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12 results on '"Ayers, K.L."'

1. Premature Ovarian Insufficiency in CLPB Deficiency: Transcriptomic, Proteomic and Phenotypic Insights

Author

Tucker, E.J., Baker, M.J., Hock, D.H., Warren, J.T., Jaillard, S., Bell, K.M., Sreenivasan, R., Bakhshalizadeh, S., Hanna, C.A., Caruana, N.J., Wortmann, S.B., Rahman, S., Pitceathly, R.D.S., Donadieu, J., Alimi, A., Launay, V., Coppo, P., Christin-Maitre, S., Robevska, G., Bergen, J. van, Kline, B.L., Ayers, K.L., Stewart, P.N., Stroud, D.A., Stojanovski, D., Sinclair, A.H., Tucker, E.J., Baker, M.J., Hock, D.H., Warren, J.T., Jaillard, S., Bell, K.M., Sreenivasan, R., Bakhshalizadeh, S., Hanna, C.A., Caruana, N.J., Wortmann, S.B., Rahman, S., Pitceathly, R.D.S., Donadieu, J., Alimi, A., Launay, V., Coppo, P., Christin-Maitre, S., Robevska, G., Bergen, J. van, Kline, B.L., Ayers, K.L., Stewart, P.N., Stroud, D.A., Stojanovski, D., and Sinclair, A.H.

Abstract

Item does not contain fulltext, CONTEXT: Premature ovarian insufficiency (POI) is a common form of female infertility that usually presents as an isolated condition but can be part of various genetic syndromes. Early diagnosis and treatment of POI can minimize comorbidity and improve health outcomes. OBJECTIVE: We aimed to determine the genetic cause of syndromic POI, intellectual disability, neutropenia, and cataracts. METHODS: We performed whole-exome sequencing (WES) followed by functional validation via RT-PCR, RNAseq, and quantitative proteomics, as well as clinical update of previously reported patients with variants in the caseinolytic peptidase B (CLPB) gene. RESULTS: We identified causative variants in CLPB, encoding a mitochondrial disaggregase. Variants in this gene are known to cause an autosomal recessive syndrome involving 3-methylglutaconic aciduria, neurological dysfunction, cataracts, and neutropenia that is often fatal in childhood; however, there is likely a reporting bias toward severe cases. Using RNAseq and quantitative proteomics we validated causation and gained insight into genotype:phenotype correlation. Clinical follow-up of patients with CLPB deficiency who survived to adulthood identified POI and infertility as a common postpubertal ailment. CONCLUSION: A novel splicing variant is associated with CLPB deficiency in an individual who survived to adulthood. POI is a common feature of postpubertal female individuals with CLPB deficiency. Patients with CLPB deficiency should be referred to pediatric gynecologists/endocrinologists for prompt POI diagnosis and hormone replacement therapy to minimize associated comorbidities.

Published
2022

3. Analysis of variants in GATA4 and FOG2/ZFPM2 demonstrates benign contribution to 46,XY disorders of sex development.

Author

Harley V., Bergman P.B., Kimber C., Jiwane A., Khan S., Krausz C., Faradz S.M.H., Sinclair A.H., Ayers K.L., Raza J., Atta I., Davis S.R., Ono M., van den Bergen J.A., Robevska G., Eggers S., Riedl S., Grover S.R., Harley V., Bergman P.B., Kimber C., Jiwane A., Khan S., Krausz C., Faradz S.M.H., Sinclair A.H., Ayers K.L., Raza J., Atta I., Davis S.R., Ono M., van den Bergen J.A., Robevska G., Eggers S., Riedl S., and Grover S.R.

Abstract

BACKGROUND: GATA-binding protein 4 (GATA4) and Friend of GATA 2 protein (FOG2, also known as ZFPM2) form a heterodimer complex that has been shown to influence transcription of genes in a number of developmental systems. Recent evidence has also shown these genes play a role in gonadal sexual differentiation in humans. Previously we identified four variants in GATA4 and an unexpectedly large number of variants in ZFPM2 in a cohort of individuals with 46,XY Differences/Disorders of Sex Development (DSD) (Eggers et al, Genome Biology, 2016; 17: 243). METHOD(S): Here, we review variant curation and test the functional activity of GATA4 and ZFPM2 variants. We assess variant transcriptional activity on gonadal specific promoters (Sox9 and AMH) and variant protein-protein interactions. RESULT(S): Our findings support that the majority of GATA4 and ZFPM2 variants we identified are benign in their contribution to 46,XY DSD. Indeed, only one variant, in the conserved N-terminal zinc finger of GATA4, was considered pathogenic, with functional analysis confirming differences in its ability to regulate Sox9 and AMH and in protein interaction with ZFPM2. CONCLUSION(S): Our study helps define the genetic factors contributing to 46,XY DSD and suggests that the majority of variants we identified in GATA4 and ZFPM2/FOG2 are not causative.Copyright © 2019 The Murdoch Children's Research Institute. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.

Published
2021

4. Marine biogeographic disjunction in central New Zealand

Author

Ayers, K.L. and Waters, J.M.

