, Armstrong, R, Noorani, S, Murng, S, Santra, S, Tuna, S, Johnson, S, Chong, S, Lear, S, Walker, S, Goddard, S, Mangles, S, Westbury, S, Mehta, S, Hackett, S, Nejentsev, S, Moledina, S, Bibi, S, Meehan, S, Othman, S, Revel-Vilk, S, Holden, S, McGowan, S, Staines, S, Savic, S, Burns, S, Grigoriadou, S, Papadia, S, Ashford, S, Schulman, S, Ali, S, Park, S-M, Davies, S, Stock, S, Deevi, SVV, Graf, S, Ghio, S, Wort, SJ, Jolles, S, Austin, S, Welch, S, Meacham, S, Rankin, S, Seneviratne, S, Holder, S, Sivapalaratnam, S, Richardson, S, Kuijpers, T, Kuijpers, TW, Bariana, TK, Bakchoul, T, Everington, T, Renton, T, Young, T, Aitman, T, Warner, TQ, Vale, T, Hammerton, T, Pollock, V, Matser, V, Cookson, V, Clowes, V, Qasim, W, Wei, W, Erber, WN, Ouwehand, WH, Astle, W, Egner, W, Turek, W, Henskens, Y, Tan, Y, Lynch, Andy G [0000-0002-7876-7338], Apollo - University of Cambridge Repository, Medical Research Council (MRC), and British Heart Foundation

Subjects
Whole genome sequencing, 0303 health sciences, Multidisciplinary, Science & Technology, lcsh:R, lcsh:Medicine, Computational biology, Biology, Telomere, Multidisciplinary Sciences, 03 medical and health sciences, 0302 clinical medicine, NIHR BioResource - Rare Diseases, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, Science & Technology - Other Topics, lcsh:Q, Ploidy, lcsh:Science, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract

Correction to: Scientific Reports https://doi.org/10.1038/s41598-017-14403-y, published online 22 January 2018 The original version of this Article contained a typographical error in the spelling of the consortium member Patrick Yu-Wai-Man which was incorrectly given as Patrick Yu Wai Man. In addition, a supplementary file containing additional algorithms and analysis was omitted from the original version of this Article. These errors have now been corrected in the HTML and PDF versions of the Article.

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. Targeted prostate cancer screening in men with mutations in BRCA1 and BRCA2 detects aggressive prostate cancer: preliminary analysis of the results of the IMPACT study

Author

Mitra, A, Bancroft, E, Barbachano, Y, Page, E, Foster, C, Jameson, C, Mitchell, G, Lindeman, G, Stapleton, A, Suthers, G, Evans, D, Cruger, D, Blanco, I, Mercer, C, Kirk, J, Maehle, L, Hodgson, S, Walker, L, Izatt, L, Douglas, F, Tucker, K, Dorkins, H, Clowes, V, Male, A, and Donaldson, A

Abstract

OBJECTIVE: To evaluate the role of targeted prostate cancer screening in men with BRCA1 or BRCA2 mutations, an international study, IMPACT (Identification of Men with a genetic predisposition to ProstAte Cancer: Targeted screening in BRCA1/2 mutation carriers and controls), was established. This is the first multicentre screening study targeted at men with a known genetic predisposition to prostate cancer. A preliminary analysis of the data is reported. PATIENTS AND METHODS: Men aged 40-69 years from families with BRCA1 or BRCA2 mutations were offered annual prostate specific antigen (PSA) testing, and those with PSA > 3 ng/mL, were offered a prostate biopsy. Controls were men age-matched (± 5 years) who were negative for the familial mutation. RESULTS: In total, 300 men were recruited (205 mutation carriers; 89 BRCA1, 116 BRCA2 and 95 controls) over 33 months. At the baseline screen (year 1), 7.0% (21/300) underwent a prostate biopsy. Prostate cancer was diagnosed in ten individuals, a prevalence of 3.3%. The positive predictive value of PSA screening in this cohort was 47·6% (10/21). One prostate cancer was diagnosed at year 2. Of the 11 prostate cancers diagnosed, nine were in mutation carriers, two in controls, and eight were clinically significant. CONCLUSIONS: The present study shows that the positive predictive value of PSA screening in BRCA mutation carriers is high and that screening detects clinically significant prostate cancer. These results support the rationale for continued screening in such men.

Published
2016

12. Classification of Variants of Reduced Penetrance in High Penetrance Cancer Susceptibility Genes: Framework for Genetics Clinicians and Clinical Scientists by CanVIG-UK (Cancer Variant Interpretation Group-UK)

Author

Garrett, Alice, Allen, Sophie, Durkie, Miranda, Burghel, George J., Robinson, Rachel, Callaway, Alison, Field, Joanne, Frugtniet, Bethan, Palmer-Smith, Sheila, Grant, Jonathan, Pagan, Judith, McDevitt, Trudi, Rowlands, Charlie F., McVeigh, Terri, Hanson, Helen, Turnbull, Clare, Turnbull, C., Garrett, A., Loong, L., Choi, S., Torr, B., Allen, S., Durkie, M., Callaway, A., Drummond, J., Burghel, G.J., Robinson, R., Berry, I.R., Wallace, A.J., Eccles, D.M., Tischkowitz, M., Ellard, S., Hanson, H., Baple, E., Evans, D.G., Woodward, E., Lalloo, F., Samant, S., Lucassen, A., Znaczko, A., Shaw, A., Ansari, A., Kumar, A., Donaldson, A., Murray, A., Ross, A., Taylor-Beadling, A., Taylor, A., Innes, A., Brady, A., Kulkarni, A., Hogg, A.C., Bowden, A. Ramsay, Hadonou, A., Coad, B., McIldowie, B., Speight, B., DeSouza, B., Mullaney, B., McKenna, C., Brewer, C., Olimpio, C., Clabby, C., Crosby, C., Jenkins, C., Armstrong, C., Bowles, C., Brooks, C., Byrne, C., Maurer, C., Baralle, D., Chubb, D., Stobo, D., Moore, D., O'Sullivan, D., Donnelly, D., Randhawa, D., Halliday, D., Atkinson, E., Rauter, E., Johnston, E., Maher, E., Sofianopoulou, E., Petrides, E., McRonald, F., Pelz, F., Frayling, I., Corbett, G., Rea, G., Clouston, H., Powell, H., Williamson, H., Carley, H., Thomas, H.J.W., Tomlinson, I., Cook, J., Hoyle, J., Tellez, J., Whitworth, J., Williams, J., Murray, J., Campbell, J., Tolmie, J., Field, J., Mason, J., Burn, J., Bruty, J., Callaway, J., Grant, J., Del Rey Jimenez, J., Pagan, J., VanCampen, J., Barwell, J., Monahan, K., Tatton-Brown, K., Ong, K.R., Murphy, K., Andrews, K., Mokretar, K., Cadoo, K., Smith, K., Baker, K., Brown, K., Reay, K., McKay Bounford, K., Bradshaw, K., Russell, K., Stone, K., Snape, K., Crookes, L., Reed, L., Taggart, L., Yarram, L., Cobbold, L., Walker, L., Walker, L., Hawkes, L., Busby, L., Izatt, L., Kiely, L., Hughes, L., Side, L., Sarkies, L., Greenhalgh, K.-L., Shanmugasundaram, M., Duff, M., Bartlett, M., Watson, M., Owens, M., Bradford, M., Huxley, M., Slean, M., Ryten, M., Smith, M., Ahmed, M., Roberts, N., O'Brien, C., Middleton, O., Tarpey, P., Logan, P., Dean, P., May, P., Brace, P., Tredwell, R., Harrison, R., Hart, R., Kirk, R., Martin, R., Nyanhete, R., Wright, R., Martin, R., Davidson, R., Cleaver, R., Talukdar, S., Butler, S., Sampson, J., Ribeiro, S., Dell, S., Mackenzie, S., Hegarty, S., Albaba, S., McKee, S., Palmer-Smith, S., Heggarty, S., MacParland, S., Greville-Heygate, S., Daniels, S., Prapa, S., Abbs, S., Tennant, S., Hardy, S., MacMahon, S., McVeigh, T., Foo, T., Bedenham, T., Cranston, T., McDevitt, T., Clowes, V., Tripathi, V., McConnell, V., Woodwaer, N., Wallis, Y., Kemp, Z., Mullan, G., Pierson, L., Rainey, L., Joyce, C., Timbs, A., Reuther, A.-M., Frugtniet, B., DeSouza, B., Husher, C., Lawn, C., Corbett, C., Nocera-Jijon, D., Reay, D., Cross, E., Ryan, F., Lindsay, H., Oliver, J., Dring, J., Spiers, J., Harper, J., Ciucias, K., Connolly, L., Tsang, M., Brown, R., Shepherd, S., Begum, S., Daniels, S., Tadiso, T., Linton-Willoughby, T., Heppell, H., Sahan, K., Worrillow, L., Allen, Z., Watt, C., Hegarty, M., Mitchell, R., Coles, R., Nickless, G., Cojocaru, E., Doal, I., Sava, F., McCarthy, C., Jeeneea, R., Goudie, D., McConachie, M., Botosneanu, S., Kavanaugh, G., Russell, K., Sherlaw, C., Tsoulaki, O., Forde, C., Petley, E., Jones, A.-B., Oprych, K., Pryde, S., Hyder, Z., Elkhateeb, N., Braham, R., Hanington, L., Huntley, C., Irving, R., Sadan, A., Ramos, M., Elliot, C., Wren, D., Lobo, D., McLean, J., May, D., Kearney, L., Campbell, T., Asakura, K., Alwadi, L., O’Shea, R., Gabriel, J., Chiecchio, L., Bowman, P., Sutton, L.A., Walsh, C., Cloke, V., Ucanok, D., Davies, J., Pleasance, B., Maguire, E., Whaite, A., Best, S., Westbury, S., Logan, A., Navarajasegaran, D., Bench, A., Wightman, P., Cartwright, A., Higgs, E., J.Bott, Whitehouse, H., Stevens, J., Martin, D., Dunlop, J., Thomas, S., Sau, C., Farndon, S., Coleman, N., Angelini, P., Duff, M., Massey, H., Rowlands, C., Garcia-Petit, C., Gillespie, K., Alder, A., Middleton, E., Cassidy, C., Orfali, N., Webb, A., Luharia, A., Walker, N., Charlton, J., Andreou, A., Peddie, J., Khan, M., Wilkinson, L., Bezuidenhout, H., Edis, M., Callard, A., Ostrowski, P., Moverley, P., Bean, K., Dunne, A., Moleirinho, A., Waller, S., Cox, K., Greensmith, L., Brittle, A., Gossan, N., Freestone, L., Shak, C., Langford, T., Clinch, Y., Livesey, H., Borland, S., Joshi, A., Wall, K., Whitworth, A., Wilsdon, A., Edgerley, K., Pugh, S., Chrysochoidi, N., Mutch, S., McMullan, C., Johnston, Y., Muraru, M., May, A., Begum, R., Smith, C., Patel, R., Bhatnagar, I., Taylor, A., Brown, D., Willan, J., Taylor, S., Jones, K., Cox, K., Ramsden, C., Taiwo, O., Jaudzemaite, J., Sharmin, R., Young, L., C.O’Dubhshlaine, McSorley, L., Rodriguez, I. Abreu, Lillis, S., Alexopoulos, P., Mortensson, E., Kingham, L., Moore, R., Kosicka-Slawinska, M., Aslam, S., Wells, R., Carter, A., Warren, H., Rolf, E., Reed, H., Pearce, L., Lock, D., Ali, F., Kolozi, A., White, N., Wood, D., and Hayden, C.

