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9 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

2. 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

Contains fulltext : 287951.pdf (Publisher’s version ) (Open Access), 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. 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

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
Full Text
View/download PDF

9. 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

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