Subjects
New Zealand -- Environmental aspects, Biogeography, Marine biology, Biological sciences
Abstract

We present a phylogeographic analysis of an abundant New Zealand endemic sea-star, Patiriella regularis, to help pinpoint the location of an important biogeographic disjunction in central New Zealand. The analysis incorporates 284 mtDNA control region sequences (approximately 800 bp) of P. regularis from 22 coastal locations around New Zealand. We detected 132 haplotypes, with a mean divergence of 0.96%. AMOVA analysis of New Zealand samples is consistent with a north-south biogeographic disjunction across central New Zealand (among-group genetic variance=6.10%; P=0.0005). Cook Strait, the shallow marine strait separating the main islands, is not correlated with the disjunction: samples from northern South Island are genetically indistinguishable from North Island samples (variance=1.69%; P=0.073). These results are consistent with the hypothesis that upwelling zones south of Cook Strait constitute a significant barrier to larval dispersal., Introduction The integration of genetic and geographic data provides a means of elucidating barriers to gene flow in the marine environment (Lessios et al. 2001). Phylogeographic studies of widespread marine [...]

Published
2005

5. Erratum to: Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits

Author

Evangelou, E. (Evangelos), Warren, H. (Helen), Mosen-Ansorena, D. (David), Mifsud, B. (Borbala), Pazoki, R. (Raha), Gao, H. (He), Ntritsos, G. (Georgios), Dimou, N. (Niki), Cabrera, C.P. (Claudia P.), Karaman, I. (Ibrahim), Ng, F.L. (Fu Liang), Evangelou, M. (Marina), Witkowska, K. (Katarzyna), Tzanis, E. (Evan), Hellwege, J.N. (Jacklyn N.), Giri, A. (Ayush), Velez Edwards, D.R. (Digna R.), Sun, Y.V. (Yan V.), Cho, K. (Kelly), Gaziano, J.M. (J. Michael), Wilson, P.W.F. (Peter W. F.), Tsao, P.S. (Philip S.), Kovesdy, C.P. (Csaba P.), Esko, T. (Tonu), Mägi, R. (Reedik), Milani, L. (Lili), Almgren, P. (Peter), Boutin, T. (Thibaud), Debette, S. (Stéphanie), Ding, J. (Jun), Giulianini, F. (Franco), Holliday, E.G. (Elizabeth), Jackson, A.U. (Anne), Li-Gao, R. (Ruifang), Lin, W.-Y. (Wei-Yu), Luan, J., Mangino, M. (Massimo), Oldmeadow, C. (Christopher), Prins, B.P. (Bram Peter), Qian, Y. (Yong), Sargurupremraj, M. (Muralidharan), Shah, N. (Nisha), Surendran, P. (Praveen), Thériault, S. (Sébastien), Verweij, N. (Niek), Willems, S.M. (Sara), Zhao, J.-H. (Jing-Hua), Amouyel, P. (Philippe), Connell, J. (John), Mutsert, R. (Reneé) de, Doney, A.S.F. (Alex), Farrall, M. (Martin), Menni, C. (Cristina), Morris, A.D. (Andrew), Noordam, R. (Raymond), Pare, G. (Guillame), Poulter, N.R. (Neil), Shields, D.C. (Denis C.), Stanton, A. (Alice), McG Thom, S.A., Abecasis, G. (Gonçalo), Amin, N. (Najaf), Arking, D.E. (Dan), Ayers, K.L. (Kristin), Barbieri, C.M. (Caterina M.), Batini, C. (Chiara), Bis, J.C. (Joshua), Blake, T. (Tineka), Bochud, M. (Murielle), Boehnke, M. (Michael), Boerwinkle, E. (Eric), Boomsma, D.I. (Dorret I.), Bottinger, E.P. (Erwin P.), Braund, P.S. (Peter), Brumat, M. (Marco), Campbell, A. (Archie), Campbell, H. (Harry), Chakravarti, A. (Aravinda), Chambers, J.C. (John C.), Chauhan, G. (Ganesh), Ciullo, M. (Marina), Cocca, M. (Massimiliano), Collins, F. (Francis), Cordell, H.J. (Heather), Davies, G. (Gail), de Borst, M.H. (Martin H.), Geus, E.J.C. (Eco) de, Deary, I.J. (Ian), Deelen, J. (Joris), Del Greco M, F. (Fabiola), Demirkale, C.Y. (Cumhur Yusuf), Dörr, M. (Marcus), Ehret, G.B. (Georg B.), Elosua, R. (Roberto), Enroth, S. (Stefan), Erzurumluoglu, A.M. (A. Mesut), Ferreira, T. (Teresa), Frånberg, M. (Mattias), Franco, O.H. (Oscar), Gandin, I. (Ilaria), Gasparini, P. (Paolo), Giedraitis, V. (Vilmantas), Gieger, C. (Christian), Girotto, G. (Giorgia), Goel, A. (Anuj), Gow, A.J. (Alan J.), Gudnason, V. (Vilmundur), Guo, X. (Xiuqing), Gyllensten, U. (Ulf), Hamsten, A. (Anders), Harris, T.B. (Tamara), Harris, S.E. (Sarah), Hartman, C.A. (Catharina A.), Havulinna, A.S. (Aki), Hicks, A.A. (Andrew A.), Hofer, E. (Edith), Hofman, A. (Albert), Hottenga, J.J. (Jouke Jan), Huffman, J.E. (Jennifer E.), Hwang, S.-J. (Shih-Jen), Ingelsson, E. (Erik), James, A. (Alan), Jansen, R. (Rick), Jarvelin, M.-R. (Marjo-Riitta), Joehanes, R. (Roby), Johansson, A. (Åsa), Johnson, A.D. (Andrew), Joshi, P.K. (Peter K.), Jousilahti, P. (Pekka), Jukema, J.W. (Jan Wouter), Jula, A. (Antti), Kähönen, M. (Mika), Kathiresan, S. (Sekar), Keavney, B.D. (Bernard D.), Khaw, K.-T. (Kay-Tee), Knekt, P., Knight, J. (Joanne), Kolcic, I. (Ivana), Kooner, J.S. (Jaspal S.), Koskinen, S. (Seppo), Kristiansson, K. (Kati), Kutalik, Z. (Zoltán), Laan, M. (Maris), Larson, M.G. (Martin), Launer, L.J. (Lenore), Lehne, B. (Benjamin), Lehtimäki, T. (Terho), Liewald, D.C.M. (David C. M.), Lin, L. (Li), Kao, W.H.L. (Wen), Lindgren, C.M. (Cecilia M.), Liu, Y. (YongMei), Loos, R.J.F. (Ruth), Lopez, L.M. (Lorna), Lu, Y. (Yingchang), Lyytikäinen, L.