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1. Variants in ZFX are associated with an X-linked neurodevelopmental disorder with recurrent facial gestalt

Author

Shepherdson, James L., Hutchison, Katie, Don, Dilan Wellalage, McGillivray, George, Choi, Tae-Ik, Allan, Carolyn A., Amor, David J., Banka, Siddharth, Basel, Donald G., Buch, Laura D., Carere, Deanna Alexis, Carroll, Renée, Clayton-Smith, Jill, Crawford, Ali, Dunø, Morten, Faivre, Laurence, Gilfillan, Christopher P., Gold, Nina B., Gripp, Karen W., Hobson, Emma, Holtz, Alexander M., Innes, A. Micheil, Isidor, Bertrand, Jackson, Adam, Katsonis, Panagiotis, Amel Riazat Kesh, Leila, Küry, Sébastien, Lecoquierre, François, Lockhart, Paul, Maraval, Julien, Matsumoto, Naomichi, McCarrier, Julie, McCarthy, Josephine, Miyake, Noriko, Moey, Lip Hen, Németh, Andrea H., Østergaard, Elsebet, Patel, Rushina, Pope, Kate, Posey, Jennifer E., Schnur, Rhonda E., Shaw, Marie, Stolerman, Elliot, Taylor, Julie P., Wadman, Erin, Wakeling, Emma, White, Susan M., Wong, Lawrence C., Lupski, James R., Lichtarge, Olivier, Corbett, Mark A., Gecz, Jozef, Nicolet, Charles M., Farnham, Peggy J., Kim, Cheol-Hee, and Shinawi, Marwan

Published
2024
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2. Assortative mating and parental genetic relatedness contribute to the pathogenicity of variably expressive variants

Author

Smolen, Corrine, Jensen, Matthew, Dyer, Lisa, Pizzo, Lucilla, Tyryshkina, Anastasia, Banerjee, Deepro, Rohan, Laura, Huber, Emily, El Khattabi, Laila, Prontera, Paolo, Caberg, Jean-Hubert, Van Dijck, Anke, Schwartz, Charles, Faivre, Laurence, Callier, Patrick, Mosca-Boidron, Anne-Laure, Lefebvre, Mathilde, Pope, Kate, Snell, Penny, Lockhart, Paul J., Castiglia, Lucia, Galesi, Ornella, Avola, Emanuela, Mattina, Teresa, Fichera, Marco, Luana Mandarà, Giuseppa Maria, Bruccheri, Maria Grazia, Pichon, Olivier, Le Caignec, Cedric, Stoeva, Radka, Cuinat, Silvestre, Mercier, Sandra, Bénéteau, Claire, Blesson, Sophie, Nordsletten, Ashley, Martin-Coignard, Dominique, Sistermans, Erik, Kooy, R. Frank, Amor, David J., Romano, Corrado, Isidor, Bertrand, Juusola, Jane, and Girirajan, Santhosh

Published
2023
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3. Bioinformatics-Based Identification of Expanded Repeats: A Non-reference Intronic Pentamer Expansion in RFC1 Causes CANVAS.

Author

Rafehi, Haloom, Szmulewicz, David, Bennett, Mark, Sobreira, Nara, Pope, Kate, Smith, Katherine, Gillies, Greta, Diakumis, Peter, Dolzhenko, Egor, Eberle, Michael, Barcina, María, Breen, David, Chancellor, Andrew, Cremer, Phillip, Delatycki, Martin, Fogel, Brent, Hackett, Anna, Halmagyi, G, Kapetanovic, Solange, Lang, Anthony, Mossman, Stuart, Mu, Weiyi, Patrikios, Peter, Perlman, Susan, Rosemergy, Ian, Storey, Elsdon, Watson, Shaun, Wilson, Michael, Zee, David, Valle, David, Amor, David, Bahlo, Melanie, and Lockhart, Paul

Subjects
CANVAS, ataxia, repeat expansions, short tandem repeats, whole-genome sequencing, Algorithms, Cerebellar Ataxia, Cohort Studies, Computational Biology, Family, Female, Genomics, Humans, Introns, Male, Microsatellite Repeats, Middle Aged, Polyneuropathies, Replication Protein C, Sensation Disorders, Syndrome, Vestibular Diseases, Whole Genome Sequencing
Abstract

Genomic technologies such as next-generation sequencing (NGS) are revolutionizing molecular diagnostics and clinical medicine. However, these approaches have proven inefficient at identifying pathogenic repeat expansions. Here, we apply a collection of bioinformatics tools that can be utilized to identify either known or novel expanded repeat sequences in NGS data. We performed genetic studies of a cohort of 35 individuals from 22 families with a clinical diagnosis of cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome (CANVAS). Analysis of whole-genome sequence (WGS) data with five independent algorithms identified a recessively inherited intronic repeat expansion [(AAGGG)exp] in the gene encoding Replication Factor C1 (RFC1). This motif, not reported in the reference sequence, localized to an Alu element and replaced the reference (AAAAG)11 short tandem repeat. Genetic analyses confirmed the pathogenic expansion in 18 of 22 CANVAS-affected families and identified a core ancestral haplotype, estimated to have arisen in Europe more than twenty-five thousand years ago. WGS of the four RFC1-negative CANVAS-affected families identified plausible variants in three, with genomic re-diagnosis of SCA3, spastic ataxia of the Charlevoix-Saguenay type, and SCA45. This study identified the genetic basis of CANVAS and demonstrated that these improved bioinformatics tools increase the diagnostic utility of WGS to determine the genetic basis of a heterogeneous group of clinically overlapping neurogenetic disorders.

