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51. Phenotypic differences between patients with familial pituitary neuroendocrine tumours due to MEN1 or AIP mutations

Author

Marques, Pedro, primary, Magalhães, Daniela, additional, Caimari, Francisca, additional, Hernández, Ramírez Laura, additional, Collier, David, additional, Lim, Chung, additional, Stals, Karen, additional, Ellard, Sian, additional, Druce, Maralyn, additional, Akker, Scott, additional, Waterhouse, Mona, additional, Drake, William, additional, Grossman, Ashley B., additional, and Korbonits, Marta, additional

Published
2020
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52. Correction: A restricted spectrum of missense KMT2D variants cause a multiple malformations disorder distinct from Kabuki syndrome

Author

Cuvertino, Sara, primary, Hartill, Verity, additional, Colyer, Alice, additional, Garner, Terence, additional, Nair, Nisha, additional, Al-Gazali, Lihadh, additional, Canham, Natalie, additional, Faundes, Victor, additional, Flinter, Frances, additional, Hertecant, Jozef, additional, Holder-Espinasse, Muriel, additional, Jackson, Brian, additional, Lynch, Sally Ann, additional, Nadat, Fatima, additional, Narasimhan, Vagheesh M., additional, Peckham, Michelle, additional, Sellers, Robert, additional, Seri, Marco, additional, Montanari, Francesca, additional, Southgate, Laura, additional, Squeo, Gabriella Maria, additional, Trembath, Richard, additional, van Heel, David, additional, Venuto, Santina, additional, Weisberg, Daniel, additional, Stals, Karen, additional, Ellard, Sian, additional, Barton, Anne, additional, Kimber, Susan J., additional, Sheridan, Eamonn, additional, Merla, Giuseppe, additional, Stevens, Adam, additional, Johnson, Colin A., additional, and Banka, Siddharth, additional

Published
2020
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54. Risk category system to identify pituitary adenoma patients with AIP mutations

Author

Caimari, Francisca, Hernández-Ramírez, Laura Cristina, Dang, Mary N, Gabrovska, Plamena, Iacovazzo, Donato, Stals, Karen, Ellard, Sian, Korbonits, Márta, Iwata, Takeo, and Yoshimoto, Katsuhiko

Abstract

Background Predictive tools to identify patients at risk for gene mutations related to pituitary adenomas are very helpful in clinical practice. We therefore aimed to develop and validate a reliable risk category system for aryl hydrocarbon receptor-interacting protein (AIP) mutations in patients with pituitary adenomas. Methods A n international cohort of 2227 subjects were consecutively recruited between 2007 and 2016, including patients with pituitary adenomas (familial and sporadic) and their relatives. All probands (n=1429) were screened for AIP mutations, and those diagnosed with a pituitary adenoma prospectively, as part of their clinical screening (n=24), were excluded from the analysis. Univariate analysis was performed comparing patients with and without AIP mutations. Based on a multivariate logistic regression model, six potential factors were identified for the development of a risk category system, classifying the individual risk into low-risk, moderate-risk and high-risk categories. An internal cross-validation test was used to validate the system. Results 1405 patients had a pituitary tumour, of which 43% had a positive family history, 55.5% had somatotrophinomas and 81.5% presented with macroadenoma. Overall, 134 patients had an AIP mutation (9.5%). We identified four independent predictors for the presence of an AIP mutation: age of onset providing an odds ratio (OR) of 14.34 for age 0-18 years, family history (OR 10.85), growth hormone excess (OR 9.74) and large tumour size (OR 4.49). In our cohort, 71% of patients were identified as low risk (

Published
2018

55. Diagnosis of lethal or prenatal‐onset autosomal recessive disorders by parental exome sequencing

Author

Stals, Karen L., Wakeling, Matthew, Baptista, Júlia, Caswell, Richard, Parrish, Andrew, Rankin, Julia, Tysoe, Carolyn, Jones, Garan, Gunning, Adam C., Lango Allen, Hana, Bradley, Lisa, Brady, Angela F., Carley, Helena, Carmichael, Jenny, Castle, Bruce, Cilliers, Deirdre, Cox, Helen, Deshpande, Charu, Dixit, Abhijit, Eason, Jacqueline, Elmslie, Frances, Fry, Andrew E., Fryer, Alan, Holder, Muriel, Homfray, Tessa, Kivuva, Emma, McKay, Victoria, Newbury‐Ecob, Ruth, Parker, Michael, Savarirayan, Ravi, Searle, Claire, Shannon, Nora, Shears, Deborah, Smithson, Sarah, Thomas, Ellen, Turnpenny, Peter D., Varghese, Vinod, Vasudevan, Pradeep, Wakeling, Emma, Baple, Emma L., and Ellard, Sian

Subjects
Male, Parents, Special Topic Issue on Advances in the Diagnosis of Single Gene Disorders, Pregnancy, Prenatal Diagnosis, Exome Sequencing, Genetic Diseases, Inborn, Humans, Female, Genes, Recessive, Congenital Abnormalities
Abstract

Objective Rare genetic disorders resulting in prenatal or neonatal death are genetically heterogeneous, but testing is often limited by the availability of fetal DNA, leaving couples without a potential prenatal test for future pregnancies. We describe our novel strategy of exome sequencing parental DNA samples to diagnose recessive monogenic disorders in an audit of the first 50 couples referred. Method Exome sequencing was carried out in a consecutive series of 50 couples who had 1 or more pregnancies affected with a lethal or prenatal‐onset disorder. In all cases, there was insufficient DNA for exome sequencing of the affected fetus. Heterozygous rare variants (MAF, What's already known about this topic? Exome sequencing is used routinely for postnatal diagnosis of rare disorders with a diagnostic yield of 20 to 40%.Insufficient quantity or quality of DNA restricts the use of exome sequencing for diagnosing lethal fetal disorders.Couples are counselled for a likely 25% recurrence risk, but without a genetic diagnosis, no molecular prenatal test is possible.A parental exome sequencing strategy has been applied successfully in a small number of couples. What does this study add? We show that exome sequencing of parental DNA samples is an effective way to diagnose lethal or prenatal‐onset disorders with a diagnostic yield of 52% in an audit of 50 consecutive cases.Testing can be carried out in the prenatal period to guide management of an ongoing pregnancy or for use in subsequent pregnancies to allow couples the option of a prenatal or preimplantation genetic test.

Published
2017

59. De Novo ZMYND8variants result in an autosomal dominant neurodevelopmental disorder with cardiac malformations

Author

Dias, Kerith-Rae, Carlston, Colleen M., Blok, Laura E.R., De Hayr, Lachlan, Nawaz, Urwah, Evans, Carey-Anne, Bayrak-Toydemir, Pinar, Htun, Stephanie, Zhu, Ying, Ma, Alan, Lynch, Sally Ann, Moorwood, Catherine, Stals, Karen, Ellard, Sian, Bainbridge, Matthew N., Friedman, Jennifer, Pappas, John G., Rabin, Rachel, Nowak, Catherine B., Douglas, Jessica, Wilson, Theodore E., Guillen Sacoto, Maria J., Mullegama, Sureni V., Palculict, Timothy Blake, Kirk, Edwin P., Pinner, Jason R., Edwards, Matthew, Montanari, Francesca, Graziano, Claudio, Pippucci, Tommaso, Dingmann, Bri, Glass, Ian, Mefford, Heather C., Shimoji, Takeyoshi, Suzuki, Toshimitsu, Yamakawa, Kazuhiro, Streff, Haley, Schaaf, Christian P., Slavotinek, Anne M., Voineagu, Irina, Carey, John C., Buckley, Michael F., Schenck, Annette, Harvey, Robert J., and Roscioli, Tony

Abstract

ZMYND8encodes a multidomain protein that serves as a central interactive hub for coordinating critical roles in transcription regulation, chromatin remodeling, regulation of super-enhancers, DNA damage response and tumor suppression. We delineate a novel neurocognitive disorder caused by variants in the ZMYND8gene.