-P. (Leo-Pekka), Mahajan, A. (Anubha), Mamasoula, C. (Chrysovalanto), Marrugat, J. (Jaume), Marten, J. (Jonathan), Milaneschi, Y. (Yuri), Morgan, A. (Anna), Morris, A.P. (Andrew), Morrison, A.C. (Alanna), Munson, P.J. (Peter), Nalls, M.A. (Michael), Nandakumar, P. (Priyanka), Nelson, C.P. (Christopher P.), Niiranen, T. (Teemu), Nolte, I.M. (Ilja), Nutile, T. (Teresa), Oldehinkel, A.J. (Albertine), Oostra, B.A. (Ben), O’Reilly, P.F. (Paul F.), Org, E. (Elin), Padmanabhan, S. (Sandosh), Palmas, W. (Walter), Palotie, A. (Aarno), Pattie, A. (Alison), Penninx, B.W.J.H. (Brenda), Perola, M. (Markus), Peters, A. (Annette), Polasek, O. (Ozren), Pramstaller, P.P. (Peter Paul), Nguyen, Q.T. (Quang Tri), Raitakari, O. (Olli), Ren, M. (Meixia), Rettig, R. (Rainer), Rice, K.M. (Kenneth), Ridker, P.M. (Paul), Ried, J.S. (Janina S.), Riese, H. (Harriëtte), Ripatti, S. (Samuli), Robino, A. (Antonietta), Rose, L.M. (Lynda M.), Rotter, J.I. (Jerome I.), Rudan, I. (Igor), Ruggiero, D., Saba, Y. (Yasaman), Sala, C. (Cinzia), Salomaa, V. (Veikko), Samani, N.J. (Nilesh J.), Sarin, A.-P., Schmidt, R. (Reinhold), Schmidt, H. (Helena), Shrine, N.R.G. (Nick), Siscovick, D. (David), Smith, A.V. (Albert), Snieder, H. (Harold), Sõber, S. (Siim), Sorice, R., Starr, J.M. (John), Stott, D.J. (David. J.), Strachan, D.P. (David), Strawbridge, R.J. (Rona), Sundström, J. (Johan), Swertz, M.A. (Morris A.), Taylor, K.D. (Kent), Teumer, A. (Alexander), Tobin, M.D. (Martin), Tomaszewski, M. (Maciej), Toniolo, D. (Daniela), Traglia, M. (Michela), Trompet, S. (Stella), Tuomilehto, J. (Jaakko), Tzourio, C. (Christophe), Uitterlinden, A.G. (André), Vaez, A. (Ahmad), Most, P.J. (Peter) van der, Duijn, C.M. (Cornelia) van, Vergnaud, A.-C. (Anne-Claire), Verwoert, G.C. (Germaine C.), Vitart, V. (Veronique), Völker, U. (Uwe), Vollenweider, P. (Peter), Vuckovic, D. (Dragana), Watkins, H. (Hugh), Wild, S.H. (Sarah), Willemsen, G. (Gonneke), Wilson, J.F. (James F.), Wright, A.F. (Alan), Yao, J. (Jie), Zemunik, T. (Tatijana), Zhang, W. (Weihua), Attia, J. (John), Butterworth, A.S. (Adam S.), Chasman, D.I. (Daniel), Conen, D. (David), Cucca, F. (Francesco), Danesh, J. (John), Hayward, C. (Caroline), Howson, J.M.M. (Joanna M. M.), Laakso, M. (Markku), Lakatta, E.G. (Edward G.), Langenberg, C. (Claudia), Melander, O. (Olle), Mook-Kanamori, D.O. (Dennis O.), Palmer, C.N.A. (Colin N. A.), Risch, L. (Lorenz), Scott, R.A. (Robert), Scott, R.J. (Rodney J.), Sever, P. (Peter), Spector, T.D. (Timothy), van der Harst, P. (Pim), Wareham, N.J. (Nick), Zeggini, E. (Eleftheria), Levy, D. (Daniel), Munroe, P. (Patricia), Newton-Cheh, C. (Christopher), Brown, M.J. (Morris), Metspalu, A. (Andres), Hung, A.M. (Adriana M.), Ódonnell, C.J. (Christopher), Edwards, T.L. (Todd L.), Psaty, B.M. (Bruce), Tzoulaki, I., Barnes, M.J. (Michael), Wain, L.V. (Louise V.), Elliott, P. (Paul), Caulfield, M. (Mark), Evangelou, E. (Evangelos), Warren, H. (Helen), Mosen-Ansorena, D. (David), Mifsud, B. (Borbala), Pazoki, R. (Raha), Gao, H. (He), Ntritsos, G. (Georgios), Dimou, N. (Niki), Cabrera, C.P. (Claudia P.), Karaman, I. (Ibrahim), Ng, F.L. (Fu Liang), Evangelou, M. (Marina), Witkowska, K. (Katarzyna), Tzanis, E. (Evan), Hellwege, J.N. (Jacklyn N.), Giri, A. (Ayush), Velez Edwards, D.R. (Digna R.), Sun, Y.V. (Yan V.), Cho, K. (Kelly), Gaziano, J.M. (J. Michael), Wilson, P.W.F. (Peter W. F.), Tsao, P.S. (Philip S.), Kovesdy, C.P. (Csaba P.), Esko, T. (Tonu), Mägi, R. (Reedik), Milani, L. (Lili), Almgren, P. (Peter), Boutin, T. (Thibaud), Debette, S. (Stéphanie), Ding, J. (Jun), Giulianini, F. (Franco), Holliday, E.G. (Elizabeth), Jackson, A.U. (Anne), Li-Gao, R. (Ruifang), Lin, W.-Y. (Wei-Yu), Luan, J., Mangino, M. (Massimo), Oldmeadow, C. (Christopher), Prins, B.P. (Bram Peter), Qian, Y. (Yong), Sargurupremraj, M. (Muralidharan), Shah, N. (Nisha), Surendran, P. (Praveen), Thériault, S. (Sébastien), Verweij, N. (Niek), Willems, S.M. (Sara), Zhao, J.