Abstract

Current practice is to report and manage likely pathogenic/pathogenic variants in a given cancer susceptibility gene (CSG) as though having equivalent penetrance, despite increasing evidence of inter-variant variability in risk associations. Using existing variant interpretation approaches, largely based on full-penetrance models, variants where reduced penetrance is suspected may be classified inconsistently and/or as variants of uncertain significance (VUS). We aimed to develop a national consensus approach for such variants within the Cancer Variant Interpretation Group UK (CanVIG-UK) multidisciplinary network.

Published
2024
Full Text
View/download PDF

13. Targeted prostate cancer screening in men with mutations in BRCA1 and BRCA2 detects aggressive prostate cancer: preliminary analysis of the results of the IMPACT study

Author

Mitra, A.V., Bancroft, E.K., Barbachano, Y., Page, E.C., Foster, C.S., Jameson, C., Mitchell, G., Lindeman, G.J., Stapleton, A., Suthers, G., Evans, D.G., Cruger, D., Blanco, I., Mercer, C., Kirk, J., Maehle, L., Hodgson, S., Walker, L., Izatt, L., Douglas, F., Tucker, K., Dorkins, H., Clowes, V., Male, A., Donaldson, A., Brewer, C., Doherty, R., Bulman, B., Osther, P.J., Salinas, M., Eccles, D., Axcrona, K., Jobson, I., Newcombe, B., Cybulski, C., Rubinstein, W.S., Buys, S., Townshend, S., Friedman, E., Domchek, S., Cajal, T.R.Y., Spigelman, A., Teo, S.H., Nicolai, N., Aaronson, N., Ardern-Jones, A., Bangma, C., Dearnaley, D., Eyfjord, J., Falconer, A., Gronberg, H., Hamdy, F., Johannsson, O., Khoo, V., Kote-Jarai, Z., Lilja, H., Lubinski, J., Melia, J., Moynihan, C., Peock, S., Rennert, G., Schroder, F., Sibley, P., Suri, M., Wilson, P., Bignon, Y.J., Strom, S., Tischkowitz, M., Liljegren, A., Ilencikova, D., Abele, A., Kyriacou, K., Asperen, C. van, Kiemeney, L., Easton, D.F., Eeles, R.A., and IMPACT Study Collaborators

Subjects
prostate cancer BRCA1 BRCA2 PSA genetic predisposition high-risk families jewish men antigen carriers erspc population history trial ng/ml 1st, skin and connective tissue diseases
Abstract

What's known on the subject? and What does the study add? Scientists have found a number of genetic factors that increase prostate cancer risk, including heritable mutations in the genes BRCA1 and BRCA2. These mutations are not common but can have major impact, as a BRCA2 mutation increases risk by up to seven-fold while a BRCA1 mutation is thought to double risk in men under 65. The IMPACT study aims to determine whether targeted screening in men with a known BRCA1 or BRCA2 mutation would lead to earlier diagnosis of prostate cancers. This data from the IMPACT study adds to the increasing evidence that BRCA mutation carriers develop more aggressive disease. Although these are early results, it appears that PSA screening is more accurate at predicting potentially aggressive prostate cancer among men at higher risk of the disease due to a genetic predisposition than general population screening. This study provides support for continued screening in men with genetic mutations. OBJECTIVE To evaluate the role of targeted prostate cancer screening in men with BRCA1 or BRCA2 mutations, an international study, IMPACT (Identification of Men with a genetic predisposition to ProstAte Cancer: Targeted screening in BRCA1/2 mutation carriers and controls), was established. This is the first multicentre screening study targeted at men with a known genetic predisposition to prostate cancer. A preliminary analysis of the data is reported. PATIENTS AND METHODS Men aged 40-69 years from families with BRCA1 or BRCA2 mutations were offered annual prostate specific antigen (PSA) testing, and those with PSA > 3 ng/mL, were offered a prostate biopsy. Controls were men age-matched (+/- 5 years) who were negative for the familial mutation. RESULTS In total, 300 men were recruited (205 mutation carriers; 89 BRCA1, 116 BRCA2 and 95 controls) over 33 months. At the baseline screen (year 1), 7.0% (21/300) underwent a prostate biopsy. Prostate cancer was diagnosed in ten individuals, a prevalence of 3.3%. The positive predictive value of PSA screening in this cohort was 47 center dot 6% (10/21). One prostate cancer was diagnosed at year 2. Of the 11 prostate cancers diagnosed, nine were in mutation carriers, two in controls, and eight were clinically significant. CONCLUSIONS The present study shows that the positive predictive value of PSA screening in BRCA mutation carriers is high and that screening detects clinically significant prostate cancer. These results support the rationale for continued screening in such men.

Published
2011

14. The rs10993994 risk allele for prostate cancer results in clinically relevant changes in microseminoprotein-beta expression in tissue and urine

Author

Whitaker, HC, Kote-Jarai, Z, Ross-Adams, H, Warren, AY, Burge, J, George, A, Bancroft, E, Jhavar, S, Leongamornlert, D, Tymrakiewicz, M, Saunders, E, Page, E, Mitra, A, Mitchell, G, Lindeman, GJ, Evans, DG, Blanco, I, Mercer, C, Rubinstein, WS, Clowes, V, Douglas, F, Hodgson, S, Walker, L, Donaldson, A, Izatt, L, Dorkins, H, Male, A, Tucker, K, Stapleton, A, Lam, J, Kirk, J, Lilja, H, Easton, D, IMPACT Study Steering Committee, IMPACT Study Collaborators, UK GPCS Collaborators, Cooper, C, Eeles, R, Neal, DE, and Universitat de Barcelona

Subjects
Oncology, Male, Pathology, Public Health and Epidemiology/Screening, lcsh:Medicine, Prostate cancer, 0302 clinical medicine, Prostate, Genotype, Medicine, lcsh:Science, Oncology/Prostate Cancer, 0303 health sciences, Multidisciplinary, Urology/Prostate Cancer, Immunohistochemistry, 3. Good health, Prostate-specific antigen, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Biomarker (medicine), Research Article, PCA3, Oncogens, medicine.medical_specialty, Single-nucleotide polymorphism, Enzyme-Linked Immunosorbent Assay, 03 medical and health sciences, Internal medicine, Biomarkers, Tumor, Humans, MSMB, Genetic Predisposition to Disease, Alleles, 030304 developmental biology, Càncer de pròstata, business.industry, lcsh:R, Prostatic Neoplasms, Prostatic Secretory Proteins, Urology/Benign Prostatic Hyperplasia, Oncogenes, Prostate-Specific Antigen, medicine.disease, Marcadors genètics, Genetic markers, lcsh:Q, business
Abstract

BACKGROUND: Microseminoprotein-beta (MSMB) regulates apoptosis and using genome-wide association studies the rs10993994 single nucleotide polymorphism in the MSMB promoter has been linked to an increased risk of developing prostate cancer. The promoter location of the risk allele, and its ability to reduce promoter activity, suggested that the rs10993994 risk allele could result in lowered MSMB in benign tissue leading to increased prostate cancer risk. \ud \ud METHODOLOGY/PRINCIPAL FINDINGS: MSMB expression in benign and malignant prostate tissue was examined using immunohistochemistry and compared with the rs10993994 genotype. Urinary MSMB concentrations were determined by ELISA and correlated with urinary PSA, the presence or absence of cancer, rs10993994 genotype and age of onset. MSMB levels in prostate tissue and urine were greatly reduced with tumourigenesis. Urinary MSMB was better than urinary PSA at differentiating men with prostate cancer at all Gleason grades. The high risk allele was associated with heterogeneity of MSMB staining and loss of MSMB in both tissue and urine in benign prostate.\ud \ud CONCLUSIONS: These data show that some high risk alleles discovered using genome-wide association studies produce phenotypic effects with potential clinical utility. We provide the first link between a low penetrance polymorphism for prostate cancer and a potential test in human tissue and bodily fluids. There is potential to develop tissue and urinary MSMB for a biomarker of prostate cancer risk, diagnosis and disease monitoring.