Published
2019

4. Mutations in DCC cause isolated agenesis of the corpus callosum with incomplete penetrance

Author

Marsh, Ashley PL, Heron, Delphine, Edwards, Timothy J, Quartier, Angélique, Galea, Charles, Nava, Caroline, Rastetter, Agnès, Moutard, Marie-Laure, Anderson, Vicki, Bitoun, Pierre, Bunt, Jens, Faudet, Anne, Garel, Catherine, Gillies, Greta, Gobius, Ilan, Guegan, Justine, Heide, Solveig, Keren, Boris, Lesne, Fabien, Lukic, Vesna, Mandelstam, Simone A, McGillivray, George, McIlroy, Alissandra, Méneret, Aurélie, Mignot, Cyril, Morcom, Laura R, Odent, Sylvie, Paolino, Annalisa, Pope, Kate, Riant, Florence, Robinson, Gail A, Spencer-Smith, Megan, Srour, Myriam, Stephenson, Sarah EM, Tankard, Rick, Trouillard, Oriane, Welniarz, Quentin, Wood, Amanda, Brice, Alexis, Rouleau, Guy, Attié-Bitach, Tania, Delatycki, Martin B, Mandel, Jean-Louis, Amor, David J, Roze, Emmanuel, Piton, Amélie, Bahlo, Melanie, Billette de Villemeur, Thierry, Sherr, Elliott H, Leventer, Richard J, Richards, Linda J, Lockhart, Paul J, and Depienne, Christel

Subjects
Biological Sciences, Genetics, Clinical Research, Pediatric, Abnormalities, Multiple, Agenesis of Corpus Callosum, Brain, Corpus Callosum, DCC Receptor, Developmental Disabilities, Family, Female, Humans, Male, Mutation, Nervous System Malformations, Neural Stem Cells, Penetrance, Phenotype, Receptors, Cell Surface, Tumor Suppressor Proteins, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract

Brain malformations involving the corpus callosum are common in children with developmental disabilities. We identified DCC mutations in four families and five sporadic individuals with isolated agenesis of the corpus callosum (ACC) without intellectual disability. DCC mutations result in variable dominant phenotypes with decreased penetrance, including mirror movements and ACC associated with a favorable developmental prognosis. Possible phenotypic modifiers include the type and location of mutation and the sex of the individual.

Published
2017

5. Diagnostic utility of exome sequencing followed by research reanalysis in human brain malformations

Author

Kooshavar, Daniz, primary, Amor, David J, additional, Boggs, Kirsten, additional, Baker, Naomi, additional, Barnett, Christopher, additional, de Silva, Michelle G, additional, Edwards, Samantha, additional, Fahey, Michael C, additional, Marum, Justine E, additional, Snell, Penny, additional, Bozaoglu, Kiymet, additional, Pope, Kate, additional, Mohammad, Shekeeb S, additional, Riney, Kate, additional, Sachdev, Rani, additional, Scheffer, Ingrid E, additional, Schenscher, Sarah, additional, Silberstein, John, additional, Smith, Nicholas, additional, Tom, Melanie, additional, Ware, Tyson L, additional, Lockhart, Paul J, additional, and Leventer, Richard J, additional

Published
2024
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6. Loss of function of SLC25A46 causes lethal congenital pontocerebellar hypoplasia.

Author

Wan, Jijun, Steffen, Janos, Yourshaw, Michael, Mamsa, Hafsa, Andersen, Erik, Rudnik-Schöneborn, Sabine, Pope, Kate, Howell, Katherine B, McLean, Catriona A, Kornberg, Andrew J, Joseph, Jörg, Lockhart, Paul J, Zerres, Klaus, Ryan, Monique M, Nelson, Stanley F, Koehler, Carla M, and Jen, Joanna C

Subjects
Biomedical and Clinical Sciences, Neurosciences, Genetics, Pediatric, Orphan Drug, Neurodegenerative, Rare Diseases, Brain Disorders, Congenital Structural Anomalies, Aetiology, 2.1 Biological and endogenous factors, Neurological, Amino Acids, Animals, Animals, Genetically Modified, Brain, Cell Line, Transformed, Cells, Cultured, Cerebellar Diseases, Cohort Studies, Embryo, Nonmammalian, Female, Genetic Predisposition to Disease, Humans, Infant, Magnetic Resonance Imaging, Male, Mitochondria, Mitochondrial Dynamics, Mitochondrial Proteins, Models, Molecular, Mutation, Phosphate Transport Proteins, Polymorphism, Single Nucleotide, Zebrafish, pontocerebellar hypoplasia, SLC25A46, mitochondria, optic atrophy spectrum disorder, Medical and Health Sciences, Psychology and Cognitive Sciences, Neurology & Neurosurgery, Biomedical and clinical sciences, Health sciences, Psychology
Abstract

Disturbed mitochondrial fusion and fission have been linked to various neurodegenerative disorders. In siblings from two unrelated families who died soon after birth with a profound neurodevelopmental disorder characterized by pontocerebellar hypoplasia and apnoea, we discovered a missense mutation and an exonic deletion in the SLC25A46 gene encoding a mitochondrial protein recently implicated in optic atrophy spectrum disorder. We performed functional studies that confirmed the mitochondrial localization and pro-fission properties of SLC25A46. Knockdown of slc24a46 expression in zebrafish embryos caused brain malformation, spinal motor neuron loss, and poor motility. At the cellular level, we observed abnormally elongated mitochondria, which was rescued by co-injection of the wild-type but not the mutant slc25a46 mRNA. Conversely, overexpression of the wild-type protein led to mitochondrial fragmentation and disruption of the mitochondrial network. In contrast to mutations causing non-lethal optic atrophy, missense mutations causing lethal congenital pontocerebellar hypoplasia markedly destabilize the protein. Indeed, the clinical severity appears inversely correlated with the relative stability of the mutant protein. This genotype-phenotype correlation underscores the importance of SLC25A46 and fine tuning of mitochondrial fission and fusion in pontocerebellar hypoplasia and central neurodevelopment in addition to optic and peripheral neuropathy across the life span.