-H. (Jing-Hua), Amouyel, P. (Philippe), Connell, J. (John), Mutsert, R. (Reneé) de, Doney, A.S.F. (Alex), Farrall, M. (Martin), Menni, C. (Cristina), Morris, A.D. (Andrew), Noordam, R. (Raymond), Pare, G. (Guillame), Poulter, N.R. (Neil), Shields, D.C. (Denis C.), Stanton, A. (Alice), McG Thom, S.A., Abecasis, G. (Gonçalo), Amin, N. (Najaf), Arking, D.E. (Dan), Ayers, K.L. (Kristin), Barbieri, C.M. (Caterina M.), Batini, C. (Chiara), Bis, J.C. (Joshua), Blake, T. (Tineka), Bochud, M. (Murielle), Boehnke, M. (Michael), Boerwinkle, E. (Eric), Boomsma, D.I. (Dorret I.), Bottinger, E.P. (Erwin P.), Braund, P.S. (Peter), Brumat, M. (Marco), Campbell, A. (Archie), Campbell, H. (Harry), Chakravarti, A. (Aravinda), Chambers, J.C. (John C.), Chauhan, G. (Ganesh), Ciullo, M. (Marina), Cocca, M. (Massimiliano), Collins, F. (Francis), Cordell, H.J. (Heather), Davies, G. (Gail), de Borst, M.H. (Martin H.), Geus, E.J.C. (Eco) de, Deary, I.J. (Ian), Deelen, J. (Joris), Del Greco M, F. (Fabiola), Demirkale, C.Y. (Cumhur Yusuf), Dörr, M. (Marcus), Ehret, G.B. (Georg B.), Elosua, R. (Roberto), Enroth, S. (Stefan), Erzurumluoglu, A.M. (A. Mesut), Ferreira, T. (Teresa), Frånberg, M. (Mattias), Franco, O.H. (Oscar), Gandin, I. (Ilaria), Gasparini, P. (Paolo), Giedraitis, V. (Vilmantas), Gieger, C. (Christian), Girotto, G. (Giorgia), Goel, A. (Anuj), Gow, A.J. (Alan J.), Gudnason, V. (Vilmundur), Guo, X. (Xiuqing), Gyllensten, U. (Ulf), Hamsten, A. (Anders), Harris, T.B. (Tamara), Harris, S.E. (Sarah), Hartman, C.A. (Catharina A.), Havulinna, A.S. (Aki), Hicks, A.A. (Andrew A.), Hofer, E. (Edith), Hofman, A. (Albert), Hottenga, J.J. (Jouke Jan), Huffman, J.E. (Jennifer E.), Hwang, S.-J. (Shih-Jen), Ingelsson, E. (Erik), James, A. (Alan), Jansen, R. (Rick), Jarvelin, M.-R. (Marjo-Riitta), Joehanes, R. (Roby), Johansson, A. (Åsa), Johnson, A.D. (Andrew), Joshi, P.K. (Peter K.), Jousilahti, P. (Pekka), Jukema, J.W. (Jan Wouter), Jula, A. (Antti), Kähönen, M. (Mika), Kathiresan, S. (Sekar), Keavney, B.D. (Bernard D.), Khaw, K.-T. (Kay-Tee), Knekt, P., Knight, J. (Joanne), Kolcic, I. (Ivana), Kooner, J.S. (Jaspal S.), Koskinen, S. (Seppo), Kristiansson, K. (Kati), Kutalik, Z. (Zoltán), Laan, M. (Maris), Larson, M.G. (Martin), Launer, L.J. (Lenore), Lehne, B. (Benjamin), Lehtimäki, T. (Terho), Liewald, D.C.M. (David C. M.), Lin, L. (Li), Kao, W.H.L. (Wen), Lindgren, C.M. (Cecilia M.), Liu, Y. (YongMei), Loos, R.J.F. (Ruth), Lopez, L.M. (Lorna), Lu, Y. (Yingchang), Lyytikäinen, L.-P. (Leo-Pekka), Mahajan, A. (Anubha), Mamasoula, C. (Chrysovalanto), Marrugat, J. (Jaume), Marten, J. (Jonathan), Milaneschi, Y. (Yuri), Morgan, A. (Anna), Morris, A.P. (Andrew), Morrison, A.C. (Alanna), Munson, P.J. (Peter), Nalls, M.A. (Michael), Nandakumar, P. (Priyanka), Nelson, C.P. (Christopher P.), Niiranen, T. (Teemu), Nolte, I.M. (Ilja), Nutile, T. (Teresa), Oldehinkel, A.J. (Albertine), Oostra, B.A. (Ben), O’Reilly, P.F. (Paul F.), Org, E. (Elin), Padmanabhan, S. (Sandosh), Palmas, W. (Walter), Palotie, A. (Aarno), Pattie, A. (Alison), Penninx, B.W.J.H. (Brenda), Perola, M. (Markus), Peters, A. (Annette), Polasek, O. (Ozren), Pramstaller, P.P. (Peter Paul), Nguyen, Q.T. (Quang Tri), Raitakari, O. (Olli), Ren, M. (Meixia), Rettig, R. (Rainer), Rice, K.M. (Kenneth), Ridker, P.M. (Paul), Ried, J.S. (Janina S.), Riese, H. (Harriëtte), Ripatti, S. (Samuli), Robino, A. (Antonietta), Rose, L.M. (Lynda M.), Rotter, J.I. (Jerome I.), Rudan, I. (Igor), Ruggiero, D., Saba, Y. (Yasaman), Sala, C. (Cinzia), Salomaa, V. (Veikko), Samani, N.J. (Nilesh J.), Sarin, A.-P., Schmidt, R. (Reinhold), Schmidt, H. (Helena), Shrine, N.R.G. (Nick), Siscovick, D. (David), Smith, A.V. (Albert), Snieder, H. (Harold), Sõber, S. (Siim), Sorice, R., Starr, J.M. (John), Stott, D.J. (David. J.), Strachan, D.P. (David), Strawbridge, R.J. (Rona), Sundström, J. (Johan), Swertz, M.A. (Morris A.), Taylor, K.D. (Kent), Teumer, A. (Alexander), Tobin, M.D. (Martin), Tomaszewski, M. (Maciej), Toniolo, D. (Daniela), Traglia, M. (Michela), Trompet, S. (Stella), Tuomilehto, J. (Jaakko), Tzourio, C. (Christophe), Uitterlinden, A.G. (André), Vaez, A. (Ahmad), Most, P.J. (Peter) van der, Duijn, C.M. (Cornelia) van, Vergnaud, A.-C. (Anne-Claire), Verwoert, G.C. (Germaine C.), Vitart, V. (Veronique), Völker, U. (Uwe), Vollenweider, P. (Peter), Vuckovic, D. (Dragana), Watkins, H. (Hugh), Wild, S.H. (Sarah), Willemsen, G. (Gonneke), Wilson, J.F. (James F.), Wright, A.F. (Alan), Yao, J. (Jie), Zemunik, T. (Tatijana), Zhang, W. (Weihua), Attia, J. (John), Butterworth, A.S. (Adam S.), Chasman, D.I. (Daniel), Conen, D. (David), Cucca, F. (Francesco), Danesh, J. (John), Hayward, C. (Caroline), Howson, J.M.M. (Joanna M. M.), Laakso, M. (Markku), Lakatta, E.G. (Edward G.), Langenberg, C. (Claudia), Melander, O. (Olle), Mook-Kanamori, D.O. (Dennis O.), Palmer, C.N.A. (Colin N. A.), Risch, L. (Lorenz), Scott, R.A. (Robert), Scott, R.J. (Rodney J.), Sever, P. (Peter), Spector, T.D. (Timothy), van der Harst, P. (Pim), Wareham, N.J. (Nick), Zeggini, E. (Eleftheria), Levy, D. (Daniel), Munroe, P. (Patricia), Newton-Cheh, C. (Christopher), Brown, M.J. (Morris), Metspalu, A. (Andres), Hung, A.M. (Adriana M.), Ódonnell, C.J. (Christopher), Edwards, T.L. (Todd L.), Psaty, B.M. (Bruce), Tzoulaki, I., Barnes, M.J. (Michael), Wain, L.V. (Louise V.), Elliott, P. (Paul), and Caulfield, M. (Mark)