Published
2022
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60. A hypomorphic allele of SLC35D1 results in Schneckenbecken-like dysplasia

Author

Rautengarten, Carsten, Quarrell, Oliver W, Stals, Karen, Caswell, Richard C, De Franco, Elisa, Baple, Emma, Burgess, Nadia, Jokhi, Roobin, Heazlewood, Joshua L, Offiah, Amaka C, Ebert, Berit, and Ellard, Sian

Subjects
Male, Heterozygote, Monosaccharide Transport Proteins, Mutation, Missense, Endoplasmic Reticulum, Osteochondrodysplasias, Schneckenbecken dysplasia, radiology, Fetal Diseases, Mice, nucleotide sugar transporters, Loss of Function Mutation, Animals, Humans, genetics, Female, General Article, Alleles, SLC35D1
Abstract

We report the case of a consanguineous couple who lost four pregnancies associated with skeletal dysplasia. Radiological examination of one fetus was inconclusive. Parental exome sequencing showed that both parents were heterozygous for a novel missense variant, p.(Pro133Leu), in the SLC35D1 gene encoding a nucleotide sugar transporter. The affected fetus was homozygous for the variant. The radiological features were reviewed, and being similar, but atypical, the phenotype was classified as a ‘Schneckenbecken-like dysplasia.’ The effect of the missense change was assessed using protein modelling techniques and indicated alterations in the mouth of the solute channel. A detailed biochemical investigation of SLC35D1 transport function and that of the missense variant p.(Pro133Leu) revealed that SLC35D1 acts as a general UDP-sugar transporter and that the p.(Pro133Leu) mutation resulted in a significant decrease in transport activity. The reduced transport activity observed for p.(Pro133Leu) was contrasted with in vitro activity for SLC35D1 p.(Thr65Pro), the loss-of-function mutation was associated with Schneckenbecken dysplasia. The functional classification of SLC35D1 as a general nucleotide sugar transporter of the endoplasmic reticulum suggests an expanded role for this transporter beyond chondroitin sulfate biosynthesis to a variety of important glycosylation reactions occurring in the endoplasmic reticulum.

Published
2019

62. Significant Benefits of AIP Testing and Clinical Screening in Familial Isolated and Young-onset Pituitary Tumors

Author

Marques, Pedro, Caimari, Francisca, Hernández-Ramírez, Laura C., Collier, David, Iacovazzo, Donato, Ronaldson, Amy, Magid, Kesson, Lim, Chung Thong, Stals, Karen, Ellard, Sian, Grossman, Ashley B., Korbonits, Márta, Iwata, Takeo, Yoshimoto, Katsuhiko, Marques, Pedro, Caimari, Francisca, Hernández-Ramírez, Laura C., Collier, David, Iacovazzo, Donato, Ronaldson, Amy, Magid, Kesson, Lim, Chung Thong, Stals, Karen, Ellard, Sian, Grossman, Ashley B., Korbonits, Márta, Iwata, Takeo, and Yoshimoto, Katsuhiko

Abstract

Context: Germline mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene are responsible for a subset of familial isolated pituitary adenoma (FIPA) cases and sporadic pituitary neuroendocrine tumors (PitNETs). Objective: To compare prospectively diagnosed AIP mutation-positive (AIPmut) PitNET patients with clinically presenting patients and to compare the clinical characteristics of AIPmut and AIPneg PitNET patients. Design: 12-year prospective, observational study. Participants & Setting: We studied probands and family members of FIPA kindreds and sporadic patients with disease onset ≤18 years or macroadenomas with onset ≤30 years (n = 1477). This was a collaborative study conducted at referral centers for pituitary diseases. Interventions & Outcome: AIP testing and clinical screening for pituitary disease. Comparison of characteristics of prospectively diagnosed (n = 22) vs clinically presenting AIPmut PitNET patients (n = 145), and AIPmut (n = 167) vs AIPneg PitNET patients (n = 1310). Results: Prospectively diagnosed AIPmut PitNET patients had smaller lesions with less suprasellar extension or cavernous sinus invasion and required fewer treatments with fewer operations and no radiotherapy compared with clinically presenting cases; there were fewer cases with active disease and hypopituitarism at last follow-up. When comparing AIPmut and AIPneg cases, AIPmut patients were more often males, younger, more often had GH excess, pituitary apoplexy, suprasellar extension, and more patients required multimodal therapy, including radiotherapy. AIPmut patients (n = 136) with GH excess were taller than AIPneg counterparts (n = 650). Conclusions: Prospectively diagnosed AIPmut patients show better outcomes than clinically presenting cases, demonstrating the benefits of genetic and clinical screening. AIP-related pituitary disease has a wide spectrum ranging from aggressively growing lesions to stable or indolent disease course.

Published
2020

63. De novo missense variants in FBXO11 alter its protein expression and subcellular localization.

Author

Gregor, Anne, Meerbrei, Tanja, Gerstner, Thorsten, Toutain, Annick, Lynch, Sally Ann, Stals, Karen, Maxton, Caroline, Lemke, Johannes R, Bernat, John A, Bombei, Hannah M, Foulds, Nicola, Hunt, David, Kuechler, Alma, Beygo, Jasmin, Stöbe, Petra, Bouman, Arjan, Palomares-Bralo, Maria, Santos-Simarro, Fernando, Garcia-Minaur, Sixto, and Pacio-Miguez, Marta

Published
2022
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64. Homozygosity mapping provides supporting evidence of pathogenicity in recessive Mendelian disease

Author

Wakeling, Matthew Neil, Laver, Thomas William, Wright, Caroline Fiona, De Franco, Elisa, Stals, Karen Lucy, Patch, Ann-Marie, Hattersley, Andrew Tym, Flanagan, Sarah Elizabeth, and Ellard, Sian

Subjects
Article
Abstract

PURPOSE: One of the greatest challenges currently facing those studying Mendelian disease is identifying the pathogenic variant from the long list produced by a next generation sequencing test. We investigate the predictive ability of homozygosity mapping for identifying the regions likely to contain the causative variant. METHODS: We use 179 homozygous pathogenic variants from three independent cohorts to investigate the predictive power of homozygosity mapping. RESULTS: We demonstrate that homozygous pathogenic variants in our cohorts are disproportionately likely to be found within one of the largest regions of homozygosity: 80% of pathogenic variants are found in a homozygous region that is in the 10 largest regions in a sample. The maximal predictive power is achieved in patients with 3Mb from a telomere, this gives an AUC of 0.735 and results in 92% of the causative variants being in one of the 10 largest homozygous regions. CONCLUSION: This predictive power can be used to prioritize the list of candidate variants in gene discovery studies. When classifying a homozygous variant the size and rank of the region of homozygosity in which the candidate variant is located can also be considered as supporting evidence for pathogenicity.

Published
2018

65. PIGGvariant pathogenicity assessment reveals characteristic features within 19 families

Author

Tremblay-Laganière, Camille, Maroofian, Reza, Nguyen, Thi Tuyet Mai, Karimiani, Ehsan Ghayoor, Kirmani, Salman, Akbar, Fizza, Ibrahim, Shahnaz, Afroze, Bushra, Doosti, Mohammad, Ashrafzadeh, Farah, Babaei, Meisam, Efthymiou, Stephanie, Christoforou, Marilena, Sultan, Tipu, Ladda, Roger L., McLaughlin, Heather M., Truty, Rebecca, Mahida, Sonal, Cohen, Julie S., Baranano, Kristin, Ismail, Fatima Y., Patel, Millan S., Lehman, Anna, Edmondson, Andrew C., Nagy, Amanda, Walker, Melissa A., Mercimek-Andrews, Saadet, Maki, Yuta, Sachdev, Rani, Macintosh, Rebecca, Palmer, Elizabeth E., Mancini, Grazia M.S., Barakat, Tahsin Stefan, Steinfeld, Robert, Rüsch, Christina T., Stettner, Georg M., Wagner, Matias, Wortmann, Saskia B., Kini, Usha, Brady, Angela F., Stals, Karen L., Ismayilova, Naila, Ellard, Sian, Bernardo, Danilo, Nugent, Kimberly, McLean, Scott D., Antonarakis, Stylianos E., Houlden, Henry, Kinoshita, Taroh, Campeau, Philippe M., and Murakami, Yoshiko

Abstract

Phosphatidylinositol Glycan Anchor Biosynthesis, class G (PIGG) is an ethanolamine phosphate transferase catalyzing the modification of glycosylphosphatidylinositol (GPI). GPI serves as an anchor on the cell membrane for surface proteins called GPI-anchored proteins (GPI-APs). Pathogenic variants in genes involved in the biosynthesis of GPI cause inherited GPI deficiency (IGD), which still needs to be further characterized.