Published
2010

15. The rs10993994 risk allele for prostate cancer results in clinically relevant changes in microseminoprotein-beta expression in tissue and urine

Author

Vickers, A., Whitaker, H. C., Kote-Jarai, Z., Ross-Adams, H., Warren, A.Y., Burge, J., George, A., Bancroft, E., Jhavar, S., Leongamornlert, D., Tymrakiewicz, M., Saunders, E., Page, E., Mitra, A., Mitchell, G., Lindeman, G.J., Evans, D. G., Blanco, I., Mercer, C., Rubinstein, W.S., Clowes, V., Douglas, F., Hodgson, S., Walker, L., Donaldson, A., Izatt, L., Dorkins, H., Male, A., Tucker, K., Stapleton, A., Lam, J., Kirk, J., Lilja, H., Easton, D., Cooper, C., Eeles, R., Neal, D.E., and Tobias, E.S.

Subjects
QH426, R1
Abstract

Background:\ud \ud Microseminoprotein-beta (MSMB) regulates apoptosis and using genome-wide association studies the rs10993994 single nucleotide polymorphism in the MSMB promoter has been linked to an increased risk of developing prostate cancer. The promoter location of the risk allele, and its ability to reduce promoter activity, suggested that the rs10993994 risk allele could result in lowered MSMB in benign tissue leading to increased prostate cancer risk.\ud Methodology/Principal Findings:\ud MSMB expression in benign and malignant prostate tissue was examined using immunohistochemistry and compared with the rs10993994 genotype. Urinary MSMB concentrations were determined by ELISA and correlated with urinary PSA, the presence or absence of cancer, rs10993994 genotype and age of onset. MSMB levels in prostate tissue and urine were greatly reduced with tumourigenesis. Urinary MSMB was better than urinary PSA at differentiating men with prostate cancer at all Gleason grades. The high risk allele was associated with heterogeneity of MSMB staining and loss of MSMB in both tissue and urine in benign prostate.\ud Conclusions:\ud These data show that some high risk alleles discovered using genome-wide association studies produce phenotypic effects with potential clinical utility. We provide the first link between a low penetrance polymorphism for prostate cancer and a potential test in human tissue and bodily fluids. There is potential to develop tissue and urinary MSMB for a biomarker of prostate cancer risk, diagnosis and disease monitoring.

Published
2010

16. Targeted prostate cancer screening in BRCA1 and BRCA2 mutation carriers: Results from the initial screening round of the IMPACT study

Author

Bancroft, E.K. (Elizabeth), Page, E. (Elizabeth), Castro, E. (Elena), Lilja, H. (Hans), Vickers, A.J. (Andrew), Sjoberg, D. (Daniel), Assel, M. (Matthias), Foster, C.S. (Christopher), Mitchell, G. (Gillian), Drew, K. (Kate), Maehle, L., Axcrona, K., Evans, D.G. (Gareth), Bulman, B., Eccles, D. (Diana), McBride, D. (Donna), Asperen, C.J. (Christi) van, Vasen, H. (Hans), Kiemeney, L.A.L.M. (Bart), Ringelberg, J. (Janneke), Cybulski, C. (Cezary), Wokolorczyk, D. (Dominika), Selkirk, C.G. (Christina), Hulick, P.J. (Peter), Bojesen, S.E. (Stig), Skytte, A.-B. (Anne-Bine), Lam, J. (Jimmy), Taylor, L. (Lorne), Oldenburg, R.A. (Rogier), Cremers, R.G.H.M. (Ruben), Verhaegh, G. (Gerald), Zelst-Stams, W.A. van, Oosterwijk, J.C. (Jan), Blanco, I. (Ignacio), Salinas, M., Cook, J. (Jackie), Rosario, K. (Karyna), Buys, S.S. (Saundra), Conner, T. (Tom), Ausems, M.G.E.M. (Margreet), Ong, K.-R. (Kai-Ren), Hoffman, J. (Jonathan), Domchek, S.M. (Susan), Powers, J. (Jacquelyn), Teixeira, P.J., Maia, S. (Sofia), Foulkes, W.D. (William), Taherian, N. (Nassim), Ruijs, M.W.G. (Marielle), Enden, A.T.H.-V. (Apollonia T. Helderman-Van) den, Izatt, L. (Louise), Davidson, R. (Rosemarie), Adank, M.A. (Muriel), Walker, L.J. (Lisa), Schmutzler, R.K. (Rita), Tucker, K. (Kathryn), Kirk, J. (Judy), Hodgson, S.V. (Shirley), Harris, M. (Marion), Douglas, F. (Fiona), Lindeman, G.J. (Geoffrey), Zgajnar, J. (Janez), Tischkowitz, M. (Marc), Clowes, V., Susman, R. (Rachel), Ramon Y Cajal, T., Patcher, N. (Nicholas), Gadea, N. (Neus), Spigelman, A., Os, T.A.M. (Theo) van, Liljegren, A. (Annelie), Side, L. (Lucy), Brewer, C. (Carole), Brady, A.F. (Angela), Donaldson, A. (Alan), Stefansdottir, V. (Vigdis), Friedman, E. (Eitan), Chen-Shtoyerman, R. (Rakefet), Amor, D. (David), Copakova, L. (Lucia), Barwell, J. (Julian), Giri, V.N. (Veda), Murthy, A.C. (Adeline C.), Nicolai, N. (Nicola), Teo, S.-H. (Soo-Hwang), Greenhalgh, T. (Trisha), Strom, S., Henderson, A. (Alex), McGrath, J. (John), Gallagher, D. (David), Aaronson, N.K. (Neil), Ardern-Jones, A. (Audrey), Bangma, C.H. (Chris), Dearnaley, D. (David), Costello, A. (Anthony), Eyfjord, J., Rothwell, J. (Jeanette), Falconer, A., Grönberg, H. (Henrik), Hamdy, F. (Freddie), Johannson, O.T. (Oskar), Khoo, V., Kote-Jarai, Z., Lubinski, J. (Jan), Melia, J., McKinley, E.T. (Enid), Mitra, A. (Anita), Moynihan, C., Rennert, G. (Gad), Suri, M. (Mohnish), Wilson, P., Killick, S.R., Moss, S.M. (Sue), Eeles, R. (Rosalind), Bancroft, E.K. (Elizabeth), Page, E. (Elizabeth), Castro, E. (Elena), Lilja, H. (Hans), Vickers, A.J. (Andrew), Sjoberg, D. (Daniel), Assel, M. (Matthias), Foster, C.S. (Christopher), Mitchell, G. (Gillian), Drew, K. (Kate), Maehle, L., Axcrona, K., Evans, D.G. (Gareth), Bulman, B., Eccles, D. (Diana), McBride, D. (Donna), Asperen, C.J. (Christi) van, Vasen, H. (Hans), Kiemeney, L.A.L.M. (Bart), Ringelberg, J. (Janneke), Cybulski, C. (Cezary), Wokolorczyk, D. (Dominika), Selkirk, C.G. (Christina), Hulick, P.J. (Peter), Bojesen, S.E. (Stig), Skytte, A.-B. (Anne-Bine), Lam, J. (Jimmy), Taylor, L. (Lorne), Oldenburg, R.A. (Rogier), Cremers, R.G.H.M. (Ruben), Verhaegh, G. (Gerald), Zelst-Stams, W.A. van, Oosterwijk, J.C. (Jan), Blanco, I. (Ignacio), Salinas, M., Cook, J. (Jackie), Rosario, K. (Karyna), Buys, S.S. (Saundra), Conner, T. (Tom), Ausems, M.G.E.M. (Margreet), Ong, K.-R. (Kai-Ren), Hoffman, J. (Jonathan), Domchek, S.M. (Susan), Powers, J. (Jacquelyn), Teixeira, P.J., Maia, S. (Sofia), Foulkes, W.D. (William), Taherian, N. (Nassim), Ruijs, M.W.G. (Marielle), Enden, A.T.H.-V. (Apollonia T. Helderman-Van) den, Izatt, L. (Louise), Davidson, R. (Rosemarie), Adank, M.A. (Muriel), Walker, L.J. (Lisa), Schmutzler, R.K. (Rita), Tucker, K. (Kathryn), Kirk, J. (Judy), Hodgson, S.V. (Shirley), Harris, M. (Marion), Douglas, F. (Fiona), Lindeman, G.J. (Geoffrey), Zgajnar, J. (Janez), Tischkowitz, M. (Marc), Clowes, V., Susman, R. (Rachel), Ramon Y Cajal, T., Patcher, N. (Nicholas), Gadea, N. (Neus), Spigelman, A., Os, T.A.M. (Theo) van, Liljegren, A. (Annelie), Side, L. (Lucy), Brewer, C. (Carole), Brady, A.F. (Angela), Donaldson, A. (Alan), Stefansdottir, V. (Vigdis), Friedman, E. (Eitan), Chen-Shtoyerman, R. (Rakefet), Amor, D. (David), Copakova, L. (Lucia), Barwell, J. (Julian), Giri, V.N. (Veda), Murthy, A.C. (Adeline C.), Nicolai, N. (Nicola), Teo, S.-H. (Soo-Hwang), Greenhalgh, T. (Trisha), Strom, S., Henderson, A. (Alex), McGrath, J. (John), Gallagher, D. (David), Aaronson, N.K. (Neil), Ardern-Jones, A. (Audrey), Bangma, C.H. (Chris), Dearnaley, D. (David), Costello, A. (Anthony), Eyfjord, J., Rothwell, J. (Jeanette), Falconer, A., Grönberg, H. (Henrik), Hamdy, F. (Freddie), Johannson, O.T. (Oskar), Khoo, V., Kote-Jarai, Z., Lubinski, J. (Jan), Melia, J., McKinley, E.T. (Enid), Mitra, A. (Anita), Moynihan, C., Rennert, G. (Gad), Suri, M. (Mohnish), Wilson, P., Killick, S.R., Moss, S.M. (Sue), and Eeles, R. (Rosalind)