Abstract

In the version of this article originally published, the name of author Martin H. de Borst was coded incorrectly in the XML. The error has now been corrected in the HTML version of the paper.

Published
2018
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6. NR5A1 gene variants repress the ovarian-specific WNT signaling pathway in 46,XX disorders of sex development patients

Author

Knarston, I.M. (Ingrid M.), Robevska, G. (Gorjana), van den Bergen, J.A. (Jocelyn A), Eggers, S. (Stefanie), Croft, B. (Brittany), Yates, J. (Jason), Hersmus, R. (Remko), Looijenga, L.H.J. (Leendert), Cameron, F.J. (Fergus J.), Monhike, K. (Klaus), Ayers, K.L. (Katie L.), Sinclair, A. (Andrew), Knarston, I.M. (Ingrid M.), Robevska, G. (Gorjana), van den Bergen, J.A. (Jocelyn A), Eggers, S. (Stefanie), Croft, B. (Brittany), Yates, J. (Jason), Hersmus, R. (Remko), Looijenga, L.H.J. (Leendert), Cameron, F.J. (Fergus J.), Monhike, K. (Klaus), Ayers, K.L. (Katie L.), and Sinclair, A. (Andrew)

Abstract

Several recent reports have described a missense variant in the gene NR5A1 (c.274C>T; p.Arg92Trp) in a significant number of 46,XX ovotesticular or testicular disorders of sex development (DSDs) cases. The affected residue falls within the

Published
2018
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7. Disorders of sex development: Insights from targeted gene sequencing of a large international patient cohort.