Published
2016

7. Genetic abnormalities in a large cohort of Coffin–Siris syndrome patients

Author

Sekiguchi, Futoshi, Tsurusaki, Yoshinori, Okamoto, Nobuhiko, Teik, Keng Wee, Mizuno, Seiji, Suzumura, Hiroshi, Isidor, Bertrand, Ong, Winnie Peitee, Haniffa, Muzhirah, White, Susan M., Matsuo, Mari, Saito, Kayoko, Phadke, Shubha, Kosho, Tomoki, Yap, Patrick, Goyal, Manisha, Clarke, Lorne A., Sachdev, Rani, McGillivray, George, Leventer, Richard J., Patel, Chirag, Yamagata, Takanori, Osaka, Hitoshi, Hisaeda, Yoshiya, Ohashi, Hirofumi, Shimizu, Kenji, Nagasaki, Keisuke, Hamada, Junpei, Dateki, Sumito, Sato, Takashi, Chinen, Yasutsugu, Awaya, Tomonari, Kato, Takeo, Iwanaga, Kougoro, Kawai, Masahiko, Matsuoka, Takashi, Shimoji, Yoshikazu, Tan, Tiong Yang, Kapoor, Seema, Gregersen, Nerine, Rossi, Massimiliano, Marie-Laure, Mathieu, McGregor, Lesley, Oishi, Kimihiko, Mehta, Lakshmi, Gillies, Greta, Lockhart, Paul J., Pope, Kate, Shukla, Anju, Girisha, Katta Mohan, Abdel-Salam, Ghada M. H., Mowat, David, Coman, David, Kim, Ok Hwa, Cordier, Marie-Pierre, Gibson, Kate, Milunsky, Jeff, Liebelt, Jan, Cox, Helen, El Chehadeh, Salima, Toutain, Annick, Saida, Ken, Aoi, Hiromi, Minase, Gaku, Tsuchida, Naomi, Iwama, Kazuhiro, Uchiyama, Yuri, Suzuki, Toshifumi, Hamanaka, Kohei, Azuma, Yoshiteru, Fujita, Atsushi, Imagawa, Eri, Koshimizu, Eriko, Takata, Atsushi, Mitsuhashi, Satomi, Miyatake, Satoko, Mizuguchi, Takeshi, Miyake, Noriko, and Matsumoto, Naomichi

Published
2019
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8. The phenotype of Floating-Harbor syndrome: clinical characterization of 52 individuals with mutations in exon 34 of SRCAP

Author

Nikkel, Sarah M, Dauber, Andrew, de Munnik, Sonja, Connolly, Meghan, Hood, Rebecca L, Caluseriu, Oana, Hurst, Jane, Kini, Usha, Nowaczyk, Malgorzata J M, Afenjar, Alexandra, Albrecht, Beate, Allanson, Judith E, Balestri, Paolo, Ben-Omran, Tawfeg, Brancati, Francesco, Cordeiro, Isabel, da Cunha, Bruna Santos, Delaney, Louisa A, Destrée, Anne, Fitzpatrick, David, Forzano, Francesca, Ghali, Neeti, Gillies, Greta, Harwood, Katerina, Hendriks, Yvonne M C, Héron, Delphine, Hoischen, Alexander, Honey, Engela Magdalena, Hoefsloot, Lies H, Ibrahim, Jennifer, Jacob, Claire M, Kant, Sarina G, Kim, Chong Ae, Kirk, Edwin P, Knoers, Nine V A M, Lacombe, Didier, Lee, Chung, Lo, Ivan F M, Lucas, Luiza S, Mari, Francesca, Mericq, Veronica, Moilanen, Jukka S, Møller, Sanne Traasdahl, Moortgat, Stephanie, Pilz, Daniela T, Pope, Kate, Price, Susan, Renieri, Alessandra, Sá, Joaquim, Schoots, Jeroen, Silveira, Elizabeth L, Simon, Marleen E H, Slavotinek, Anne, Temple, I Karen, van der Burgt, Ineke, de Vries, Bert B A, Weisfeld-Adams, James D, Whiteford, Margo L, Wierczorek, Dagmar, Wit, Jan M, Yee, Connie Fung On, Beaulieu, Chandree L, cpgdsconsortium@cheo.on.ca, White, Sue M, Bulman, Dennis E, Bongers, Ernie, Brunner, Han, Feingold, Murray, and Boycott, Kym M

Abstract

Abstract Background Floating-Harbor syndrome (FHS) is a rare condition characterized by short stature, delays in expressive language, and a distinctive facial appearance. Recently, heterozygous truncating mutations in SRCAP were determined to be disease-causing. With the availability of a DNA based confirmatory test, we set forth to define the clinical features of this syndrome. Methods and results Clinical information on fifty-two individuals with SRCAP mutations was collected using standardized questionnaires. Twenty-four males and twenty-eight females were studied with ages ranging from 2 to 52 years. The facial phenotype and expressive language impairments were defining features within the group. Height measurements were typically between minus two and minus four standard deviations, with occipitofrontal circumferences usually within the average range. Thirty-three of the subjects (63%) had at least one major anomaly requiring medical intervention. We did not observe any specific phenotype-genotype correlations. Conclusions This large cohort of individuals with molecularly confirmed FHS has allowed us to better delineate the clinical features of this rare but classic genetic syndrome, thereby facilitating the development of management protocols.