Abstract

Background Men with germline breast cancer 1, early onset (BRCA1) or breast cancer 2, early onset (BRCA2) gene mutations have a higher risk of developing prostate cancer (PCa) than noncarriers. IMPACT (Identification of Men with a genetic predisposition to ProstAte Cancer: Targeted screening in BRCA1/2 mutation carriers and controls) is an international consortium of 62 centres in 20 countries evaluating the use of targeted PCa screening in men with BRCA1/2 mutations. Objective To report the first year's screening results for all men at enrolment in the study. Design, setting and participants We recruited men aged 40-69 yr with germline BRCA1/2 mutations and a control group of men who have tested negative for a pathogenic BRCA1 or BRCA2 mutation known to be present in their families. All men underwent prostate-specific antigen (PSA) testing at enrolment, and those men with PSA >3 ng/ml were offered prostate biopsy. Outcome measurements and statistical analysis PSA levels, PCa incidence, and tumour characteristics were evaluated. The Fisher exact test was used to compare the number of PCa cases among groups and the differences among disease types. Results and limitations We recruited 2481 men (791 BRCA1 carriers, 531 BRCA1 controls; 731 BRCA2 carriers, 428 BRCA2 controls). A total of 199 men (8%) presented with PSA >3.0 ng/ml, 162 biopsies were performed, and 59 PCas were diagnosed (18 BRCA1 carriers, 10 BRCA1 controls; 24 BRCA2 carriers, 7 BRCA2 controls); 66% of the tumours were classified as intermediate- or high

Published
2014
Full Text
View/download PDF

17. Fenofibrate intervention and event lowering in diabetes (FIELD) study: baseline characteristics and short-term effects of fenofibrate [ISRCTN64783481]

Author

Scott, R, Best, J, Forder, P, Taskinen, M-R, Simes, J, Barter, P, Keech, A, Colman, P, D'Emden, M, Davis, T, Drury, P, Ehnholm, C, Glasziou, P, Hunt, D, Kesaniemi, YA, Laakso, M, Simes, RJ, Sullivan, D, Whiting, M, Ansquer, J-C, Fraitag, B, Anderson, N, Hankey, G, Lehto, S, Mann, S, Romo, M, Li, LP, Hennekens, C, MacMahon, S, Pocock, S, Tonkin, A, Wilhelmsen, L, Akauola, H, Alford, F, Beinart, I, Bohra, S, Boyages, S, Connor, H, Darnell, D, Davoren, P, Lepre, F, De Looze, F, Duffield, A, Fassett, R, Flack, J, Fulcher, G, Grant, S, Hamwood, S, Harmelin, D, Jackson, R, Jeffries, W, Kamp, M, Kritharides, L, Mahar, L, McCann, V, McIntyre, D, Moses, R, Newnham, H, Nicholson, G, O'Brien, R, Park, K, Petrovsky, N, Phillips, P, Pinn, G, Simmons, D, Stanton, K, Stuckey, B, Sullivan, DR, Suranyi, M, Suthers, M, Tan, Y, Templer, M, Topliss, D, Waites, JH, Watts, G, Welborn, T, Wyndham, R, Haapamaki, H, Kesaniemi, A, Lahtela, J, Levanen, H, Saltevo, J, Sodervik, H, Taskinen, M, Vanhala, M, Baker, J, Burton, A, Dixon, P, Doran, J, Dunn, P, Graham, N, Hamer, A, Hedley, J, Lloyd, J, Manning, P, McPherson, I, Morris, S, Renner, C, Smith, R, Wackrow, M, Young, S, Alard, F, Alcoe, J, Allan, C, Amerena, J, Anderson, R, Arnold, N, Arsov, T, Ashby, D, Atkinson, C, Badhni, L, Balme, M, Barton, D, Batrouney, B, Beare, C, Beattie, T, Beggs, J, Bendall, C, Benz, A, Bond, A, Bradfield, R, Bradshaw, J, Brearley, S, Bruce, D, Burgess, J, Butler, J, Callary, M, Campbell, J, Chambers, K, Chow, J, Chow, S, Ciszek, K, Clifton, P, Clifton-Bligh, P, Clowes, V, Coates, P, Cocks, C, Cole, S, Colquhoun, D, Correcha, M, Costa, B, Coverdale, S, Croft, M, Crowe, J, Dal Sasso, S, Davis, W, Dunn, J, Edwards, S, Elder, R, El-Kaissi, S, Emery, L, England, M, Farouque, O, Fernandez, M, Fitzpatrick, B, Francis, N, Freeman, P, Fuller, A, Gale, D, Gaylard, V, Gillzan, C, Glatthaar, C, Goddard, J, Grange, V, Greenaway, T, Griffin, J, Grogan, A, Guha, S, Gustafson, J, Hamblin, PS, Hannay, T, Hardie, C, Harper, A, Hartl, G, Harvey, A, Havlin, S, Haworth, K, Hay, P, Hay, L, Heenan, B, Hesketh, R, Heyworth, A, Hines, M, Hockings, G, Hodge, A, Hoffman, L, Hoskin, L, Howells, M, Hunt, A, Inder, W, Jackson, D, Jovanovska, A, Kearins, K, Kee, P, Keen, J, Kilpatrick, D, Kindellan, J, Kingston-Ray, M, Kotowicz, M, Lassig, A, Layton, M, Lean, S, Lim, E, Long, F, Lucas, L, Ludeman, D, Ludeman-Robertson, C, Lyall, M, Lynch, L, Maddison, C, Malkus, B, Marangou, A, Margrie, F, Matthiesson, K, Matthiesson, J, Maxwell, S, McCarthy, K, McElduff, A, Mckee, H, McKenzie, J, McLachan, K, McNair, P, Meischke, M, Miller, AMC, Morrison, B, Morton, A, Mossman, W, Mowat, A, Muecke, J, Murie, P, Murray, S, Nadorp, P, Nair, S, Nairn, J, Nankervis, A, Narayan, K, Nattrass, N, Ngui, J, Nicholls, S, Nicholls, V, Nye, JA, Nye, E, O'Neal, D, O'Neill, M, O'Rourke, S, Pearse, J, Pearson, C, Phillips, J, Pittis, L, Playford, D, Porter, L, Portley, R, Powell, M, Preston, C, Pringle, S, Quinn, WA, Raffaele, J, Ramnath, G, Ramsden, J, Richtsteiger, D, Roffe, S, Rosen, S, Ross, G, Ross, Z, Rowe, J, Rumble, D, Ryan, S, Sansom, J, Seymour, C, Shanahan, E, Shelly, S, Shepherd, J, Sherman, G, Siddall, R, Silva, D, Simmons, S, Simpson, R, Sinha, A, Slobodniuk, R, Smith, M, Smith, P, Smith, S, Smith-Orr, V, Snow, J, Socha, L, Stack, T, Steed, K, Steele, K, Stephensen, J, Stevens, P, Stewart, G, Stewart, R, Strakosch, C, Sullivan, M, Sunder, S, Sunderland, J, Tapp, E, Taylor, J, Thorn, D, Tolley, A, Torpy, D, Truran, G, Turner, F, Turner, J, Van de Velde, J, Varley, S, Wallace, J, Walsh, J, Walshe, J, Ward, G, Watson, B, Watson, J, Webb, A, Werner, F, White, E, Whitehouse, A, Whitehouse, N, Wigg, S, Wilkinson, J, Wilmshurst, E, Wilson, D, Wittert, G, Wong, B, Wong, M, Worboys, S, Wright, S, Wu, S, Yarker, J, Yeo, M, Young, K, Youssef, J, Yuen, R, Zeimer, H, Ziffer, RW, Aura, A, Friman, A, Hanninen, J, Henell, J, Hyvarinen, N, Ikonen, M, Itkonen, A, Jappinen, J, Jarva, A, Jerkkola, T, Jokinen, V, Juutilainen, J, Kahkonen, H, Kangas, T, Karttunen, M, Kauranen, P, Kortelainen, S, Koukkunen, H, Kumpulainen, L, Laitinen, T, Laitinen, M, Lehto, R, Leinonen, E, Lindstron-Karjalainen, M, Lumiaho, A, Makela, J, Makinen, K, Mannermaa, L, Mard, T, Miettinen, J, Naatti, V, Paavola, S, Parssinen, N, Ripatti, J, Ruotsalainen, S, Salo, A, Siiskonen, M, Soppela, A, Starck, J, Suonranta, I, Ukkola, L, Valli, K, Virolainen, J, Allan, P, Arnold, W, Bagg, W, Balfour, K, Ball, T, Ballantine, B, Ballantyne, C, Barker, C, Bartley, F, Berry, E, Braatvedt, G, Campbell, A, Clarke, T, Clarke, R, Claydon, A, Clayton, S, Cresswell, P, Cutfield, R, Daffurn, J, Delahunt, J, Dissnayake, A, Eagleton, C, Ferguson, C, Florkowski, C, Fry, D, Giles, P, Gluyas, M, Grant, C, Guile, P, Guolo, M, Hale, P, Hammond, M, Healy, P, Hills, M, Hinge, J, Holland, J, Hyne, B, Ireland, A, Johnstone, A, Jones, S, Kerr, G, Kerr, K, Khant, M, Krebs, J, Law, L, Lydon, B, MacAuley, K, McEwan, R, McGregor, P, McLaren, B, McLeod, L, Medforth, J, Miskimmin, R, Moffat, J, Pickup, M, Prentice, C, Rahman, M, Reda, E, Ross, C, Ryalls, A, Schmid, D, Shergill, N, Snaddon, A, Snell, H, Stevens, L, Waterman, A, Watts, V, Jayne, K, Keirnan, E, Newman, P, Ritchie, G, Rosenfeld, A, Beller, E, Gebski, V, Pillai, A, Anderson, C, Blakesmith, S, Chan, S-Y, Czyniewski, S, Dobbie, A, Doshi, S, Dupuy, A, Eckermann, S, Edwards, M, Fields, N, Flood, K, Ford, S, French, C, Gillies, S, Greig, C, Groshens, M, Gu, J, Guo, Y, Hague, W, Healy, S, Hones, L, Hossain, Z, Howlett, M, Lee, J, Li, L-P, Matthews, T, Micallef, J, Martin, A, Minns, I, Nguyen, A, Papuni, F, Patel, A, Pike, R, Pena, M, Pinto, K, Schipp, D, Schroeder, J, Sim, B, Sodhi, C, Sourjina, T, Sutton, C, Taylor, R, Vlagsma, P, Walder, S, Walker, R, Wong, W, Zhang, J, Zhong, B, Kokkonen, A, Narva, P, Niemi, E-L, Syrjanen, A-M, Lintott, C, Tirimacco, R, Kajosaari, M, Raman, L, Sundvall, J, Tukianen, M, Crimet, D, Sirugue, I, and Aubonnet, P