Author

Srinivasan S., Khadilkar A., Bhatia V., Dung V.C., Atta I., Raza J., thi Diem Chi N., Eggers S., Sadedin S., van den Bergen J.A., Robevska G., Ohnesorg T., Hewitt J., Lambeth L., Bouty A., Knarston I.M., Tan T.Y., Cameron F., Werther G., Hutson J., O'Connell M., Grover S.R., Heloury Y., Zacharin M., Bergman P., Kimber C., Brown J., Webb N., Hunter M.F., Titmuss A., Verge C.F., Mowat D., Smith G., Smith J., Ewans L., Shalhoub C., Crock P., Cowell C., Leong G.M., Ono M., Lafferty A.R., Huynh T., Visser U., Choong C.S., McKenzie F., Pachter N., Thompson E.M., Couper J., Baxendale A., Gecz J., Wheeler B.J., Jefferies C., MacKenzie K., Hofman P., Carter P., King R.I., Krausz C., van Ravenswaaij-Arts C.M.A., Looijenga L., Drop S., Riedl S., Cools M., Dawson A., Juniarto A.Z., Khadilkar V., Hao T.K., Harley V., Koopman P., Warne G., Faradz S., Oshlack A., Ayers K.L., Sinclair A.H., Srinivasan S., Khadilkar A., Bhatia V., Dung V.C., Atta I., Raza J., thi Diem Chi N., Eggers S., Sadedin S., van den Bergen J.A., Robevska G., Ohnesorg T., Hewitt J., Lambeth L., Bouty A., Knarston I.M., Tan T.Y., Cameron F., Werther G., Hutson J., O'Connell M., Grover S.R., Heloury Y., Zacharin M., Bergman P., Kimber C., Brown J., Webb N., Hunter M.F., Titmuss A., Verge C.F., Mowat D., Smith G., Smith J., Ewans L., Shalhoub C., Crock P., Cowell C., Leong G.M., Ono M., Lafferty A.R., Huynh T., Visser U., Choong C.S., McKenzie F., Pachter N., Thompson E.M., Couper J., Baxendale A., Gecz J., Wheeler B.J., Jefferies C., MacKenzie K., Hofman P., Carter P., King R.I., Krausz C., van Ravenswaaij-Arts C.M.A., Looijenga L., Drop S., Riedl S., Cools M., Dawson A., Juniarto A.Z., Khadilkar V., Hao T.K., Harley V., Koopman P., Warne G., Faradz S., Oshlack A., Ayers K.L., and Sinclair A.H.

Abstract

Background: Disorders of sex development (DSD) are congenital conditions in which chromosomal, gonadal, or phenotypic sex is atypical. Clinical management of DSD is often difficult and currently only 13% of patients receive an accurate clinical genetic diagnosis. To address this we have developed a massively parallel sequencing targeted DSD gene panel which allows us to sequence all 64 known diagnostic DSD genes and candidate genes simultaneously. Result(s): We analyzed DNA from the largest reported international cohort of patients with DSD (278 patients with 46,XY DSD and 48 with 46,XX DSD). Our targeted gene panel compares favorably with other sequencing platforms. We found a total of 28 diagnostic genes that are implicated in DSD, highlighting the genetic spectrum of this disorder. Sequencing revealed 93 previously unreported DSD gene variants. Overall, we identified a likely genetic diagnosis in 43% of patients with 46,XY DSD. In patients with 46,XY disorders of androgen synthesis and action the genetic diagnosis rate reached 60%. Surprisingly, little difference in diagnostic rate was observed between singletons and trios. In many cases our findings are informative as to the likely cause of the DSD, which will facilitate clinical management. Conclusion(s): Our massively parallel sequencing targeted DSD gene panel represents an economical means of improving the genetic diagnostic capability for patients affected by DSD. Implementation of this panel in a large cohort of patients has expanded our understanding of the underlying genetic etiology of DSD. The inclusion of research candidate genes also provides an invaluable resource for future identification of novel genes.Copyright © 2016 The Author(s).