Published
2013

9. Rare variants in the genetic background modulate cognitive and developmental phenotypes in individuals carrying disease-associated variants

Author

Pizzo, Lucilla, Jensen, Matthew, Polyak, Andrew, Rosenfeld, Jill A., Mannik, Katrin, Krishnan, Arjun, McCready, Elizabeth, Pichon, Olivier, Le Caignec, Cedric, Van Dijck, Anke, Pope, Kate, Voorhoeve, Els, Yoon, Jieun, Stankiewicz, Paweł, Cheung, Sau Wai, Pazuchanics, Damian, Huber, Emily, Kumar, Vijay, Kember, Rachel L., Mari, Francesca, Curró, Aurora, Castiglia, Lucia, Galesi, Ornella, Avola, Emanuela, Mattina, Teresa, Fichera, Marco, Mandarà, Luana, Vincent, Marie, Nizon, Mathilde, Mercier, Sandra, Bénéteau, Claire, Blesson, Sophie, Martin-Coignard, Dominique, Mosca-Boidron, Anne-Laure, Caberg, Jean-Hubert, Bucan, Maja, Zeesman, Susan, Nowaczyk, Małgorzata J. M., Lefebvre, Mathilde, Faivre, Laurence, Callier, Patrick, Skinner, Cindy, Keren, Boris, Perrine, Charles, Prontera, Paolo, Marle, Nathalie, Renieri, Alessandra, Reymond, Alexandre, Kooy, R. Frank, Isidor, Bertrand, Schwartz, Charles, Romano, Corrado, Sistermans, Erik, Amor, David J., Andrieux, Joris, and Girirajan, Santhosh

Published
2019
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10. An intronic GAA repeat expansion in FGF14 causes the autosomal-dominant adult-onset ataxia SCA27B/ATX-FGF14

Author

Rafehi, Haloom, primary, Read, Justin, additional, Szmulewicz, David J., additional, Davies, Kayli C., additional, Snell, Penny, additional, Fearnley, Liam G., additional, Scott, Liam, additional, Thomsen, Mirja, additional, Gillies, Greta, additional, Pope, Kate, additional, Bennett, Mark F., additional, Munro, Jacob E., additional, Ngo, Kathie J., additional, Chen, Luke, additional, Wallis, Mathew J., additional, Butler, Ernest G., additional, Kumar, Kishore R., additional, Wu, Kathy HC., additional, Tomlinson, Susan E., additional, Tisch, Stephen, additional, Malhotra, Abhishek, additional, Lee-Archer, Matthew, additional, Dolzhenko, Egor, additional, Eberle, Michael A., additional, Roberts, Leslie J., additional, Fogel, Brent L., additional, Brüggemann, Norbert, additional, Lohmann, Katja, additional, Delatycki, Martin B., additional, Bahlo, Melanie, additional, and Lockhart, Paul J., additional

Published
2023
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12. Assortative mating and parental genetic relatedness drive the pathogenicity of variably expressive variants

Author

Smolen, Corrine, primary, Jensen, Matthew, additional, Dyer, Lisa, additional, Pizzo, Lucilla, additional, Tyryshkina, Anastasia, additional, Banerjee, Deepro, additional, Rohan, Laura, additional, Huber, Emily, additional, El Khattabi, Laila, additional, Prontera, Paolo, additional, Caberg, Jean-Hubert, additional, Van Dijck, Anke, additional, Schwartz, Charles, additional, Faivre, Laurence, additional, Callier, Patrick, additional, Mosca-Boidron, Anne-Laure, additional, Lefebvre, Mathilde, additional, Pope, Kate, additional, Snell, Penny, additional, Lockhart, Paul J., additional, Castiglia, Lucia, additional, Galesi, Ornella, additional, Avola, Emanuela, additional, Mattina, Teresa, additional, Fichera, Marco, additional, Luana Mandara, Giuseppa Maria, additional, Grazia Bruccheri, Maria, additional, Pichon, Olivier, additional, Le Caignec, Cedric, additional, Stoeva, Radka, additional, Cuinat, Silvestre, additional, Mercier, Sandra, additional, Beneteau, Claire, additional, Blesson, Sophie, additional, Nordsletten, Ashley, additional, Martin-Coignard, Dominique, additional, Sistermans, Erik, additional, Kooy, R. Frank, additional, Amor, David J., additional, Romano, Corrado, additional, Isidor, Bertrand, additional, Juusola, Jane, additional, and Girirajan, Santhosh, additional

Published
2023
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13. Somatic GNAQ mutation in the forme fruste of Sturge-Weber syndrome

Author

Hildebrand, Michael S., Harvey, A. Simon, Malone, Stephen, Damiano, John A., Do, Hongdo, Ye, Zimeng, McQuillan, Lara, Maixner, Wirginia, Kalnins, Renate, Nolan, Bernadette, Wood, Martin, Ozturk, Ezgi, Jones, Nigel C., Gillies, Greta, Pope, Kate, Lockhart, Paul J., Dobrovic, Alexander, Leventer, Richard J., Scheffer, Ingrid E., and Berkovic, Samuel F.