Published
2021
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66. In-frame seven amino-acid duplication in AIP arose over the last 3000 years, disrupts protein interaction and stability and is associated with gigantism

Author

Salvatori, Roberto, primary, Radian, Serban, additional, Diekmann, Yoan, additional, Iacovazzo, Donato, additional, David, Alessia, additional, Gabrovska, Plamena, additional, Grassi, Giorgia, additional, Bussell, Anna-Marie, additional, Stals, Karen, additional, Weber, Astrid, additional, Quinton, Richard, additional, Crowne, Elizabeth C, additional, Corazzini, Valentina, additional, Metherell, Lou, additional, Kearney, Tara, additional, Du Plessis, Daniel, additional, Sinha, Ajay Kumar, additional, Baborie, Atik, additional, Lecoq, Anne-Lise, additional, Chanson, Philippe, additional, Ansorge, Olaf, additional, Ellard, Sian, additional, Trainer, Peter J, additional, Balding, David, additional, Thomas, Mark G, additional, and Korbonits, Márta, additional

Published
2017
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69. Increased Population Risk ofAIP-Related Acromegaly and Gigantism in Ireland

Author

Radian, Serban, primary, Diekmann, Yoan, additional, Gabrovska, Plamena, additional, Holland, Brendan, additional, Bradley, Lisa, additional, Wallace, Helen, additional, Stals, Karen, additional, Bussell, Anna-Marie, additional, McGurren, Karen, additional, Cuesta, Martin, additional, Ryan, Anthony W., additional, Herincs, Maria, additional, Hernández-Ramírez, Laura C., additional, Holland, Aidan, additional, Samuels, Jade, additional, Aflorei, Elena Daniela, additional, Barry, Sayka, additional, Dénes, Judit, additional, Pernicova, Ida, additional, Stiles, Craig E., additional, Trivellin, Giampaolo, additional, McCloskey, Ronan, additional, Ajzensztejn, Michal, additional, Abid, Noina, additional, Akker, Scott A., additional, Mercado, Moises, additional, Cohen, Mark, additional, Thakker, Rajesh V., additional, Baldeweg, Stephanie, additional, Barkan, Ariel, additional, Musat, Madalina, additional, Levy, Miles, additional, Orme, Stephen M., additional, Unterländer, Martina, additional, Burger, Joachim, additional, Kumar, Ajith V., additional, Ellard, Sian, additional, McPartlin, Joseph, additional, McManus, Ross, additional, Linden, Gerard J., additional, Atkinson, Brew, additional, Balding, David J., additional, Agha, Amar, additional, Thompson, Chris J., additional, Hunter, Steven J., additional, Thomas, Mark G., additional, Morrison, Patrick J., additional, and Korbonits, Márta, additional

Published
2016
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70. Biallelic CRELD1variants cause a multisystem syndrome, including neurodevelopmental phenotypes, cardiac dysrhythmias, and frequent infections