Published
2016

8. Disorders of sex development: Insights from targeted gene sequencing of a large international patient cohort

Author

Eggers, S. (Stefanie), Sadedin, S. (Simon), van den Bergen, J.A. (Jocelyn A.), Robevska, G. (Gorjana), Ohnesorg, T. (Thomas), Hewitt, J. (Joanne), Lambeth, L. (Luke), Bouty, A. (Aurore), Knarston, I.M. (Ingrid M.), Tan, T.Y. (Tiong Yang), Cameron, F.J. (Fergus), Werther, G. (George), Hutson, J. (John), O'Connell, M. (Michele), Grover, S.R. (Sonia R.), Heloury, Y. (Yves), Zacharin, M. (Margaret), Bergman, P. (Philip), Kimber, C. (Chris), Brown, J. (Justin), Webb, N. (Nathalie), Hunter, M.F. (Matthew F.), Shubha Srinivasan, Titmuss, A. (Angela), Verge, C.F. (Charles F.), Mowat, D. (David), Smith, G. (Grahame), Smith, J. (Janine), Ewans, L. (Lisa), Shalhoub, C. (Carolyn), Crock, P. (Patricia), Cowell, C. (Chris), Leong, G.M. (GaryM.), Ono, M. (Makato), Lafferty, A.R. (Antony R.), Huynh, T. (Tony), Visser, U. (Uma), Choong, C.S. (Catherine S.), McKenzie, F. (Fiona), Pachter, N. (Nicholas), Thompson, E.M. (Elizabeth M.), Couper, J. (Jennifer), Baxendale, A. (Anne), Gecz, J. (Jozef), Wheeler, B.J. (Benjamin J.), Jefferies, C. (Craig), MacKenzie, K. (Karen), Hofman, P. (Paul), Carter, P. (Philippa), King, R.I. (Richard I.), Krausz, C. (Csilla), Ravenswaaij-Arts, C.M.A. (Conny) van, Looijenga, L.H.J. (Leendert), Drop, S. (Sten), Riedl, S. (Stefan), Cools, M.B.C.M. (Martine), Dawson, A. (Angelika), Juniarto, A.Z. (Achmad), Khadilkar, V. (Vaman), Khadilkar, A. (Anuradha), Bhatia, V. (Vijayalakshmi), Dũng, V.C. (Vũ Chí), Atta, I. (Irum), Raza, J. (Jamal), thi Diem Chi, N. (Nguyen), Hao, T.K. (Tran Kiem), Harley, V.R. (Vincent), Koopman, P. (Peter), Warne, G. (Garry), Faradz, S.M.H. (Sultana), Oshlack, A. (Alicia), Ayers, K.L. (Katie L.), Sinclair, A. (Andrew), Eggers, S. (Stefanie), Sadedin, S. (Simon), van den Bergen, J.A. (Jocelyn A.), Robevska, G. (Gorjana), Ohnesorg, T. (Thomas), Hewitt, J. (Joanne), Lambeth, L. (Luke), Bouty, A. (Aurore), Knarston, I.M. (Ingrid M.), Tan, T.Y. (Tiong Yang), Cameron, F.J. (Fergus), Werther, G. (George), Hutson, J. (John), O'Connell, M. (Michele), Grover, S.R. (Sonia R.), Heloury, Y. (Yves), Zacharin, M. (Margaret), Bergman, P. (Philip), Kimber, C. (Chris), Brown, J. (Justin), Webb, N. (Nathalie), Hunter, M.F. (Matthew F.), Shubha Srinivasan, Titmuss, A. (Angela), Verge, C.F. (Charles F.), Mowat, D. (David), Smith, G. (Grahame), Smith, J. (Janine), Ewans, L. (Lisa), Shalhoub, C. (Carolyn), Crock, P. (Patricia), Cowell, C. (Chris), Leong, G.M. (GaryM.), Ono, M. (Makato), Lafferty, A.R. (Antony R.), Huynh, T. (Tony), Visser, U. (Uma), Choong, C.S. (Catherine S.), McKenzie, F. (Fiona), Pachter, N. (Nicholas), Thompson, E.M. (Elizabeth M.), Couper, J. (Jennifer), Baxendale, A. (Anne), Gecz, J. (Jozef), Wheeler, B.J. (Benjamin J.), Jefferies, C. (Craig), MacKenzie, K. (Karen), Hofman, P. (Paul), Carter, P. (Philippa), King, R.I. (Richard I.), Krausz, C. (Csilla), Ravenswaaij-Arts, C.M.A. (Conny) van, Looijenga, L.H.J. (Leendert), Drop, S. (Sten), Riedl, S. (Stefan), Cools, M.B.C.M. (Martine), Dawson, A. (Angelika), Juniarto, A.Z. (Achmad), Khadilkar, V. (Vaman), Khadilkar, A. (Anuradha), Bhatia, V. (Vijayalakshmi), Dũng, V.C. (Vũ Chí), Atta, I. (Irum), Raza, J. (Jamal), thi Diem Chi, N. (Nguyen), Hao, T.K. (Tran Kiem), Harley, V.R. (Vincent), Koopman, P. (Peter), Warne, G. (Garry), Faradz, S.M.H. (Sultana), Oshlack, A. (Alicia), Ayers, K.L. (Katie L.), and Sinclair, A. (Andrew)

Abstract

Background: Disorders of sex development (DSD) are congenital conditions in which chromosomal, gonadal, or phenotypic sex is atypical. Clinical management of DSD is often difficult and currently only 13% of patients receive an accurate clinical genetic diagnosis. To address this we have developed a massively p

Published
2016
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9. Genome-wide linkage analysis for human longevity: Genetics of Healthy Aging Study