Published
2018
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14. Somatic GNAQ mutation in the forme fruste of Sturge-Weber syndrome

Author

Hildebrand, Michael S, Harvey, A Simon, Malone, Stephen, Damiano, John A, Do, Hongdo, Ye, Zimeng, McQuillan, Lara, Maixner, Wirginia, Kalnins, Renate, Nolan, Bernadette, Wood, Martin, Ozturk, Ezgi, Jones, Nigel C, Gillies, Greta, Pope, Kate, Lockhart, Paul J, Dobrovic, Alexander, Leventer, Richard J, Scheffer, Ingrid E, and Berkovic, Samuel F

Subjects
Uncategorized
Abstract

Objective: To determine whether the GNAQ R183Q mutation is present in the forme fruste cases of Sturge-Weber syndrome (SWS) to establish a definitive molecular diagnosis. Methods: We used sensitive droplet digital PCR (ddPCR) to detect and quantify the GNAQ mutation in tissues from epilepsy surgery in 4 patients with leptomeningeal angiomatosis; none had ocular or cutaneous manifestations. Results: Low levels of the GNAQ mutation were detected in the brain tissue of all 4 cases - ranging from 0.42% to 7.1% frequency - but not in blood-derived DNA. Molecular evaluation confirmed the diagnosis in 1 case in which the radiologic and pathologic data were equivocal. Conclusions: We detected the mutation at low levels, consistent with mosaicism in the brain or skin (1.0%-18.1%) of classic cases. Our data confirm that the forme fruste is part of the spectrum of SWS, with the same molecular mechanism as the classic disease and that ddPCR is helpful where conventional diagnosis is uncertain.

Published
2023
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15. An intronic GAA repeat expansion in FGF14 causes the autosomal-dominant adult-onset ataxia SCA50/ATX-FGF14

Author

Rafehi, Haloom, Read, Justin, Szmulewicz, David J., Davies, Kayli C., Snell, Penny, Fearnley, Liam G., Scott, Liam, Thomsen, Mirja, Gillies, Greta, Pope, Kate, Bennett, Mark F., Munro, Jacob E., Ngo, Kathie J., Chen, Luke, Wallis, Mathew J., Butler, Ernest G., Kumar, Kishore R., Wu, Kathy HC., Tomlinson, Susan E., Tisch, Stephen, Malhotra, Abhishek, Lee-Archer, Matthew, Dolzhenko, Egor, Eberle, Michael A., Roberts, Leslie J., Fogel, Brent L., Brüggemann, Norbert, Lohmann, Katja, Delatycki, Martin B., Bahlo, Melanie, and Lockhart, Paul J.

Subjects
Article
Abstract

Adult-onset cerebellar ataxias are a group of neurodegenerative conditions that challenge both genetic discovery and molecular diagnosis. In this study, we identified an intronic (GAA) repeat expansion in fibroblast growth factor 14 (FGF14). Genetic analysis of 95 Australian individuals with adult-onset ataxia identified four (4.2%) with (GAA)(>300) and a further nine individuals with (GAA)(>250). PCR and long-read sequence analysis revealed these were pure (GAA) repeats. In comparison, no control subjects had (GAA)(>300) and only 2/311 control individuals (0.6%) had a pure (GAA)(>250). In a German validation cohort, 9/104 (8.7%) of affected individuals had (GAA)(>335) and a further six had (GAA)(>250), whereas 10/190 (5.3%) control subjects had (GAA)(>250) but none were (GAA)(>335). The combined data suggest (GAA)(>335) are disease causing and fully penetrant (p = 6.0 × 10(−8), OR = 72 [95% CI = 4.3–1,227]), while (GAA)(>250) is likely pathogenic with reduced penetrance. Affected individuals had an adult-onset, slowly progressive cerebellar ataxia with variable features including vestibular impairment, hyper-reflexia, and autonomic dysfunction. A negative correlation between age at onset and repeat length was observed (R(2) = 0.44, p = 0.00045, slope = −0.12) and identification of a shared haplotype in a minority of individuals suggests that the expansion can be inherited or generated de novo during meiotic division. This study demonstrates the power of genome sequencing and advanced bioinformatic tools to identify novel repeat expansions via model-free, genome-wide analysis and identifies SCA50/ATX-FGF14 as a frequent cause of adult-onset ataxia.

Published
2022

16. A novel intronic GAA repeat expansion inFGF14causes autosomal dominant adult-onset ataxia (SCA50, ATX-FGF14)

Author

Rafehi, Haloom, primary, Read, Justin, additional, Szmulewicz, David J, additional, Davies, Kayli C., additional, Snell, Penny, additional, Fearnley, Liam G, additional, Scott, Liam, additional, Thomsen, Mirja, additional, Gillies, Greta, additional, Pope, Kate, additional, Bennett, Mark F, additional, Munro, Jacob E, additional, Ngo, Kathie J., additional, Chen, Luke, additional, Wallis, Mathew J, additional, Butler, Ernest G, additional, Kumar, Kishore R, additional, Wu, Kathy HC, additional, Tomlinson, Susan E, additional, Tisch, Stephen, additional, Malhotra, Abhishek, additional, Lee-Archer, Matthew, additional, Dolzhenko, Egor, additional, Eberle, Michael A., additional, Roberts, Leslie J, additional, Fogel, Brent L, additional, Brüggemann, Norbert, additional, Lohmann, Katja, additional, Delatycki, Martin B., additional, Bahlo, Melanie, additional, and Lockhart, Paul J, additional

Published
2022
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18. Familial cortical dysplasia caused by mutation in the mammalian target of rapamycin regulator NPRL3

Author

Sim, Joe C., Scerri, Thomas, Fanjul-Fernández, Miriam, Riseley, Jessica R., Gillies, Greta, Pope, Kate, van Roozendaal, Hanna, Heng, Julian I., Mandelstam, Simone A., McGillivray, George, MacGregor, Duncan, Kannan, Lakshminarayanan, Maixner, Wirginia, Harvey, Simon A., Amor, David J., Delatycki, Martin B., Crino, Peter B., Bahlo, Melanie, Lockhart, Paul J., and Leventer, Richard J.