Author

Jeffries, Lauren, Mis, Emily K., McWalter, Kirsty, Donkervoort, Sandra, Brodsky, Nina N., Carpier, Jean-Marie, Ji, Weizhen, Ionita, Cristian, Roy, Bhaskar, Morrow, Jon S., Darbinyan, Armine, Iyer, Krishna, Aul, Ritu B., Banka, Siddharth, Chao, Katherine R., Cobbold, Laura, Cohen, Stacey, Custodio, Helena M., Drummond-Borg, Margaret, Elmslie, Frances, Finanger, Erika, Hainline, Bryan E., Helbig, Ingo, Hewson, Stacy, Hu, Ying, Jackson, Adam, Josifova, Dragana, Konstantino, Monica, Leach, Meganne E., Mak, Bryan, McCormick, David, McGee, Elisabeth, Nelson, Stanley, Nguyen, Joanne, Nugent, Kimberly, Ortega, Lucy, Goodkin, Howard P., Roeder, Elizabeth, Roy, Sani, Sapp, Katie, Saade, Dimah, Sisodiya, Sanjay M., Stals, Karen, Towner, Shelley, Wilson, William, Borras, Silvia, Clark, Caroline, Dean, John, Miedzybrodzka, Zosia, Ross, Alison, Tennant, Stephen, Dabir, Tabib, Donnelly, Deirdre, Humphreys, Mervyn, Magee, Alex, McConnell, Vivienne, McKee, Shane, McNerlan, Susan, Morrison, Patrick J., Rea, Gillian, Stewart, Fiona, Cole, Trevor, Cooper, Nicola, Cooper-Charles, Lisa, Cox, Helen, Islam, Lily, Jarvis, Joanna, Keelagher, Rebecca, Lim, Derek, McMullan, Dominic, Morton, Jenny, Naik, Swati, O’Driscoll, Mary, Ong, Kai-Ren, Osio, Deborah, Ragge, Nicola, Turton, Sarah, Vogt, Julie, Williams, Denise, Bodek, Simon, Donaldson, Alan, Hills, Alison, Low, Karen, Newbury-Ecob, Ruth, Norman, Andrew M., Roberts, Eileen, Scurr, Ingrid, Smithson, Sarah, Tooley, Madeleine, Abbs, Steve, Armstrong, Ruth, Dunn, Carolyn, Holden, Simon, Park, Soo-Mi, Paterson, Joan, Raymond, Lucy, Reid, Evan, Sandford, Richard, Simonic, Ingrid, Tischkowitz, Marc, Woods, Geoff, Bradley, Lisa, Comerford, Joanne, Green, Andrew, Lynch, Sally, McQuaid, Shirley, Mullaney, Brendan, Berg, Jonathan, Goudie, David, Mavrak, Eleni, McLean, Joanne, McWilliam, Catherine, Reavey, Eleanor, Azam, Tara, Cleary, Elaine, Jackson, Andrew, Lam, Wayne, Lampe, Anne, Moore, David, Porteous, Mary, Baple, Emma, Baptista, Júlia, Brewer, Carole, Castle, Bruce, Kivuva, Emma, Owens, Martina, Rankin, Julia, Shaw-Smith, Charles, Turner, Claire, Turnpenny, Peter, Tysoe, Carolyn, Bradley, Therese, Davidson, Rosemarie, Gardiner, Carol, Joss, Shelagh, Kinning, Esther, Longman, Cheryl, McGowan, Ruth, Murday, Victoria, Pilz, Daniela, Tobias, Edward, Whiteford, Margo, Williams, Nicola, Barnicoat, Angela, Clement, Emma, Faravelli, Francesca, Hurst, Jane, Jenkins, Lucy, Jones, Wendy, Ajith Kumar, V.K., Lees, Melissa, Loughlin, Sam, Male, Alison, Morrogh, Deborah, Rosser, Elisabeth, Scott, Richard, Wilson, Louise, Beleza, Ana, Deshpande, Charu, Flinter, Frances, Holder, Muriel, Irving, Melita, Izatt, Louise, Josifova, Dragana, Mohammed, Shehla, Molenda, Aneta, Robert, Leema, Roworth, Wendy, Ruddy, Deborah, Ryten, Mina, Yau, Shu, Bennett, Christopher, Blyth, Moira, Campbell, Jennifer, Coates, Andrea, Dobbie, Angus, Hewitt, Sarah, Hobson, Emma, Jackson, Eilidh, Jewell, Rosalyn, Kraus, Alison, Prescott, Katrina, Sheridan, Eamonn, Thomson, Jenny, Bradshaw, Kirsty, Dixit, Abhijit, Eason, Jacqueline, Haines, Rebecca, Harrison, Rachel, Mutch, Stacey, Sarkar, Ajoy, Searle, Claire, Shannon, Nora, Sharif, Abid, Suri, Mohnish, Vasudevan, Pradeep, Canham, Natalie, Ellis, Ian, Greenhalgh, Lynn, Howard, Emma, Stinton, Victoria, Swale, Andrew, Weber, Astrid, Banka, Siddharth, Breen, Catherine, Briggs, Tracy, Burkitt-Wright, Emma, Chandler, Kate, Clayton-Smith, Jill, Donnai, Dian, Douzgou, Sofia, Gaunt, Lorraine, Jones, Elizabeth, Kerr, Bronwyn, Langley, Claire, Metcalfe, Kay, Smith, Audrey, Wright, Ronnie, Bourn, David, Burn, John, Fisher, Richard, Hellens, Steve, Henderson, Alex, Montgomery, Tara, Splitt, Miranda, Straub, Volker, Wright, Michael, Zwolinski, Simon, Allen, Zoe, Bernhard, Birgitta, Brady, Angela, Brooks, Claire, Busby, Louise, Clowes, Virginia, Ghali, Neeti, Holder, Susan, Ibitoye, Rita, Wakeling, Emma, Blair, Edward, Carmichael, Jenny, Cilliers, Deirdre, Clasper, Susan, Gibbons, Richard, Kini, Usha, Lester, Tracy, Nemeth, Andrea, Poulton, Joanna, Price, Sue, Shears, Debbie, Stewart, Helen, Wilkie, Andrew, Albaba, Shadi, Baker, Duncan, Balasubramanian, Meena, Johnson, Diana, Parker, Michael, Quarrell, Oliver, Stewart, Alison, Willoughby, Josh, Crosby, Charlene, Elmslie, Frances, Homfray, Tessa, Jin, Huilin, Lahiri, Nayana, Mansour, Sahar, Marks, Karen, McEntagart, Meriel, Saggar, Anand, Tatton-Brown, Kate, Butler, Rachel, Clarke, Angus, Corrin, Sian, Fry, Andrew, Kamath, Arveen, McCann, Emma, Mugalaasi, Hood, Pottinger, Caroline, Procter, Annie, Sampson, Julian, Sansbury, Francis, Varghese, Vinod, Baralle, Diana, Callaway, Alison, Cassidy, Emma J., Daniels, Stacey, Douglas, Andrew, Foulds, Nicola, Hunt, David, Kharbanda, Mira, Lachlan, Katherine, Mercer, Catherine, Side, Lucy, Temple, I. Karen, Wellesley, Diana, Ambrose, J.C., Arumugam, P., Baple, E.L., Bleda, M., Boardman-Pretty, F., Boissiere, J.M., Boustred, C.R., Caulfield, M.J., Chan, G.C., Craig, C.E.H., Daugherty, L.C., de Burca, A., Devereau, A., Elgar, G., Foulger, R.E., Fowler, T., FurióTarí, P., Hackett, J.M., Halai, D., Hamblin, A., Henderson, S., Holman, J.E., Hubbard, T.J.P., Ibáñez, K., Jackson, R., Jones, L.J., Kasperaviciute, D., Kayikci, M., Lahnstein, L., Lawson, K., Leigh, S.E.A., Leong, I.U.S., Lopez, F.J., MaleadyCrowe, F., Mason, J., McDonagh, E.M., Moutsianas, L., Mueller, M., Murugaesu, N., Need, A.C., Odhams, C.A., Patch, C., Perez-Gil, D., Polychronopoulos, D., Pullinger, J., Rahim, T., Rendon, A., Riesgo-Ferreiro, P., Rogers, T., Ryten, M., Savage, K., Sawant, K., Scott, R.H., Siddiq, A., Sieghart, A., Smedley, D., Smith, K.R., Sosinsky, A., Spooner, W., Stevens, H.E., Stuckey, A., Sultana, R., Thomas, E.R.A., Thompson, S.R., Tucci, A., Walsh, E., Watters, S.A., Welland, M.J., Williams, E., Witkowska, K., Acosta, Maria T., Adam, Margaret, Adams, David R., Agrawal, Pankaj B., Alejandro, Mercedes E., Alvey, Justin, Amendola, Laura, Andrews, Ashley, Ashley, Euan A., Azamian, Mahshid S., Bacino, Carlos A., Bademci, Guney, Baker, Eva, Balasubramanyam, Ashok, Baldridge, Dustin, Bale, Jim, Bamshad, Michael, Barbouth, Deborah, Bayrak-Toydemir, Pinar, Beck, Anita, Beggs, Alan H., Behrens, Edward, Bejerano, Gill, Bennet, Jimmy, Berg-Rood, Beverly, Bernstein, Jonathan A., Berry, Gerard T., Bican, Anna, Bivona, Stephanie, Blue, Elizabeth, Bohnsack, John, Bonnenmann, Carsten, Bonner, Devon, Botto, Lorenzo, Boyd, Brenna, Briere, Lauren C., Brokamp, Elly, Brown, Gabrielle, Burke, Elizabeth A., Burrage, Lindsay C., Butte, Manish J., Byers, Peter, Byrd, William E., Carey, John, Carrasquillo, Olveen, Peter Chang, Ta Chen, Chanprasert, Sirisak, Chao, Hsiao-Tuan, Clark, Gary D., Coakley, Terra R., Cobban, Laurel A., Cogan, Joy D., Coggins, Matthew, Cole, F. Sessions, Colley, Heather A., Cooper, Cynthia M., Craigen, William J., Crouse, Andrew B., Cunningham, Michael, D'Souza, Precilla, Dai, Hongzheng, Dasari, Surendra, Davids, Mariska, Dayal, Jyoti G., Deardorff, Matthew, Dell'Angelica, Esteban C., Dhar, Shweta U., Dipple, Katrina, Doherty, Daniel, Dorrani, Naghmeh, Douine, Emilie D., Draper, David D., Duncan, Laura, Earl, Dawn, Eckstein, David J., Emrick, Lisa T., Eng, Christine M., Esteves, Cecilia, Estwick, Tyra, Falk, Marni, Fernandez, Liliana, Ferreira, Carlos, Fieg, Elizabeth L., Findley, Laurie C., Fisher, Paul G., Fogel, Brent L., Forghani, Irman, Fresard, Laure, Gahl, William A., Glass, Ian, Godfrey, Rena A., Golden-Grant, Katie, Goldman, Alica M., Goldstein, David B., Grajewski, Alana, Groden, Catherine A., Gropman, Andrea L., Gutierrez, Irma, Hahn, Sihoun, Hamid, Rizwan, Hanchard, Neil A., Hassey, Kelly, Hayes, Nichole, High, Frances, Hing, Anne, Hisama, Fuki M., Holm, Ingrid A., Hom, Jason, Horike-Pyne, Martha, Huang, Alden, Huang, Yong, Isasi, Rosario, Jamal, Fariha, Jarvik, Gail P., Jarvik, Jeffrey, Jayadev, Suman, Johnston, Jean M., Karaviti, Lefkothea, Kelley, Emily G., Kennedy, Jennifer, Kiley, Dana, Kohane, Isaac S., Kohler, Jennefer N., Krakow, Deborah, Krasnewich, Donna M., Kravets, Elijah, Korrick, Susan, Koziura, Mary, Krier, Joel B., Lalani, Seema R., Lam, Byron, Lam, Christina, Lanpher, Brendan C., Lanza, Ian R., Lau, C. Christopher, LeBlanc, Kimberly, Lee, Brendan H., Lee, Hane, Levitt, Roy, Lewis, Richard A., Lincoln, Sharyn A., Liu, Pengfei, Liu, Xue Zhong, Longo, Nicola, Loo, Sandra K., Loscalzo, Joseph, Maas, Richard L., Macnamara, Ellen F., MacRae, Calum A., Maduro, Valerie V., Majcherska, Marta M., Mak, Bryan, Malicdan, May Christine V., Mamounas, Laura A., Manolio, Teri A., Mao, Rong, Maravilla, Kenneth, Markello, Thomas C., Marom, Ronit, Marth, Gabor, Martin, Beth A., Martin, Martin G., Martínez-Agosto, Julian A., Marwaha, Shruti, McCauley, Jacob, McCormack, Colleen E., McCray, Alexa T., McGee, Elisabeth, Mefford, Heather, Merritt, J. Lawrence, Might, Matthew, Mirzaa, Ghayda, Morava, Eva, Moretti, Paolo M., Morimoto, Marie, Mulvihill, John J., Murdock, David R., Nakano-Okuno, Mariko, Nath, Avi, Nelson, Stan F., Newman, John H., Nicholas, Sarah K., Nickerson, Deborah, Nieves-Rodriguez, Shirley, Novacic, Donna, Oglesbee, Devin, Orengo, James P., Pace, Laura, Pak, Stephen, Pallais, J. Carl, Papp, Jeanette C., Parker, Neil H., Phillips, John A., Posey, Jennifer E., Potocki, Lorraine, Pusey, Barbara N., Quinlan, Aaron, Raskind, Wendy, Raja, Archana N., Rao, Deepak A., Renteria, Genecee, Reuter, Chloe M., Rives, Lynette, Robertson, Amy K., Rodan, Lance H., Rosenfeld, Jill A., Rosenwasser, Natalie, Ruzhnikov, Maura, Sacco, Ralph, Sampson, Jacinda B., Samson, Susan L., Saporta, Mario, Scott, C. Ron, Schaechter, Judy, Schedl, Timothy, Scott, Daryl A., Sharma, Prashant, Shin, Jimann, Signer, Rebecca, Sillari, Catherine H., Silverman, Edwin K., Sinsheimer, Janet S., Sisco, Kathy, Smith, Edward C., Smith, Kevin S., Solem, Emily, Solnica-Krezel, Lilianna, Stoler, Joan M., Stong, Nicholas, Sullivan, Jennifer A., Sun, Angela, Sutton, Shirley, Sweetser, David A., Sybert, Virginia, Tabor, Holly K., Tamburro, Cecelia P., Tekin, Mustafa, Telischi, Fred, Thorson, Willa, Tifft, Cynthia J., Toro, Camilo, Tran, Alyssa A., Tucker, Brianna M., Urv, Tiina K., Vanderver, Adeline, Velinder, Matt, Viskochil, Dave, Vogel, Tiphanie P., Wahl, Colleen E., Wallace, Stephanie, Walley, Nicole M., Walsh, Chris A., Walker, Melissa, Wambach, Jennifer, Wan, Jijun, Wang, Lee-Kai, Wangler, Michael F., Ward, Patricia A., Wegner, Daniel, Wener, Mark, Wenger, Tara, Perry, Katherine Wesseling, Westerfield, Monte, Wheeler, Matthew T., Whitlock, Jordan, Wolfe, Lynne A., Woods, Jeremy D., Yamamoto, Shinya, Yang, John, Yu, Guoyun, Zastrow, Diane B., Zhao, Chunli, Zuchner, Stephan, Khokha, Mustafa K., Bönnemann, Carsten G., Lucas, Carrie L., and Lakhani, Saquib A.