Subjects
Male, Cardiac & Cardiovascular Systems, Endocrinology, Diabetes and Metabolism, Atorvastatin, Coronary Disease, Fibrate, SECONDARY PREVENTION, ATORVASTATIN, law.invention, Placebos, Randomized controlled trial, Fenofibrate, law, Myocardial infarction, 1102 Cardiorespiratory Medicine and Haematology, Finland, Original Investigation, Hypolipidemic Agents, PLASMA, CHOLESTEROL, Middle Aged, INSULIN, CARDIOVASCULAR-DISEASE, Cardiovascular Diseases, Female, Cardiology and Cardiovascular Medicine, Life Sciences & Biomedicine, medicine.drug, medicine.medical_specialty, medicine.drug_class, Diabetes Complications, Endocrinology & Metabolism, Double-Blind Method, Internal medicine, Diabetes mellitus, Intervention (counseling), medicine, Humans, CORONARY-HEART-DISEASE, Obesity, Triglycerides, Aged, Apolipoproteins B, Bezafibrate, Science & Technology, business.industry, Cholesterol, HDL, Australia, Cholesterol, LDL, medicine.disease, BEZAFIBRATE, FIELD Study Investigators, MYOCARDIAL-INFARCTION, Diabetes Mellitus, Type 2, Cardiovascular System & Hematology, Cardiovascular System & Cardiology, business, HIGH-DENSITY-LIPOPROTEIN, New Zealand
Abstract

Objective The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) Study is examining the effects of long-term fibrate therapy on coronary heart disease (CHD) event rates in patients with diabetes mellitus. This article describes the trial's run-in phase and patients' baseline characteristics. Research design and methods FIELD is a double-blind, placebo-controlled trial in 63 centres in 3 countries evaluating the effects of fenofibrate versus placebo on CHD morbidity and mortality in 9795 patients with type 2 diabetes mellitus. Patients were to have no indication for lipid-lowering therapy on randomization, but could start these or other drugs at any time after randomization. Follow-up in the study was to be for a median duration of not less than 5 years and until 500 major coronary events (fatal coronary heart disease plus nonfatal myocardial infarction) had occurred. Results About 2100 patients (22%) had some manifestation of cardiovascular disease (CVD) at baseline and thus high risk status. Less than 25% of patients without CVD had a (UKPDS determined) calculated 5-year CHD risk of 30), most were men, two-thirds were aged over 60 years, and substantial proportions had NCEP ATP III features of the metabolic syndrome independent of their diabetes, including low HDL (60%), high blood pressure measurement or treatment for hypertension (84%), high waist measurement (68%), and raised triglycerides (52%). After a 6-week run-in period before randomisation with all participants receiving 200 mg comicronized fenofibrate, there were declines in total and LDL cholesterol (10%) and triglycerides (26%) and an increase in HDL cholesterol (6.5%). Conclusion The study will show the effect of PPAR-alpha agonist action on CHD and other vascular outcomes in patients with type 2 diabetes including substantial numbers with low to moderate CVD risk but with the various components of the metabolic syndrome. The main results of the study will be reported in late 2005.

Published
2005

19. Role of Engrailed-2 (EN2) as a prostate cancer detection biomarker in genetically high risk men

Author

Killick, E, Morgan, R, Launchbury, F, Bancroft, E, Page, E, Castro, E, Kote-Jarai, Z, Aprikian, A, Blanco, I, Clowes, V, Domchek, S, Douglas, F, Eccles, D, Evans, DG, Harris, M, Kirk, J, Lam, J, Lindeman, G, Mitchell, G, Pachter, N, Selkirk, C, Tucker, K, Zgajnar, J, Eeles, R, Pandha, H, Killick, E, Morgan, R, Launchbury, F, Bancroft, E, Page, E, Castro, E, Kote-Jarai, Z, Aprikian, A, Blanco, I, Clowes, V, Domchek, S, Douglas, F, Eccles, D, Evans, DG, Harris, M, Kirk, J, Lam, J, Lindeman, G, Mitchell, G, Pachter, N, Selkirk, C, Tucker, K, Zgajnar, J, Eeles, R, and Pandha, H

Abstract

Controversy surrounds the use of PSA as a biomarker for prostate cancer detection, leaving an unmet need for a novel biomarker in this setting; urinary EN2 may identify individuals with clinically relevant prostate cancer. Male BRCA1 and BRCA2 mutation carriers are at increased risk of clinically significant prostate cancer and may benefit from screening. Urine samples from 413 BRCA1 and BRCA2 mutation carriers and controls were evaluated. Subjects underwent annual PSA screening with diagnostic biopsy triggered by PSA > 3.0 ng/ml; 21 men were diagnosed with prostate cancer. Urinary EN2 levels were measured by ELISA and had a sensitivity of 66.7% and specificity of 89.3% for cancer detection. There was no statistically significant difference in EN2 levels according to genetic status or Gleason score. Urinary EN2 may be useful as a non-invasive early biomarker for prostate cancer detection in genetically high-risk individuals.

Published
2013

20. The rs10993994 risk allele for prostate cancer results in clinically relevant changes in microseminoprotein-beta expression in tissue and urine.

Author

Whitaker, H.C., Kote-Jarai, Z., Ross-Adams, H., Warren, A.Y., Burge, J., George, A., Bancroft, E., Jhavar, S., Leongamornlert, D., Tymrakiewicz, M., Saunders, E., Page, E., Mitra, A., Mitchell, G., Lindeman, G.J., Evans, D.G., Blanco, I., Mercer, C., Rubinstein, W.S., Clowes, V., Douglas, F., Hodgson, S., Walker, L., Donaldson, A., Izatt, L., Dorkins, H., Male, A., Tucker, K., Stapleton, A., Lam, J., Kirk, J., Lilja, H., Easton, D., Cooper, C., Eeles, R., Neal, D.E., Whitaker, H.C., Kote-Jarai, Z., Ross-Adams, H., Warren, A.Y., Burge, J., George, A., Bancroft, E., Jhavar, S., Leongamornlert, D., Tymrakiewicz, M., Saunders, E., Page, E., Mitra, A., Mitchell, G., Lindeman, G.J., Evans, D.G., Blanco, I., Mercer, C., Rubinstein, W.S., Clowes, V., Douglas, F., Hodgson, S., Walker, L., Donaldson, A., Izatt, L., Dorkins, H., Male, A., Tucker, K., Stapleton, A., Lam, J., Kirk, J., Lilja, H., Easton, D., Cooper, C., Eeles, R., and Neal, D.E.