Author

Beekman, M., Blanche, H., Perola, M., Hervonen, A., Bezrukov, V., Sikora, E., Flachsbart, F., Christiansen, L., Craen, A.J.M. de, Kirkwood, T.B.L., Rea, I.M., Poulain, M., Robine, J.M., Valensin, S., Stazi, M.A., Passarino, G., Deiana, L., Gonos, E.S., Paternoster, L., Sorensen, T.I.A., Tan, Q.H., Helmer, Q., Akker, E.B. van den, Deelen, J., Martella, F., Cordell, H.J., Ayers, K.L., Vaupel, J.W., Tornwall, O., Johnson, T.E., Schreiber, S., Lathrop, M., Skytthe, A., Westendorp, R.G.J., Christensen, K., Gampe, J., Nebel, A., Houwing-Duistermaat, J.J., Slagboom, P.E., Franceschi, C., GEHA Consortium, Leiden University Medical Center (LUMC), Fondation Jean Dausset - Centre d’Etudes du Polymorphisme Humain [Paris] (CEPH), National Institute for Health and Welfare [Helsinki], Tampere School of Public Health, Institute of Gerontology [Kiev], Nencki Institute of Experimental Biology, Polska Akademia Nauk = Polish Academy of Sciences (PAN), Christian-Albrechts University of Kiel, University of Southern Denmark (SDU), Netherlands Consortium for Healthy Ageing, Newcastle University [Newcastle], The Queen’s University of Belfast, Université Catholique de Louvain = Catholic University of Louvain (UCL), CERMES3 - Centre de recherche Médecine, sciences, santé, santé mentale, société (CERMES3 - UMR 8211 / U988 / UM 7), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-École des hautes études en sciences sociales (EHESS), University of Bologna, Istituto Superiore di Sanita [Rome], Università della Calabria [Arcavacata di Rende] (Unical), Università degli Studi di Sassari = University of Sassari [Sassari] (UNISS), Theoretical and Physical Chemistry Institute NHRF, National Hellenic Research Foundation, University of Bristol [Bristol], Novo Nordisk Foundation Center for Basic Metabolic Research (CBMR), Faculty of Health and Medical Sciences, University of Copenhagen = Københavns Universitet (KU)-University of Copenhagen = Københavns Universitet (KU), Odense University Hospital (OUH), Institute for Ageing and Health, Newcastle University, Max Planck Institute for Demographic Research (MPIDR), Max-Planck-Gesellschaft, University of Colorado [Boulder], Leiden University Medical Centre [Leyde, Pays-Bas], Leiden University, Netherlands Consortium for Healthy Ageing, Leiden, The Netherlands, Institute for Ageing and Health, École des hautes études en sciences sociales (EHESS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), University of Sassari, Danish Aging Research Center, Institute of Public Health, and Institute for Behavioral Genetics

Subjects
Aging, Genetic Linkage, APOE gene, Genome-wide association study, Association analysis, Human familial longevity, [SHS]Humanities and Social Sciences, 0302 clinical medicine, Mitochondrial Precursor Protein Import Complex Proteins, Cluster Analysis, Nonagenarian sibling pairs, media_common, Aged, 80 and over, Genetics, 0303 health sciences, Longevity, Chromosome Mapping, Middle Aged, Europe, genome-wide linkage analysis, association analysis, nonagenarian sibling pairs, apoe gene, human familial longevity, congenital, hereditary, and neonatal diseases and abnormalities, media_common.quotation_subject, Locus (genetics), Biology, Article, 03 medical and health sciences, Apolipoproteins E, SDG 3 - Good Health and Well-being, Genetic linkage, Humans, Allele, Alleles, Aged, 030304 developmental biology, Genetic association, Chromosomes, Human, Pair 14, Apolipoprotein C-I, Genome, Human, Siblings, Membrane Transport Proteins, Cell Biology, Heritability, Apoe gene, Genetic Loci, Human genome, Lod Score, Chromosomes, Human, Pair 19, Genome-wide linkage analysis, 030217 neurology & neurosurgery, Chromosomes, Human, Pair 17, Genome-Wide Association Study
Abstract

Clear evidence exists for heritability of humanlongevity, and much interest is focused on identifying genes associated with longer lives. To identify such longevity alleles, we performed the largest genome-wide linkage scan thus far reported. Linkage analyses included 2118nonagenarian Caucasian sibling pairs that have been enrolled in 15 study centers of 11 European countries as part of the Genetics of Healthy Aging (GEHA) project. In the joint linkage analyses, we observed four regions that show linkage with longevity; chromosome 14q11.2 (LOD = 3.47), chromosome 17q12-q22 (LOD = 2.95), chromosome 19p13.3-p13.11 (LOD = 3.76), and chromosome 19q13.11-q13.32 (LOD = 3.57). To fine map these regions linked to longevity, we performed association analysis using GWAS data in a subgroup of 1228 unrelated nonagenarian and 1907 geographically matched controls. Using a fixed-effect meta-analysis approach, rs4420638 at the TOMM40/ APOE/APOC1 gene locus showed significant association with longevity (P-value = 9.6 × 10 -8). By combined modeling of linkage and association, we showed that association of longevity with APOEe4 and APOEe2 alleles explain the linkage at 19q13.11-q13.32 with P-value = 0.02 and P-value = 1.0 × 10 -5, respectively. In the largest linkage scan thus far performed for human familial longevity, we confirm that the APOE locus is a longevity gene and that additional longevity loci may be identified at 14q11.2, 17q12-q22, and 19p13.3-p13.11. As the latter linkage results are not explained by common variants, we suggest that rare variants play an important role in human familial longevity.

Published
2013

12. A duplication in a patient with 46, XX ovo-testicular disorder of sex development refines the SOX9 testis-specific regulatory region to 24 kb.

Author

Ohnesorg, T., Bergen, J.A., Belluoccio, D., Shankara‐Narayana, N., Kean, A.‐M., Vasilaras, A., Ewans, L., Ayers, K.L., and Sinclair, A.H.

Subjects
TESTICULAR diseases, PHENOTYPES, PATIENTS
Abstract

A custom CGH microarray that covers the SOX9 regulatory region. Log2 ratio scatterplot showing individual data points. Blue box highlights copy number gain with 3′ breakpoint region magnified. [ABSTRACT FROM AUTHOR]

Published
2017
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