Abstract

We sought to delineate a multisystem disorder caused by recessive cysteine-rich with epidermal growth factor–like domains 1 (CRELD1) gene variants.

Published
2024
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71. The founder R304*AIPmutation is prevalent in Irish acromegaly and gigantism patients as well as in the general population of Ireland

Author

Radian, Serban, primary, Diekmann, Yoan, additional, Gabrovska, Plamena, additional, Holland, Brendan, additional, Bradley, Lisa, additional, Wallace, Helen, additional, Stals, Karen, additional, Bussell, Anna-Marie, additional, McGurren, Karen, additional, Cuesta, Martin, additional, Ryan, Anthony W, additional, Herincs, Maria, additional, Hernandez-Ramirez, Laura C, additional, Holland, Aidan, additional, Samuels, Jade, additional, Aflorei, Elena Daniela, additional, Barry, Sayka, additional, Denes, Judit, additional, Pernicova, Ida, additional, Stiles, Craig E, additional, Trivellin, Giampaolo, additional, McCloskey, Ronan, additional, Ajzensztejn, Michal, additional, Abid, Noina, additional, Akker, Scott A, additional, Mercado, Moises, additional, Cohen, Mark, additional, Thakker, Rajesh V, additional, Baldeweg, Stephanie, additional, Barkan, Ariel, additional, Musat, Madalina, additional, Levy, Miles, additional, Orme, Steve, additional, Unterlander, Martina, additional, Burger, Joachim, additional, Kumar, Ajith V, additional, Ellard, Sian, additional, McPartlin, Joseph, additional, McManus, Ross, additional, Linden, Gerard J, additional, Atkinson, Brew, additional, Thomas, Mark G, additional, Balding, David J, additional, Agha, Amar, additional, Thompson, Chris J, additional, Hunter, Steve J, additional, Morrison, Patrick J, additional, and Korbonits, Marta, additional

Published
2015
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74. Brief Report : AIP Mutation in Pituitary Adenomas in the 18th Century and Today

Author

Chahal, Harvinder S., Stals, Karen, Unterlander, Martina, Balding, David J., Thomas, Mark G., Kumar, Ajith V., Besser, G. Michael, Atkinson, A. Brew, Morrison, Patrick J., Howlett, Trevor A., Levy, Miles J., Orme, Steve M., Akker, Scott A., Abel, Richard L., Grossman, Ashley B., Burger, Joachim, Ellard, Sian, Korbonits, Marta, Chahal, Harvinder S., Stals, Karen, Unterlander, Martina, Balding, David J., Thomas, Mark G., Kumar, Ajith V., Besser, G. Michael, Atkinson, A. Brew, Morrison, Patrick J., Howlett, Trevor A., Levy, Miles J., Orme, Steve M., Akker, Scott A., Abel, Richard L., Grossman, Ashley B., Burger, Joachim, Ellard, Sian, and Korbonits, Marta

Abstract

Gigantism results when a growth hormone-secreting pituitary adenoma is present before epiphyseal fusion. In 1909, when Harvey Cushing examined the skeleton of an Irish patient who lived from 1761 to 1783, *RF 1-3* he noted an enlarged pituitary fossa. We extracted DNA from the patient's teeth and identified a germline mutation in the aryl hydrocarbon-interacting protein gene (AIP). Four contemporary Northern Irish families who presented with gigantism, acromegaly, or prolactinoma have the same mutation and haplotype associated with the mutated gene. Using coalescent theory, we infer that these persons share a common ancestor who lived about 57 to 66 generations earlier.

Published
2011
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75. Pituitary adenoma and phaeochromocytoma/paraganglioma - a novel syndrome with a heterogeneous genetic background

Author

Denes, Judit, primary, Swords, Francesca, additional, Rattenberry, Eleanor, additional, Xekouki, Paraskevi, additional, Kumar, Ajith, additional, Wassif, Christopher, additional, Fersht, Naomi, additional, Baldeweg, Stephanie, additional, Morris, Damian, additional, Lightman, Stafford, additional, Thompson, Chris J, additional, Agha, Amar, additional, Rees, Aled, additional, Druce, Maralyn, additional, Grieve, Joan, additional, Powell, Michael, additional, Boguszewski, Cesar Luiz, additional, Higham, Claire, additional, Davis, Julian, additional, Preda, Cristina, additional, Trouillas, Jacqueline, additional, Dalantaeva, Nadezhda, additional, Ribeiro-Oliveira, Antonio, additional, Dutta, Pinaki, additional, Roncaroli, Federico, additional, Thakker, Rajesh V, additional, Stevenson, Mark, additional, O'Sullivan, Brendan, additional, Taniere, Phillipe, additional, Skordilis, Kassiani, additional, Gabrovska, Plamena, additional, Barlier, Anne, additional, Ellard, Sian, additional, Stals, Karen, additional, Stratakis, Constantine A, additional, Grossman, Ashley B, additional, Maher, Eamonn, additional, and Korbonits, Marta, additional

Published
2013
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76. Creation of a locus-specific database for AIP mutations

Author

Begum, Fauzia, primary, Trivellin, Giampaolo, additional, Gabrovska, Plamena, additional, Tysarowska, Katarzyna Wertheim, additional, Jones, Michael, additional, Stals, Karen, additional, Ellard, Sian, additional, Radian, Serban, additional, and Korbonits, Marta, additional

Published
2013
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77. Genetic studies in a coexistence of acromegaly, pheochromocytoma, gastrointestinal stromal tumor (GIST) and thyroid follicular adenoma

Author

Boguszewski, César Luiz, primary, Fighera, Tayane Muniz, additional, Bornschein, Andressa, additional, Marques, Fabricio Machado, additional, Dénes, Judit, additional, Rattenbery, Eleanor, additional, Maher, Eamonn R., additional, Stals, Karen, additional, Ellard, Sian, additional, and Korbonits, Marta, additional

Published
2012
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78. AIPMutation in Pituitary Adenomas in the 18th Century and Today

Author

Chahal, Harvinder S., primary, Stals, Karen, additional, Unterländer, Martina, additional, Balding, David J., additional, Thomas, Mark G., additional, Kumar, Ajith V., additional, Besser, G. Michael, additional, Atkinson, A. Brew, additional, Morrison, Patrick J., additional, Howlett, Trevor A., additional, Levy, Miles J., additional, Orme, Steve M., additional, Akker, Scott A., additional, Abel, Richard L., additional, Grossman, Ashley B., additional, Burger, Joachim, additional, Ellard, Sian, additional, and Korbonits, Márta, additional

Published
2011
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80. An exome sequencing strategy to diagnose lethal autosomal recessive disorders.