Abstract

Contains fulltext : 87729.pdf (publisher's version ) (Open Access), BACKGROUND: Microseminoprotein-beta (MSMB) regulates apoptosis and using genome-wide association studies the rs10993994 single nucleotide polymorphism in the MSMB promoter has been linked to an increased risk of developing prostate cancer. The promoter location of the risk allele, and its ability to reduce promoter activity, suggested that the rs10993994 risk allele could result in lowered MSMB in benign tissue leading to increased prostate cancer risk. METHODOLOGY/PRINCIPAL FINDINGS: MSMB expression in benign and malignant prostate tissue was examined using immunohistochemistry and compared with the rs10993994 genotype. Urinary MSMB concentrations were determined by ELISA and correlated with urinary PSA, the presence or absence of cancer, rs10993994 genotype and age of onset. MSMB levels in prostate tissue and urine were greatly reduced with tumourigenesis. Urinary MSMB was better than urinary PSA at differentiating men with prostate cancer at all Gleason grades. The high risk allele was associated with heterogeneity of MSMB staining and loss of MSMB in both tissue and urine in benign prostate. CONCLUSIONS: These data show that some high risk alleles discovered using genome-wide association studies produce phenotypic effects with potential clinical utility. We provide the first link between a low penetrance polymorphism for prostate cancer and a potential test in human tissue and bodily fluids. There is potential to develop tissue and urinary MSMB for a biomarker of prostate cancer risk, diagnosis and disease monitoring.

Published
2010

21. The rs10993994 Risk Allele for Prostate Cancer Results in Clinically Relevant Changes in Microseminoprotein-Beta Expression in Tissue and Urine

Author

Vickers, A, Whitaker, HC, Kote-Jarai, Z, Ross-Adams, H, Warren, AY, Burge, J, George, A, Bancroft, E, Jhavar, S, Leongamornlert, D, Tymrakiewicz, M, Saunders, E, Page, E, Mitra, A, Mitchell, G, Lindeman, GJ, Evans, DG, Blanco, I, Mercer, C, Rubinstein, WS, Clowes, V, Douglas, F, Hodgson, S, Walker, L, Donaldson, A, Izatt, L, Dorkins, H, Male, A, Tucker, K, Stapleton, A, Lam, J, Kirk, J, Lilja, H, Easton, D, Cooper, C, Eeles, R, Neal, DE, Vickers, A, Whitaker, HC, Kote-Jarai, Z, Ross-Adams, H, Warren, AY, Burge, J, George, A, Bancroft, E, Jhavar, S, Leongamornlert, D, Tymrakiewicz, M, Saunders, E, Page, E, Mitra, A, Mitchell, G, Lindeman, GJ, Evans, DG, Blanco, I, Mercer, C, Rubinstein, WS, Clowes, V, Douglas, F, Hodgson, S, Walker, L, Donaldson, A, Izatt, L, Dorkins, H, Male, A, Tucker, K, Stapleton, A, Lam, J, Kirk, J, Lilja, H, Easton, D, Cooper, C, Eeles, R, and Neal, DE

Abstract

BACKGROUND: Microseminoprotein-beta (MSMB) regulates apoptosis and using genome-wide association studies the rs10993994 single nucleotide polymorphism in the MSMB promoter has been linked to an increased risk of developing prostate cancer. The promoter location of the risk allele, and its ability to reduce promoter activity, suggested that the rs10993994 risk allele could result in lowered MSMB in benign tissue leading to increased prostate cancer risk. METHODOLOGY/PRINCIPAL FINDINGS: MSMB expression in benign and malignant prostate tissue was examined using immunohistochemistry and compared with the rs10993994 genotype. Urinary MSMB concentrations were determined by ELISA and correlated with urinary PSA, the presence or absence of cancer, rs10993994 genotype and age of onset. MSMB levels in prostate tissue and urine were greatly reduced with tumourigenesis. Urinary MSMB was better than urinary PSA at differentiating men with prostate cancer at all Gleason grades. The high risk allele was associated with heterogeneity of MSMB staining and loss of MSMB in both tissue and urine in benign prostate. CONCLUSIONS: These data show that some high risk alleles discovered using genome-wide association studies produce phenotypic effects with potential clinical utility. We provide the first link between a low penetrance polymorphism for prostate cancer and a potential test in human tissue and bodily fluids. There is potential to develop tissue and urinary MSMB for a biomarker of prostate cancer risk, diagnosis and disease monitoring.

Published
2010

23. "I'm quite proud of how we've handled it": health professionals' experiences of returning additional findings from the 100,000 genomes project.

Author

Stafford-Smith B, Gurasashvili J, Peter M, Daniel M, Balasubramanian M, Bownass L, Brennan P, Cleaver R, Clowes V, Costello P, DeSouza B, Dubois L, Harrison R, Hawkes L, Jones EA, Kraus A, McEntagart M, Somarathi S, Taylor A, Tripathi V, Chitty LS, and Hill M

Abstract

Participants in the 100,000 Genomes Project (100kGP) could consent to receive additional finding (AF) results, individual variants relating to genes associated with susceptibility to cancer and familial hypercholesterolemia (FH). In the study reported here, qualitative interviews were used to explore the experiences of National Health Service (NHS) professionals from across England who were tasked with returning over 80,000 "no AF" results and 700 positive AF results to 100kGP participants. Interviews were conducted with 45 professionals from a range of backgrounds, including Genetic Counsellors, Clinical Geneticists, FH Clinical Nurse Specialists and Clinical Scientists. Interviews were analysed using a codebook thematic analysis approach. Returning AF results has been a significant endeavour, with challenges for pathways, administrative processes and clinical and laboratory time when the capacity of NHS services is already stretched. Professionals discussed going "above and beyond" to prioritise patient care through pathway design, additional clinics, overtime, longer appointments and provision of follow-up appointments. Professionals also described facing practical and emotional challenges when returning AFs. Benefits for patients from receiving AFs in the 100kGP were highlighted and professionals were generally positive about offering clinically actionable AFs within routine NHS clinical care. Professionals were, however, cautious around the implementation of AFs into routine care and felt more research and discussion was needed to determine which AFs to offer, approaches to consent and communication of results, costs and the potential strain on NHS capacity and resources. Further consultation is required with careful review of pathways and resources before offering AFs in clinical practice., (© 2024. The Author(s).)

Published
2024
Full Text
View/download PDF

24. Deleterious ZNRF3 germline variants cause neurodevelopmental disorders with mirror brain phenotypes via domain-specific effects on Wnt/β-catenin signaling.

Author

Boonsawat P, Asadollahi R, Niedrist D, Steindl K, Begemann A, Joset P, Bhoj EJ, Li D, Zackai E, Vetro A, Barba C, Guerrini R, Whalen S, Keren B, Khan A, Jing D, Palomares Bralo M, Rikeros Orozco E, Hao Q, Schlott Kristiansen B, Zheng B, Donnelly D, Clowes V, Zweier M, Papik M, Siegel G, Sabatino V, Mocera M, Horn AHC, Sticht H, and Rauch A

Subjects
Humans, Female, Male, Child, Child, Preschool, beta Catenin genetics, beta Catenin metabolism, Adolescent, Mutation, Missense, Genetic Association Studies, Protein Domains, Wnt Signaling Pathway genetics, Germ-Line Mutation, Neurodevelopmental Disorders genetics, Neurodevelopmental Disorders pathology, Phenotype, Ubiquitin-Protein Ligases genetics, Ubiquitin-Protein Ligases metabolism, Brain metabolism, Brain pathology
Abstract

Zinc and RING finger 3 (ZNRF3) is a negative-feedback regulator of Wnt/β-catenin signaling, which plays an important role in human brain development. Although somatically frequently mutated in cancer, germline variants in ZNRF3 have not been established as causative for neurodevelopmental disorders (NDDs). We identified 12 individuals with ZNRF3 variants and various phenotypes via GeneMatcher/Decipher and evaluated genotype-phenotype correlation. We performed structural modeling and representative deleterious and control variants were assessed using in vitro transcriptional reporter assays with and without Wnt-ligand Wnt3a and/or Wnt-potentiator R-spondin (RSPO). Eight individuals harbored de novo missense variants and presented with NDD. We found missense variants associated with macrocephalic NDD to cluster in the RING ligase domain. Structural modeling predicted disruption of the ubiquitin ligase function likely compromising Wnt receptor turnover. Accordingly, the functional assays showed enhanced Wnt/β-catenin signaling for these variants in a dominant negative manner. Contrarily, an individual with microcephalic NDD harbored a missense variant in the RSPO-binding domain predicted to disrupt binding affinity to RSPO and showed attenuated Wnt/β-catenin signaling in the same assays. Additionally, four individuals harbored de novo truncating or de novo or inherited large in-frame deletion variants with non-NDD phenotypes, including heart, adrenal, or nephrotic problems. In contrast to NDD-associated missense variants, the effects on Wnt/β-catenin signaling were comparable between the truncating variant and the empty vector and between benign variants and the wild type. In summary, we provide evidence for mirror brain size phenotypes caused by distinct pathomechanisms in Wnt/β-catenin signaling through protein domain-specific deleterious ZNRF3 germline missense variants., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Published
2024
Full Text
View/download PDF