Published
2016
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21. One-Stage, Limited-Resection Epilepsy Surgery for Bottom-of-Sulcus Dysplasia

Author

Macdonald-Laurs, Emma, primary, Maixner, Wirginia J., additional, Bailey, Catherine A., additional, Barton, Sarah M., additional, Mandelstam, Simone A., additional, Yuan-Mou Yang, Joseph, additional, Warren, Aaron E.L., additional, Kean, Michael J., additional, Francis, Peter, additional, MacGregor, Duncan, additional, D'Arcy, Colleen, additional, Wrennall, Jacquie A., additional, Davidson, Andrew, additional, Pope, Kate, additional, Leventer, Richard J., additional, Freeman, Jeremy L., additional, Wray, Alison, additional, Jackson, Graeme D., additional, and Harvey, A. Simon, additional

Published
2021
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22. The relevance of deep genomic analyses in families with variably expressive CNVs in the era of personalized medicine

Author

Pizzo, Lucilla, primary, Jensen, Matthew, additional, Tyryshkina, Anastasia, additional, Smolen, Corrine, additional, Taylor, Cora, additional, Rohan, Laura, additional, Huber, Emily, additional, Snell, Penny, additional, Pope, Kate, additional, Pounraja, Vijay Kumar, additional, Rosenfeld, Jill, additional, McCready, Elizabeth, additional, Zeesman, Susan, additional, Nowaczyk, Małgorzata, additional, Schwartz, Charles, additional, Keren, Boris, additional, Perrine, Charles, additional, Prontera, Paolo, additional, Van Dijck, Anke, additional, Kooy, Frank, additional, Caberg, Jean-Hubert, additional, Voorhoeve, Els, additional, Banka, Siddharth, additional, Sistermans, Erik, additional, Marle, Nathalie, additional, Renieri, Alessandra, additional, Martin-Coignard, Dominique, additional, Isidor, Bertrand, additional, Reymond, Alexandre, additional, Mannik, Katrin, additional, Andrieux, Joris, additional, Amor, David, additional, Romano, Corrado, additional, and Girirajan, Santhosh, additional

Published
2021
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24. Cerebrospinal fluid liquid biopsy for detecting somatic mosaicism in brain

Author

Ye, Zimeng, primary, Chatterton, Zac, additional, Pflueger, Jahnvi, additional, Damiano, John A, additional, McQuillan, Lara, additional, Simon Harvey, A, additional, Malone, Stephen, additional, Do, Hongdo, additional, Maixner, Wirginia, additional, Schneider, Amy, additional, Nolan, Bernadette, additional, Wood, Martin, additional, Lee, Wei Shern, additional, Gillies, Greta, additional, Pope, Kate, additional, Wilson, Michael, additional, Lockhart, Paul J, additional, Dobrovic, Alexander, additional, Scheffer, Ingrid E, additional, Bahlo, Melanie, additional, Leventer, Richard J, additional, Lister, Ryan, additional, Berkovic, Samuel F, additional, and Hildebrand, Michael S, additional

Published
2021
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27. Pathogenic variants in nucleoporin TPR (translocated promoter region, nuclear basket protein) cause severe intellectual disability in humans.

Author

Bergen, Nicole J Van, Bell, Katrina M, Carey, Kirsty, Gear, Russell, Massey, Sean, Murrell, Edward K, Gallacher, Lyndon, Pope, Kate, Lockhart, Paul J, Kornberg, Andrew, Pais, Lynn, Walkiewicz, Marzena, Simons, Cas, Flagship, MCRI Rare Diseases, Wickramasinghe, Vihandha O, White, Susan M, and Christodoulou, John

Published
2022
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29. Generation of seven iPSC lines from peripheral blood mononuclear cells suitable to investigate Autism Spectrum Disorder

Author

Bozaoglu, Kiymet, primary, Gao, Yujing, additional, Stanley, Edouard, additional, Fanjul-Fernández, Miriam, additional, Brown, Natasha J., additional, Pope, Kate, additional, Green, Cherie C., additional, Vlahos, Katerina, additional, Sourris, Koula, additional, Bahlo, Melanie, additional, Delatycki, Martin, additional, Scheffer, Ingrid, additional, and Lockhart, Paul J., additional

Published
2019
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30. Second‐hit DEPDC5 mutation is limited to dysmorphic neurons in cortical dysplasia type IIA

Author

Lee, Wei Shern, primary, Stephenson, Sarah E. M., additional, Howell, Katherine B., additional, Pope, Kate, additional, Gillies, Greta, additional, Wray, Alison, additional, Maixner, Wirginia, additional, Mandelstam, Simone A., additional, Berkovic, Samuel F., additional, Scheffer, Ingrid E., additional, MacGregor, Duncan, additional, Harvey, Anthony Simon, additional, Lockhart, Paul J., additional, and Leventer, Richard J., additional

Published
2019
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31. Validation of new bioinformatic tools to identify expanded repeats: a non-reference intronic pentamer expansion inRFC1causes CANVAS