Author

Ellard, Sian, Kivuva, Emma, Turnpenny, Peter, Stals, Karen, Johnson, Matthew, Xie, Weijia, Caswell, Richard, and Lango Allen, Hana

Subjects
NUCLEOTIDE sequencing, RARE diseases, LETHAL mutations, HUMAN genetic variation, POLYDACTYLY, NEONATAL death, DIAGNOSIS
Abstract

Rare disorders resulting in prenatal or neonatal death are genetically heterogeneous. For some conditions, affected fetuses can be diagnosed by ultrasound scan, but this is not usually possible until mid-gestation. There is often limited fetal DNA available for investigation. We investigated a strategy for diagnosing autosomal recessive lethal disorders in non-consanguineous pedigrees with multiple affected fetuses. Exome sequencing was performed to identify genes where each parent is heterozygous for a rare non-synonymous-coding or splicing variant. Putative pathogenic variants were tested for cosegregation in affected fetuses and unaffected siblings. In eight couples of European ancestry, we found on average 1.75 genes (range 0-4) where both parents were heterozygous for rare potentially deleterious variants. A proof-of-principle study detected heterozygous DYNC2H1 variants in a couple whose five fetuses had short-rib polydactyly. Prospective analysis of two couples with multiple pregnancy terminations for fetal akinesia syndrome was performed and a diagnosis was obtained in both the families. The first couple were each heterozygous for a previously reported GLE1 variant, p.Arg569His or p.Val617Met; both were inherited by their two affected fetuses. The second couple were each heterozygous for a novel RYR1 variant, c.14130-2A>G or p.Ser3074Phe; both were inherited by their three affected fetuses but not by their unaffected child. Biallelic GLE1 and RYR1 disease-causing variants have been described in other cases with fetal akinesia syndrome. We conclude that exome sequencing of parental samples can be an effective tool for diagnosing lethal recessive disorders in outbred couples. This permits early prenatal diagnosis in future pregnancies. [ABSTRACT FROM AUTHOR]

Published
2015
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81. AIPmutations in young patients with acromegaly and the Tampico Giant: the Mexican experience

Author

Ramírez-Rentería, Claudia, Hernández-Ramírez, Laura, Portocarrero-Ortiz, Lesly, Vargas, Guadalupe, Melgar, Virgilio, Espinosa, Etual, Espinosa-de-los-Monteros, Ana, Sosa, Ernesto, González, Baldomero, Zúñiga, Sergio, Unterländer, Martina, Burger, Joachim, Stals, Karen, Bussell, Anne-Marie, Ellard, Sian, Dang, Mary, Iacovazzo, Donato, Kapur, Sonal, Gabrovska, Plamena, Radian, Serban, Roncaroli, Federico, Korbonits, Márta, and Mercado, Moisés

Abstract

Although aryl hydrocarbon receptor-interacting protein (AIP) mutations are rare in sporadic acromegaly, their prevalence among young patients is nonnegligible. The objectives of this study were to evaluate the frequency of AIPmutations in a cohort of Mexican patients with acromegaly with disease onset before the age of 30 and to search for molecular abnormalities in the AIPgene in teeth obtained from the “Tampico Giant”. Peripheral blood DNA from 71 patients with acromegaly (51 females) with disease onset <30 years was analysed (median age of disease onset of 23 years) and correlated with clinical, biochemical and imaging characteristics. Sequencing was also carried out in DNA extracted from teeth of the Tampico Giant. Five patients (7 %) harboured heterozygous, germline mutations of the AIPgene. In two of them (a 9-year-old girl with gigantism and a young man with symptoms of GH excess since age 14) the c.910C>T (p.Arg304Ter), well-known truncating mutation was identified; in one of these two cases and her identical twin sister, the mutation proved to be a de novo event, since neither of their parents were found to be carriers. In the remaining three patients, new mutations were identified: a frameshift mutation (c.976_977insC, p.Gly326AfsTer), an in-frame deletion (c.872_877del, p.Val291_Leu292del) and a nonsense mutation (c.868A > T, p.Lys290Ter), which are predicted to be pathogenic based on in silico analysis. Patients with AIPmutations tended to have an earlier onset of acromegaly and harboured larger and more invasive tumours. A previously described genetic variant of unknown significance (c.869C > T, p.Ala299Val) was identified in DNA from the Tampico Giant. The prevalence of AIPmutations in young Mexican patients with acromegaly is similar to that of European cohorts. Our results support the need for genetic evaluation of patients with early onset acromegaly.

Published
2016
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83. Landscape of Familial Isolated and Young-Onset Pituitary Adenomas: Prospective Diagnosis in AIPMutation Carriers

Author

Hernández-Ramírez, Laura C., Gabrovska, Plamena, Dénes, Judit, Stals, Karen, Trivellin, Giampaolo, Tilley, Daniel, Ferraù, Francesco, Evanson, Jane, Ellard, Sian, Grossman, Ashley B., Roncaroli, Federico, Gadelha, Mônica R., and Korbonits, Márta

Abstract

Context:Familial isolated pituitary adenoma (FIPA) due to aryl hydrocarbon receptor interacting protein (AIP) gene mutations is an autosomal dominant disease with incomplete penetrance. Clinical screening of apparently unaffected AIPmutation (AIPmut) carriers could identify previously unrecognized disease.Objective:To determine the AIPmutational status of FIPA and young pituitary adenoma patients, analyzing their clinical characteristics, and to perform clinical screening of apparently unaffected AIPmut carrier family members.Design:This was an observational, longitudinal study conducted over 7 years.Setting:International collaborative study conducted at referral centers for pituitary diseases.Participants:FIPA families (n = 216) and sporadic young-onset (≤30 y) pituitary adenoma patients (n = 404) participated in the study.Interventions:We performed genetic screening of patients for AIPmuts, clinical assessment of their family members, and genetic screening for somatic GNAS1mutations and the germline FGFR4p.G388R variant.Main Outcome Measure(s):We assessed clinical disease in mutation carriers, comparison of characteristics of AIPmut positive and negative patients, results of GNAS1, and FGFR4analysis.Results:Thirty-seven FIPA families and 34 sporadic patients had AIPmuts. Patients with truncating AIPmuts had a younger age at disease onset and diagnosis, compared with patients with nontruncating AIPmuts. Somatic GNAS1mutations were absent in tumors from AIPmut-positive patients, and the studied FGFR4variant did not modify the disease behavior or penetrance in AIPmut-positive individuals. A total of 164 AIPmut-positive unaffected family members were identified; pituitary disease was detected in 18 of those who underwent clinical screening.Conclusions:A quarter of the AIPmut carriers screened were diagnosed with pituitary disease, justifying this screening and suggesting a variable clinical course for AIPmut-positive pituitary adenomas.

Published
2015
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85. Diagnosis of lethal or prenatal-onset autosomal recessive disorders by parental exome sequencing

Author

Stals, Karen L, Wakeling, Matthew, Baptista, Júlia, Caswell, Richard, Parrish, Andrew, Rankin, Julia, Tysoe, Carolyn, Jones, Garan, Gunning, Adam C, Lango Allen, Hana, Bradley, Lisa, Brady, Angela F, Carley, Helena, Carmichael, Jenny, Castle, Bruce, Cilliers, Deirdre, Cox, Helen, Deshpande, Charu, Dixit, Abhijit, Eason, Jacqueline, Elmslie, Frances, Fry, Andrew E, Fryer, Alan, Holder, Muriel, Homfray, Tessa, Kivuva, Emma, McKay, Victoria, Newbury-Ecob, Ruth, Parker, Michael, Savarirayan, Ravi, Searle, Claire, Shannon, Nora, Shears, Deborah, Smithson, Sarah, Thomas, Ellen, Turnpenny, Peter D, Varghese, Vinod, Vasudevan, Pradeep, Wakeling, Emma, Baple, Emma L, and Ellard, Sian

Subjects
Male, Parents, Pregnancy, Prenatal Diagnosis, Genetic Diseases, Inborn, Humans, Female, Genes, Recessive, Whole Exome Sequencing, 3. Good health, Congenital Abnormalities
Abstract