25. Functional and clinical studies reveal pathophysiological complexity of CLCN4-related neurodevelopmental condition.

Author

Palmer EE, Pusch M, Picollo A, Forwood C, Nguyen MH, Suckow V, Gibbons J, Hoff A, Sigfrid L, Megarbane A, Nizon M, Cogné B, Beneteau C, Alkuraya FS, Chedrawi A, Hashem MO, Stamberger H, Weckhuysen S, Vanlander A, Ceulemans B, Rajagopalan S, Nunn K, Arpin S, Raynaud M, Motter CS, Ward-Melver C, Janssens K, Meuwissen M, Beysen D, Dikow N, Grimmel M, Haack TB, Clement E, McTague A, Hunt D, Townshend S, Ward M, Richards LJ, Simons C, Costain G, Dupuis L, Mendoza-Londono R, Dudding-Byth T, Boyle J, Saunders C, Fleming E, El Chehadeh S, Spitz MA, Piton A, Gerard B, Abi Warde MT, Rea G, McKenna C, Douzgou S, Banka S, Akman C, Bain JM, Sands TT, Wilson GN, Silvertooth EJ, Miller L, Lederer D, Sachdev R, Macintosh R, Monestier O, Karadurmus D, Collins F, Carter M, Rohena L, Willemsen MH, Ockeloen CW, Pfundt R, Kroft SD, Field M, Laranjeira FER, Fortuna AM, Soares AR, Michaud V, Naudion S, Golla S, Weaver DD, Bird LM, Friedman J, Clowes V, Joss S, Pölsler L, Campeau PM, Blazo M, Bijlsma EK, Rosenfeld JA, Beetz C, Powis Z, McWalter K, Brandt T, Torti E, Mathot M, Mohammad SS, Armstrong R, and Kalscheuer VM

Subjects
Male, Female, Humans, Mutation, Missense, Genes, X-Linked, Phenotype, Chloride Channels genetics, Neurodevelopmental Disorders genetics
Abstract

Missense and truncating variants in the X-chromosome-linked CLCN4 gene, resulting in reduced or complete loss-of-function (LOF) of the encoded chloride/proton exchanger ClC-4, were recently demonstrated to cause a neurocognitive phenotype in both males and females. Through international clinical matchmaking and interrogation of public variant databases we assembled a database of 90 rare CLCN4 missense variants in 90 families: 41 unique and 18 recurrent variants in 49 families. For 43 families, including 22 males and 33 females, we collated detailed clinical and segregation data. To confirm causality of variants and to obtain insight into disease mechanisms, we investigated the effect on electrophysiological properties of 59 of the variants in Xenopus oocytes using extended voltage and pH ranges. Detailed analyses revealed new pathophysiological mechanisms: 25% (15/59) of variants demonstrated LOF, characterized by a "shift" of the voltage-dependent activation to more positive voltages, and nine variants resulted in a toxic gain-of-function, associated with a disrupted gate allowing inward transport at negative voltages. Functional results were not always in line with in silico pathogenicity scores, highlighting the complexity of pathogenicity assessment for accurate genetic counselling. The complex neurocognitive and psychiatric manifestations of this condition, and hitherto under-recognized impacts on growth, gastrointestinal function, and motor control are discussed. Including published cases, we summarize features in 122 individuals from 67 families with CLCN4-related neurodevelopmental condition and suggest future research directions with the aim of improving the integrated care for individuals with this diagnosis., (© 2022. The Author(s).)

Published
2023
Full Text
View/download PDF

26. Individuals with heterozygous variants in the Wnt-signalling pathway gene FZD5 delineate a phenotype characterized by isolated coloboma and variable expressivity.

Author

Holt R, Goudie D, Verde AD, Gardham A, Ramond F, Putoux A, Sarkar A, Clowes V, Clayton-Smith J, Banka S, Cortazar Galarza L, Thuret G, Ubeda Erviti M, Zurutuza Ibarguren A, Sáez Villaverde R, Tamayo Durán A, Ayuso C, Bax DA, Plaisancie J, Corton M, Chassaing N, Calvas P, and Ragge NK

Subjects
Humans, Eye, Phenotype, Frizzled Receptors genetics, Solute Carrier Family 12, Member 2 genetics, Microphthalmos genetics, Coloboma diagnosis, Coloboma genetics, Anophthalmos genetics
Abstract

Background: Anophthalmia, microphthalmia and coloboma are a genetically heterogenous spectrum of developmental eye disorders. Recently, variants in the Wnt-pathway gene Frizzled Class Receptor 5 (FZD5) have been identified in individuals with coloboma and rarely microphthalmia, sometimes with additional phenotypes and variable penetrance., Materials and Methods: We identified variants in FZD5 in individuals with developmental eye disorders from the UK (including the DDD Study [www.ddduk.org/access.html]), France and Spain using whole genome/exome sequencing or customized NGS panels of ocular development genes., Results: We report eight new families with FZD5 variants and ocular coloboma. Three individuals presented with additional syndromic features, two explicable by additional variants in other genes ( SLC12A2 and DDX3X ). In two families initially showing incomplete penetrance, re-examination of apparently unaffected carrier individuals revealed subtle ocular colobomatous phenotypes. Finally, we report two families with microphthalmia in addition to coloboma, representing the second and third reported cases of this phenotype in conjunction with FZD5 variants., Conclusions: Our findings indicate FZD5 variants are typically associated with isolated ocular coloboma, occasionally microphthalmia, and that extraocular phenotypes are likely to be explained by other gene alterations.

Published
2022
Full Text
View/download PDF

27. The Phenotypic Continuum of ATP1A3 -Related Disorders.

Author

Vezyroglou A, Akilapa R, Barwick K, Koene S, Brownstein CA, Holder-Espinasse M, Fry AE, Németh AH, Tofaris GK, Hay E, Hughes I, Mansour S, Mordekar SR, Splitt M, Turnpenny PD, Demetriou D, Koopmann TT, Ruivenkamp CAL, Agrawal PB, Carr L, Clowes V, Ghali N, Holder SE, Radley J, Male A, Sisodiya SM, Kurian MA, Cross JH, and Balasubramanian M

Subjects
Hemiplegia genetics, Humans, Mutation genetics, Phenotype, Sodium-Potassium-Exchanging ATPase genetics, Cerebellar Ataxia genetics, Dystonic Disorders genetics
Abstract

Background and Objectives: ATP1A3 is associated with a broad spectrum of predominantly neurologic disorders, which continues to expand beyond the initially defined phenotypes of alternating hemiplegia of childhood, rapid-onset dystonia parkinsonism, and cerebellar ataxia, areflexia, pes cavus, optic atrophy, sensorineural hearing loss syndrome. This phenotypic variability makes it challenging to assess the pathogenicity of an ATP1A3 variant found in an undiagnosed patient. We describe the phenotypic features of individuals carrying a pathogenic/likely pathogenic ATP1A3 variant and perform a literature review of all ATP1A3 variants published thus far in association with human neurologic disease. Our aim is to demonstrate the heterogeneous clinical spectrum of the gene and look for phenotypic overlap between patients that will streamline the diagnostic process., Methods: Undiagnosed individuals with ATP1A3 variants were identified within the cohort of the Deciphering Developmental Disorders study with additional cases contributed by collaborators internationally. Detailed clinical data were collected with consent through a questionnaire completed by the referring clinicians. PubMed was searched for publications containing the term "ATP1A3" from 2004 to 2021., Results: Twenty-four individuals with a previously undiagnosed neurologic phenotype were found to carry 21 ATP1A3 variants. Eight variants have been previously published. Patients experienced on average 2-3 different types of paroxysmal events. Permanent neurologic features were common including microcephaly (7; 29%), ataxia (13; 54%), dystonia (10; 42%), and hypotonia (7; 29%). All patients had cognitive impairment. Neuropsychiatric diagnoses were reported in 16 (66.6%) individuals. Phenotypes were extremely varied, and most individuals did not fit clinical criteria for previously published phenotypes. On review of the literature, 1,108 individuals have been reported carrying 168 different ATP1A3 variants. The most common variants are associated with well-defined phenotypes, while more rare variants often result in very rare symptom correlations, such as are seen in our study. Combined Annotation-Dependent Depletion (CADD) scores of pathogenic and likely pathogenic variants were significantly higher and variants clustered within 6 regions of constraint., Discussion: Our study shows that looking for a combination of paroxysmal events, hyperkinesia, neuropsychiatric symptoms, and cognitive impairment and evaluating the CADD score and variant location can help identify an ATP1A3 -related condition, rather than applying diagnostic criteria alone., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Published
2022
Full Text
View/download PDF

28. Clinical findings of 21 previously unreported probands with HNRNPU-related syndrome and comprehensive literature review.