Author

Rafehi, Haloom, primary, Szmulewicz, David J, additional, Bennett, Mark F, additional, Sobreira, Nara LM, additional, Pope, Kate, additional, Smith, Katherine R, additional, Gillies, Greta, additional, Diakumis, Peter, additional, Dolzhenko, Egor, additional, Eberle, Michael A, additional, Barcina, María García, additional, Breen, David P, additional, Chancellor, Andrew M, additional, Cremer, Phillip D, additional, Delatycki, Martin B., additional, Fogel, Brent L, additional, Hackett, Anna, additional, Halmagyi, G. Michael, additional, Kapetanovic, Solange, additional, Lang, Anthony, additional, Mossman, Stuart, additional, Mu, Weiyi, additional, Patrikios, Peter, additional, Perlman, Susan L, additional, Rosemargy, Ian, additional, Storey, Elsdon, additional, Watson, Shaun RD, additional, Wilson, Michael A, additional, Zee, David, additional, Valle, David, additional, Amor, David J, additional, Bahlo, Melanie, additional, and Lockhart, Paul J, additional

Published
2019
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32. ‘Staying strong on the inside and outside’ to keep walking and moving around: Perspectives from Aboriginal people with Machado Joseph Disease and their families from the Groote Eylandt Archipelago, Australia

Author

Carr, Jennifer J., primary, Lalara, Joyce, additional, Lalara, Gayangwa, additional, O’Hare, Gloria, additional, Massey, Libby, additional, Kenny, Nick, additional, Pope, Kate E., additional, Clough, Alan R., additional, Lowell, Anne, additional, and Barker, Ruth N., additional

Published
2019
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33. Rapid Diagnosis of Spinocerebellar Ataxia 36 in a Three-Generation Family Using Short-Read Whole-Genome Sequencing Data.

Author

Rafehi, Haloom, Szmulewicz, David J., Pope, Kate, Wallis, Mathew, Christodoulou, John, White, Susan M., Delatycki, Martin B., Lockhart, Paul J., and Bahlo, Melanie

Subjects
RESEARCH, DNA, RESEARCH methodology, MEDICAL cooperation, EVALUATION research, COMPARATIVE studies, SPINOCEREBELLAR ataxia, GENETIC techniques, GENEALOGY, ATAXIA
Abstract

Background: Spinocerebellar ataxias are often caused by expansions of short tandem repeats. Recent methodological advances have made repeat expansion (RE) detection with whole-genome sequencing (WGS) feasible.Objectives: The objective of this study was to determine the genetic basis of ataxia in a multigenerational Australian pedigree with autosomal-dominant inheritance.Methods and Results: WGS was performed on 3 affected relatives. The sequence data were screened for known pathogenic REs using 2 RE detection tools: exSTRa and ExpansionHunter. This screen provided a clear and rapid diagnosis (<5 days from receiving the sequencing data) of spinocerebellar ataxia 36, a rare form of ataxia caused by an intronic GGCCTG RE in NOP56.Conclusions: The diagnosis of rare ataxias caused by REs is highly feasible and cost-effective with WGS. We propose that WGS could potentially be implemented as the frontline, cost-effective methodology for the molecular testing of individuals with a clinical diagnosis of ataxia. © 2020 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Published
2020
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34. Rare variants in the genetic background modulate the expressivity of neurodevelopmental disorders

Author

Pizzo, Lucilla, primary, Jensen, Matthew, additional, Polyak, Andrew, additional, Rosenfeld, Jill A., additional, Mannik, Katrin, additional, Krishnan, Arjun, additional, McCready, Elizabeth, additional, Pichon, Olivier, additional, Le Caignec, Cedric, additional, Van Dijck, Anke, additional, Pope, Kate, additional, Voorhoeve, Els, additional, Yoon, Jieun, additional, Stankiewicz, Paweł, additional, Cheung, Sau Wai, additional, Pazuchanics, Damian, additional, Huber, Emily, additional, Kumar, Vijay, additional, Kember, Rachel, additional, Mari, Francesca, additional, Curró, Aurora, additional, Castiglia, Lucia, additional, Galesi, Ornella, additional, Avola, Emanuela, additional, Mattina, Teresa, additional, Fichera, Marco, additional, Mandarà, Luana, additional, Vincent, Marie, additional, Nizon, Mathilde, additional, Mercier, Sandra, additional, Bénéteau, Claire, additional, Blesson, Sophie, additional, Martin-Coignard, Dominique, additional, Mosca-Boidron, Anne-Laure, additional, Caberg, Jean-Hubert, additional, Bucan, Maja, additional, Zeesman, Susan, additional, Nowaczyk, Małgorzata J.M., additional, Lefebvre, Mathilde, additional, Faivre, Laurence, additional, Callier, Patrick, additional, Skinner, Cindy, additional, Keren, Boris, additional, Perrine, Charles, additional, Prontera, Paolo, additional, Marle, Nathalie, additional, Renieri, Alessandra, additional, Reymond, Alexandre, additional, Kooy, R Frank, additional, Isidor, Bertrand, additional, Schwartz, Charles, additional, Romano, Corrado, additional, Sistermans, Erik, additional, Amor, David J., additional, Andrieux, Joris, additional, and Girirajan, Santhosh, additional

Published
2018
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35. Mutations in DCC cause isolated agenesis of the corpus callosum with incomplete penetrance