OBJECTIVE: Rare genetic disorders resulting in prenatal or neonatal death are genetically heterogeneous, but testing is often limited by the availability of fetal DNA, leaving couples without a potential prenatal test for future pregnancies. We describe our novel strategy of exome sequencing parental DNA samples to diagnose recessive monogenic disorders in an audit of the first 50 couples referred. METHOD: Exome sequencing was carried out in a consecutive series of 50 couples who had 1 or more pregnancies affected with a lethal or prenatal-onset disorder. In all cases, there was insufficient DNA for exome sequencing of the affected fetus. Heterozygous rare variants (MAF < 0.001) in the same gene in both parents were selected for analysis. Likely, disease-causing variants were tested in fetal DNA to confirm co-segregation. RESULTS: Parental exome analysis identified heterozygous pathogenic (or likely pathogenic) variants in 24 different genes in 26/50 couples (52%). Where 2 or more fetuses were affected, a genetic diagnosis was obtained in 18/29 cases (62%). In most cases, the clinical features were typical of the disorder, but in others, they result from a hypomorphic variant or represent the most severe form of a variable phenotypic spectrum. CONCLUSION: We conclude that exome sequencing of parental samples is a powerful strategy with high clinical utility for the genetic diagnosis of lethal or prenatal-onset recessive disorders. © 2017 The Authors Prenatal Diagnosis published by John Wiley & Sons Ltd.

86. SPEN haploinsufficiency causes a neurodevelopmental disorder overlapping proximal 1p36 deletion syndrome with an episignature of X chromosomes in females

Author

Radio, Francesca Clementina, Pang, Kaifang, Ciolfi, Andrea, Levy, Michael A., Pedace, Lucia, Boer, Elke, Jackson, Adam, Stellacci, Emilia, Lo Cicero, Stefania, Dentici, Maria Lisa, Mcwalter, Kirsty, Sanchez-Lara, Pedro A., Lindstrom, Kristin, Madan-Khetarpal, Suneeta, Mackenzie, Jennifer J., Monteleone, Berrin, Zhou, Dihong, Sawyer, Sarah L., Monteiro, Fabiola Paoli, Macke, Erica L., Maria Iascone, Selicorni, Angelo, Tenconi, Romano, Amor, David J., Stals, Karen, Cabet, Sara, Steindl, Katharina, Weiss, Karin, Castle, Alison M. R., Kalsner, Louisa, Chandler, Kate E., Sheehan, Willow, Shinde, Deepali N., Goodloe, Dana, Bluske, Krista, Faletra, Flavio, Kurtz-Nelson, Evangeline C., Anderlid, Britt-Marie, Barakat, Tahsin Stefan, Graham, John M., Faivre, Laurence, Banka, Siddharth, Wang, Tianyun, Priolo, Manuela, Dallapiccola, Bruno, Vissers, Lisenka E. L. M., Sadikovic, Bekim, Scott, Daryl A., Holder, Jimmy Lloyd, and Tartaglia, Marco

87. Population Screening for the Irish Founder AIP Mutation R304*Reveals a Prevalence of 1/500 in the Local Population, While High Mutation Frequency Is Present Among Irish Familial and Sporadic Somatotropinoma Patients

Author

Radian, Serban, Gabrovska, Plamena, Holland, Brendan, Wallace, Helen, Ryan, Anthony W., Mcgurren, Karen, Stals, Karen, Bussell, Anna-Marie, Thomas, Mark G., Holland, Aidan, Aflorei, Elena Daniela, Barry, Sayka, Stiles, Craig E., Pernicova, Ida, Giampaolo Trivellin, Denes, Judit, Herincs, Maria, Hernandez-Ramirez, Laura C., Samuels, Jade, Mccloskey, Ronan, Azjensztejn, Michal, Abid, Noina, Kumar, Ajith V., Atkinson, Brew A., Ellard, Sian, Mcmanus, Ross, Thompson, Chris John, Linden, Gerard J., Bradley, Lisa, Agha, Amar, Hunter, Steven J., Morrison, Patrick J., and Korbonits, Marta

89. COA5 has an essential role in the early stage of mitochondrial complex IV assembly.

Author

Tang JX, Cabrera-Orefice A, Meisterknecht J, Taylor LS, Monteuuis G, Stensland ME, Szczepanek A, Stals K, Davison J, He L, Hopton S, Nyman TA, Jackson CB, Pyle A, Winter M, Wittig I, and Taylor RW

Subjects
Humans, Male, Female, Mitochondrial Proteins metabolism, Mitochondrial Proteins genetics, Mitochondrial Diseases genetics, Mitochondrial Diseases metabolism, Mitochondrial Diseases pathology, Pedigree, CRISPR-Cas Systems, Fibroblasts metabolism, Mutation, Missense, Mitochondria metabolism, Mitochondria genetics, Electron Transport Complex IV metabolism, Electron Transport Complex IV genetics
Abstract

Pathogenic variants in cytochrome c oxidase assembly factor 5 (COA5), a proposed complex IV (CIV) assembly factor, have been shown to cause clinical mitochondrial disease with two siblings affected by neonatal hypertrophic cardiomyopathy manifesting a rare, homozygous COA5 missense variant (NM&#95;001008215.3: c.157G>C, p.Ala53Pro). The most striking observation in the affected individuals was an isolated impairment in the early stage of mitochondrial CIV assembly. In this study, we report an unrelated family in whom we have identified the same COA5 variant with patient-derived fibroblasts and skeletal muscle biopsies replicating an isolated CIV deficiency. A CRISPR/Cas9-edited homozygous COA5 knockout U2OS cell line with a similar biochemical profile was generated to interrogate the functional role of the human COA5 protein. Mitochondrial complexome profiling pinpointed a role of COA5 in early CIV assembly, more specifically, its involvement in the stage between MTCO1 maturation and the incorporation of MTCO2. We therefore propose that the COA5 protein plays an essential role in the biogenesis of MTCO2 and its integration into the early CIV assembly intermediate for downstream assembly of the functional holocomplex., (© 2025 Tang et al.)

Published
2025
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90. PSMF1 variants cause a phenotypic spectrum from early-onset Parkinson's disease to perinatal lethality by disrupting mitochondrial pathways.

Author

Magrinelli F, Tesson C, Angelova PR, Salazar-Villacorta A, Rodriguez JA, Scardamaglia A, Chung BH, Jaconelli M, Vona B, Esteras N, Kwong AK, Courtin T, Maroofian R, Alavi S, Nirujogi R, Severino M, Lewis PA, Efthymiou S, O'Callaghan B, Buchert R, Sofan L, Lis P, Pinon C, Breedveld GJ, Chui MM, Murphy D, Pitz V, Makarious MB, Cassar M, Hassan BA, Iftikhar S, Rocca C, Bauer P, Tinazzi M, Svetel M, Samanci B, Hanağası HA, Bilgiç B, Obeso JA, Kurtis MM, Cogan G, Başak AN, Kiziltan G, Gül T, Yalçın G, Elibol B, Barišić N, Ng EW, Fan SS, Hershkovitz T, Weiss K, Raza Alvi J, Sultan T, Azmi Alkhawaja I, Froukh T, E Alrukban HA, Fauth C, Schatz UA, Zöggeler T, Zech M, Stals K, Varghese V, Gandhi S, Blauwendraat C, Hardy JA, Lesage S, Bonifati V, Haack TB, Bertoli-Avella AM, Steinfeld R, Alessi DR, Steller H, Brice A, Abramov AY, Bhatia KP, and Houlden H

Abstract

Dissecting biological pathways highlighted by Mendelian gene discovery has provided critical insights into the pathogenesis of Parkinson's disease (PD) and neurodegeneration. This approach ultimately catalyzes the identification of potential biomarkers and therapeutic targets. Here, we identify PSMF1 as a new gene implicated in PD and childhood neurodegeneration. We find that biallelic PSMF1 missense and loss-of-function variants co-segregate with phenotypes from early-onset PD and parkinsonism to perinatal lethality with neurological manifestations across 15 unrelated pedigrees with 22 affected subjects, showing clear genotype-phenotype correlation. PSMF1 encodes the proteasome regulator PSMF1/PI31, a highly conserved, ubiquitously expressed partner of the 20S proteasome and neurodegeneration-associated F-box-O 7 and valosin-containing proteins. We demonstrate that PSMF1 variants impair mitochondrial membrane potential, dynamics and mitophagy in patient-derived fibroblasts. Additionally, we develop models of psmf1 knockdown Drosophila and Psmf1 conditional knockout mouse exhibiting age-dependent motor impairment, with diffuse gliosis in mice. These findings unequivocally link defective PSMF1 to early-onset PD and neurodegeneration and suggest mitochondrial dysfunction as a mechanistic contributor.