Author

Durkin A, Albaba S, Fry AE, Morton JE, Douglas A, Beleza A, Williams D, Volker-Touw CML, Lynch SA, Canham N, Clowes V, Straub V, Lachlan K, Gibbon F, El Gamal M, Varghese V, Parker MJ, Newbury-Ecob R, Turnpenny PD, Gardham A, Ghali N, and Balasubramanian M

Subjects
Adolescent, Brain diagnostic imaging, Child, Child, Preschool, Craniofacial Abnormalities etiology, Female, Haploinsufficiency genetics, Humans, Infant, Intellectual Disability genetics, Male, Microcephaly etiology, Neurodevelopmental Disorders genetics, Pregnancy, Seizures genetics, Syndrome, Heterogeneous-Nuclear Ribonucleoprotein U genetics, Neurodevelopmental Disorders etiology
Abstract

With advances in genetic testing and improved access to such advances, whole exome sequencing is becoming a first-line investigation in clinical work-up of children with developmental delay/intellectual disability (ID). As a result, the need to understand the importance of genetic variants and its effect on the clinical phenotype is increasing. Here, we report on the largest cohort of patients with HNRNPU variants. These 21 patients follow on from the previous study published by Yates et al. in 2017 from our group predominantly identified from the Deciphering Developmental Disorders study that reported seven patients with HNRNPU variants. All the probands reported here have a de novo loss-of-function variant. These probands have craniofacial dysmorphic features, in the majority including widely spaced teeth, microcephaly, high arched eyebrows, and palpebral fissure abnormalities. Many of the patients in the group also have moderate to severe ID and seizures that tend to start in early childhood. This series has allowed us to define a novel neurodevelopmental syndrome, with a likely mechanism of haploinsufficiency, and expand substantially on already published literature on HNRNPU-related neurodevelopmental syndrome., (© 2020 The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals, Inc.)

Published
2020
Full Text
View/download PDF

29. Pathogenicity and selective constraint on variation near splice sites.

Author

Lord J, Gallone G, Short PJ, McRae JF, Ironfield H, Wynn EH, Gerety SS, He L, Kerr B, Johnson DS, McCann E, Kinning E, Flinter F, Temple IK, Clayton-Smith J, McEntagart M, Lynch SA, Joss S, Douzgou S, Dabir T, Clowes V, McConnell VPM, Lam W, Wright CF, FitzPatrick DR, Firth HV, Barrett JC, and Hurles ME

Subjects
Exome, Humans, Exome Sequencing, Developmental Disabilities genetics, Mutation, RNA Splice Sites
Abstract

Mutations that perturb normal pre-mRNA splicing are significant contributors to human disease. We used exome sequencing data from 7833 probands with developmental disorders (DDs) and their unaffected parents, as well as more than 60,000 aggregated exomes from the Exome Aggregation Consortium, to investigate selection around the splice sites and quantify the contribution of splicing mutations to DDs. Patterns of purifying selection, a deficit of variants in highly constrained genes in healthy subjects, and excess de novo mutations in patients highlighted particular positions within and around the consensus splice site of greater functional relevance. By using mutational burden analyses in this large cohort of proband-parent trios, we could estimate in an unbiased manner the relative contributions of mutations at canonical dinucleotides (73%) and flanking noncanonical positions (27%), and calculate the positive predictive value of pathogenicity for different classes of mutations. We identified 18 patients with likely diagnostic de novo mutations in dominant DD-associated genes at noncanonical positions in splice sites. We estimate 35%-40% of pathogenic variants in noncanonical splice site positions are missing from public databases., (© 2019 Lord et al.; Published by Cold Spring Harbor Laboratory Press.)

Published
2019
Full Text
View/download PDF

30. MYT1L mutations cause intellectual disability and variable obesity by dysregulating gene expression and development of the neuroendocrine hypothalamus.

Author

Blanchet P, Bebin M, Bruet S, Cooper GM, Thompson ML, Duban-Bedu B, Gerard B, Piton A, Suckno S, Deshpande C, Clowes V, Vogt J, Turnpenny P, Williamson MP, Alembik Y, Glasgow E, and McNeill A

Subjects
Adult, Animals, CRISPR-Cas Systems, Cell Line, Child, Chromosome Deletion, Chromosomes, Human, Pair 2 genetics, Female, Gene Knockout Techniques, Humans, Hypothalamus metabolism, Hypothalamus pathology, Intellectual Disability physiopathology, Male, Mutation, Obesity physiopathology, Polymorphism, Single Nucleotide genetics, Zebrafish, Gene Expression Regulation genetics, Hypothalamus physiology, Intellectual Disability genetics, Nerve Tissue Proteins genetics, Obesity genetics, Transcription Factors genetics
Abstract

Deletions at chromosome 2p25.3 are associated with a syndrome consisting of intellectual disability and obesity. The smallest region of overlap for deletions at 2p25.3 contains PXDN and MYT1L. MYT1L is expressed only within the brain in humans. We hypothesized that single nucleotide variants (SNVs) in MYT1L would cause a phenotype resembling deletion at 2p25.3. To examine this we sought MYT1L SNVs in exome sequencing data from 4, 296 parent-child trios. Further variants were identified through a genematcher-facilitated collaboration. We report 9 patients with MYT1L SNVs (4 loss of function and 5 missense). The phenotype of SNV carriers overlapped with that of 2p25.3 deletion carriers. To identify the transcriptomic consequences of MYT1L loss of function we used CRISPR-Cas9 to create a knockout cell line. Gene Ontology analysis in knockout cells demonstrated altered expression of genes that regulate gene expression and that are localized to the nucleus. These differentially expressed genes were enriched for OMIM disease ontology terms "mental retardation". To study the developmental effects of MYT1L loss of function we created a zebrafish knockdown using morpholinos. Knockdown zebrafish manifested loss of oxytocin expression in the preoptic neuroendocrine area. This study demonstrates that MYT1L variants are associated with syndromic obesity in humans. The mechanism is related to dysregulated expression of neurodevelopmental genes and altered development of the neuroendocrine hypothalamus.

Published
2017
Full Text
View/download PDF

32. SAMS, a syndrome of short stature, auditory-canal atresia, mandibular hypoplasia, and skeletal abnormalities is a unique neurocristopathy caused by mutations in Goosecoid.

Author

Parry DA, Logan CV, Stegmann AP, Abdelhamed ZA, Calder A, Khan S, Bonthron DT, Clowes V, Sheridan E, Ghali N, Chudley AE, Dobbie A, Stumpel CT, and Johnson CA

Subjects
Abnormalities, Multiple diagnosis, Adult, Animals, Child, DNA Mutational Analysis, Female, Genetic Association Studies, Homozygote, Humans, Male, Mice, Pedigree, Phenotype, Syndrome, Young Adult, Abnormalities, Multiple genetics, Bone and Bones abnormalities, Dwarfism genetics, Ear Canal abnormalities, Goosecoid Protein genetics, Mandible abnormalities, Mutation
Abstract

Short stature, auditory canal atresia, mandibular hypoplasia, and skeletal abnormalities (SAMS) has been reported previously to be a rare, autosomal-recessive developmental disorder with other, unique rhizomelic skeletal anomalies. These include bilateral humeral hypoplasia, humeroscapular synostosis, pelvic abnormalities, and proximal defects of the femora. To identify the genetic basis of SAMS, we used molecular karyotyping and whole-exome sequencing (WES) to study small, unrelated families. Filtering of variants from the WES data included segregation analysis followed by comparison of in-house exomes. We identified a homozygous 306 kb microdeletion and homozygous predicted null mutations of GSC, encoding Goosecoid homeobox protein, a paired-like homeodomain transcription factor. This confirms that SAMS is a human malformation syndrome resulting from GSC mutations. Previously, Goosecoid has been shown to be a determinant at the Xenopus gastrula organizer region and a segment-polarity determinant in Drosophila. In the present report, we present data on Goosecoid protein localization in staged mouse embryos. These data and the SAMS clinical phenotype both suggest that Goosecoid is a downstream effector of the regulatory networks that define neural-crest cell-fate specification and subsequent mesoderm cell lineages in mammals, particularly during shoulder and hip formation. Our findings confirm that Goosecoid has an essential role in human craniofacial and joint development and suggest that Goosecoid is an essential regulator of mesodermal patterning in mammals and that it has specific functions in neural crest cell derivatives., (Copyright © 2013 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Published
2013
Full Text
View/download PDF

33. Role of Engrailed-2 (EN2) as a prostate cancer detection biomarker in genetically high risk men.

Author

Killick E, Morgan R, Launchbury F, Bancroft E, Page E, Castro E, Kote-Jarai Z, Aprikian A, Blanco I, Clowes V, Domchek S, Douglas F, Eccles D, Evans DG, Harris M, Kirk J, Lam J, Lindeman G, Mitchell G, Pachter N, Selkirk C, Tucker K, Zgajnar J, Eeles R, and Pandha H

Subjects
Adult, Aged, Genes, BRCA1, Genes, BRCA2, Humans, Male, Middle Aged, Prostate-Specific Antigen blood, Prostatic Neoplasms genetics, Biomarkers, Tumor urine, Homeodomain Proteins urine, Nerve Tissue Proteins urine, Prostatic Neoplasms diagnosis
Abstract

Controversy surrounds the use of PSA as a biomarker for prostate cancer detection, leaving an unmet need for a novel biomarker in this setting; urinary EN2 may identify individuals with clinically relevant prostate cancer. Male BRCA1 and BRCA2 mutation carriers are at increased risk of clinically significant prostate cancer and may benefit from screening. Urine samples from 413 BRCA1 and BRCA2 mutation carriers and controls were evaluated. Subjects underwent annual PSA screening with diagnostic biopsy triggered by PSA > 3.0 ng/ml; 21 men were diagnosed with prostate cancer. Urinary EN2 levels were measured by ELISA and had a sensitivity of 66.7% and specificity of 89.3% for cancer detection. There was no statistically significant difference in EN2 levels according to genetic status or Gleason score. Urinary EN2 may be useful as a non-invasive early biomarker for prostate cancer detection in genetically high-risk individuals.

Published
2013
Full Text
View/download PDF

Catalog

Books, media, physical & digital resources
See catalog results