Published
2024
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91. Dominant negative variants in KIF5B cause osteogenesis imperfecta via down regulation of mTOR signaling.

Author

Marom R, Zhang B, Washington ME, Song IW, Burrage LC, Rossi VC, Berrier AS, Lindsey A, Lesinski J, Nonet ML, Chen J, Baldridge D, Silverman GA, Sutton VR, Rosenfeld JA, Tran AA, Hicks MJ, Murdock DR, Dai H, Weis M, Jhangiani SN, Muzny DM, Gibbs RA, Caswell R, Pottinger C, Cilliers D, Stals K, Eyre D, Krakow D, Schedl T, Pak SC, and Lee BH

Subjects
Animals, Humans, Mice, Caenorhabditis elegans genetics, Caenorhabditis elegans metabolism, Carrier Proteins genetics, Down-Regulation, NIH 3T3 Cells, Proteomics, Signal Transduction genetics, TOR Serine-Threonine Kinases genetics, TOR Serine-Threonine Kinases metabolism, Kinesins genetics, Kinesins metabolism, Osteogenesis Imperfecta
Abstract

Background: Kinesin motor proteins transport intracellular cargo, including mRNA, proteins, and organelles. Pathogenic variants in kinesin-related genes have been implicated in neurodevelopmental disorders and skeletal dysplasias. We identified de novo, heterozygous variants in KIF5B, encoding a kinesin-1 subunit, in four individuals with osteogenesis imperfecta. The variants cluster within the highly conserved kinesin motor domain and are predicted to interfere with nucleotide binding, although the mechanistic consequences on cell signaling and function are unknown., Methods: To understand the in vivo genetic mechanism of KIF5B variants, we modeled the p.Thr87Ile variant that was found in two patients in the C. elegans ortholog, unc-116, at the corresponding position (Thr90Ile) by CRISPR/Cas9 editing and performed functional analysis. Next, we studied the cellular and molecular consequences of the recurrent p.Thr87Ile variant by microscopy, RNA and protein analysis in NIH3T3 cells, primary human fibroblasts and bone biopsy., Results: C. elegans heterozygous for the unc-116 Thr90Ile variant displayed abnormal body length and motility phenotypes that were suppressed by additional copies of the wild type allele, consistent with a dominant negative mechanism. Time-lapse imaging of GFP-tagged mitochondria showed defective mitochondria transport in unc-116 Thr90Ile neurons providing strong evidence for disrupted kinesin motor function. Microscopy studies in human cells showed dilated endoplasmic reticulum, multiple intracellular vacuoles, and abnormal distribution of the Golgi complex, supporting an intracellular trafficking defect. RNA sequencing, proteomic analysis, and bone immunohistochemistry demonstrated down regulation of the mTOR signaling pathway that was partially rescued with leucine supplementation in patient cells., Conclusion: We report dominant negative variants in the KIF5B kinesin motor domain in individuals with osteogenesis imperfecta. This study expands the spectrum of kinesin-related disorders and identifies dysregulated signaling targets for KIF5B in skeletal development., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Marom et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Published
2023
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92. Significant Benefits of AIP Testing and Clinical Screening in Familial Isolated and Young-onset Pituitary Tumors.

Author

Marques P, Caimari F, Hernández-Ramírez LC, Collier D, Iacovazzo D, Ronaldson A, Magid K, Lim CT, Stals K, Ellard S, Grossman AB, and Korbonits M

Subjects
Adolescent, Adult, Age of Onset, Female, Follow-Up Studies, Growth Hormone-Secreting Pituitary Adenoma genetics, Humans, Male, Pituitary Neoplasms genetics, Prognosis, Prospective Studies, Young Adult, Biomarkers analysis, Genetic Testing methods, Growth Hormone-Secreting Pituitary Adenoma diagnosis, Intracellular Signaling Peptides and Proteins genetics, Mass Screening methods, Mutation, Pituitary Neoplasms diagnosis
Abstract

Context: Germline mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene are responsible for a subset of familial isolated pituitary adenoma (FIPA) cases and sporadic pituitary neuroendocrine tumors (PitNETs)., Objective: To compare prospectively diagnosed AIP mutation-positive (AIPmut) PitNET patients with clinically presenting patients and to compare the clinical characteristics of AIPmut and AIPneg PitNET patients., Design: 12-year prospective, observational study., Participants & Setting: We studied probands and family members of FIPA kindreds and sporadic patients with disease onset ≤18 years or macroadenomas with onset ≤30 years (n = 1477). This was a collaborative study conducted at referral centers for pituitary diseases., Interventions & Outcome: AIP testing and clinical screening for pituitary disease. Comparison of characteristics of prospectively diagnosed (n = 22) vs clinically presenting AIPmut PitNET patients (n = 145), and AIPmut (n = 167) vs AIPneg PitNET patients (n = 1310)., Results: Prospectively diagnosed AIPmut PitNET patients had smaller lesions with less suprasellar extension or cavernous sinus invasion and required fewer treatments with fewer operations and no radiotherapy compared with clinically presenting cases; there were fewer cases with active disease and hypopituitarism at last follow-up. When comparing AIPmut and AIPneg cases, AIPmut patients were more often males, younger, more often had GH excess, pituitary apoplexy, suprasellar extension, and more patients required multimodal therapy, including radiotherapy. AIPmut patients (n = 136) with GH excess were taller than AIPneg counterparts (n = 650)., Conclusions: Prospectively diagnosed AIPmut patients show better outcomes than clinically presenting cases, demonstrating the benefits of genetic and clinical screening. AIP-related pituitary disease has a wide spectrum ranging from aggressively growing lesions to stable or indolent disease course., (© Endocrine Society 2020.)

Published
2020
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93. A hypomorphic allele of SLC35D1 results in Schneckenbecken-like dysplasia.

Author

Rautengarten C, Quarrell OW, Stals K, Caswell RC, De Franco E, Baple E, Burgess N, Jokhi R, Heazlewood JL, Offiah AC, Ebert B, and Ellard S

Subjects
Alleles, Animals, Endoplasmic Reticulum genetics, Endoplasmic Reticulum metabolism, Female, Fetal Diseases metabolism, Fetal Diseases pathology, Heterozygote, Humans, Loss of Function Mutation, Male, Mice, Monosaccharide Transport Proteins metabolism, Mutation, Missense, Osteochondrodysplasias embryology, Osteochondrodysplasias metabolism, Fetal Diseases genetics, Monosaccharide Transport Proteins genetics, Osteochondrodysplasias genetics
Abstract

We report the case of a consanguineous couple who lost four pregnancies associated with skeletal dysplasia. Radiological examination of one fetus was inconclusive. Parental exome sequencing showed that both parents were heterozygous for a novel missense variant, p.(Pro133Leu), in the SLC35D1 gene encoding a nucleotide sugar transporter. The affected fetus was homozygous for the variant. The radiological features were reviewed, and being similar, but atypical, the phenotype was classified as a 'Schneckenbecken-like dysplasia.' The effect of the missense change was assessed using protein modelling techniques and indicated alterations in the mouth of the solute channel. A detailed biochemical investigation of SLC35D1 transport function and that of the missense variant p.(Pro133Leu) revealed that SLC35D1 acts as a general UDP-sugar transporter and that the p.(Pro133Leu) mutation resulted in a significant decrease in transport activity. The reduced transport activity observed for p.(Pro133Leu) was contrasted with in vitro activity for SLC35D1 p.(Thr65Pro), the loss-of-function mutation was associated with Schneckenbecken dysplasia. The functional classification of SLC35D1 as a general nucleotide sugar transporter of the endoplasmic reticulum suggests an expanded role for this transporter beyond chondroitin sulfate biosynthesis to a variety of important glycosylation reactions occurring in the endoplasmic reticulum., (© The Author(s) 2019. Published by Oxford University Press.)

Published
2019
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