Author

Marsh, Ashley P.L., Heron, Delphine, Edwards, Timothy J., Quartier, Angélique, Galea, Charles, Nava, Caroline, Rastetter, Agnès, Moutard, Marie-laure, Anderson, Vicki, Bitoun, Pierre, Bunt, Jens, Faudet, Anne, Garel, Catherine, Gillies, Greta, Gobius, Ilan, Guegan, Justine, Heide, Solveig, Keren, Boris, Lesne, Fabien, Lukic, Vesna, Mandelstam, Simone A., Mcgillivray, George, Mcilroy, Alissandra, Méneret, Aurélie, Mignot, Cyril, Morcom, Laura R., Odent, Sylvie, Paolino, Annalisa, Pope, Kate, Riant, Florence, Robinson, Gail A., Spencer-Smith, Megan, Srour, Myriam, Stephenson, Sarah E.M., Tankard, Rick, Trouillard, Oriane, Welniarz, Quentin, Wood, Amanda, Brice, Alexis, Rouleau, Guy, Attié-bitach, Tania, Delatycki, Martin B., Mandel, Jean-louis, Amor, David J., Roze, Emmanuel, Piton, Amélie, Bahlo, Melanie, Billette de Villemeur, Thierry, Sherr, Elliott H., Leventer, Richard J., Richards, Linda J., Lockhart, Paul J., Depienne, Christel, Marsh, Ashley P.L., Heron, Delphine, Edwards, Timothy J., Quartier, Angélique, Galea, Charles, Nava, Caroline, Rastetter, Agnès, Moutard, Marie-laure, Anderson, Vicki, Bitoun, Pierre, Bunt, Jens, Faudet, Anne, Garel, Catherine, Gillies, Greta, Gobius, Ilan, Guegan, Justine, Heide, Solveig, Keren, Boris, Lesne, Fabien, Lukic, Vesna, Mandelstam, Simone A., Mcgillivray, George, Mcilroy, Alissandra, Méneret, Aurélie, Mignot, Cyril, Morcom, Laura R., Odent, Sylvie, Paolino, Annalisa, Pope, Kate, Riant, Florence, Robinson, Gail A., Spencer-Smith, Megan, Srour, Myriam, Stephenson, Sarah E.M., Tankard, Rick, Trouillard, Oriane, Welniarz, Quentin, Wood, Amanda, Brice, Alexis, Rouleau, Guy, Attié-bitach, Tania, Delatycki, Martin B., Mandel, Jean-louis, Amor, David J., Roze, Emmanuel, Piton, Amélie, Bahlo, Melanie, Billette de Villemeur, Thierry, Sherr, Elliott H., Leventer, Richard J., Richards, Linda J., Lockhart, Paul J., and Depienne, Christel

Abstract

Brain malformations involving the corpus callosum are common in children with developmental disabilities. We identified DCC mutations in four families and five sporadic individuals with isolated agenesis of the corpus callosum (ACC) without intellectual disability. DCC mutations result in variable dominant phenotypes with decreased penetrance, including mirror movements and ACC associated with a favorable developmental prognosis. Possible phenotypic modifiers include the type and location of mutation and the sex of the individual.

Published
2017

36. Mutations in DCC cause isolated agenesis of the corpus callosum with incomplete penetrance.

Author

Marsh, Ashley, Marsh, Ashley, Heron, Delphine, Edwards, Timothy, Quartier, Angélique, Galea, Charles, Nava, Caroline, Rastetter, Agnès, Moutard, Marie-Laure, Anderson, Vicki, Bitoun, Pierre, Bunt, Jens, Faudet, Anne, Garel, Catherine, Gillies, Greta, Gobius, Ilan, Guegan, Justine, Heide, Solveig, Keren, Boris, Lesne, Fabien, Lukic, Vesna, Mandelstam, Simone, McGillivray, George, McIlroy, Alissandra, Méneret, Aurélie, Mignot, Cyril, Morcom, Laura, Odent, Sylvie, Paolino, Annalisa, Pope, Kate, Riant, Florence, Robinson, Gail, Spencer-Smith, Megan, Srour, Myriam, Stephenson, Sarah, Tankard, Rick, Trouillard, Oriane, Welniarz, Quentin, Wood, Amanda, Brice, Alexis, Rouleau, Guy, Attié-Bitach, Tania, Delatycki, Martin, Mandel, Jean-Louis, Amor, David, Roze, Emmanuel, Piton, Amélie, Bahlo, Melanie, Billette de Villemeur, Thierry, Leventer, Richard, Richards, Linda, Lockhart, Paul, Depienne, Christel, Sherr, Elliott, Marsh, Ashley, Marsh, Ashley, Heron, Delphine, Edwards, Timothy, Quartier, Angélique, Galea, Charles, Nava, Caroline, Rastetter, Agnès, Moutard, Marie-Laure, Anderson, Vicki, Bitoun, Pierre, Bunt, Jens, Faudet, Anne, Garel, Catherine, Gillies, Greta, Gobius, Ilan, Guegan, Justine, Heide, Solveig, Keren, Boris, Lesne, Fabien, Lukic, Vesna, Mandelstam, Simone, McGillivray, George, McIlroy, Alissandra, Méneret, Aurélie, Mignot, Cyril, Morcom, Laura, Odent, Sylvie, Paolino, Annalisa, Pope, Kate, Riant, Florence, Robinson, Gail, Spencer-Smith, Megan, Srour, Myriam, Stephenson, Sarah, Tankard, Rick, Trouillard, Oriane, Welniarz, Quentin, Wood, Amanda, Brice, Alexis, Rouleau, Guy, Attié-Bitach, Tania, Delatycki, Martin, Mandel, Jean-Louis, Amor, David, Roze, Emmanuel, Piton, Amélie, Bahlo, Melanie, Billette de Villemeur, Thierry, Leventer, Richard, Richards, Linda, Lockhart, Paul, Depienne, Christel, and Sherr, Elliott

Abstract

Brain malformations involving the corpus callosum are common in children with developmental disabilities. We identified DCC mutations in four families and five sporadic individuals with isolated agenesis of the corpus callosum (ACC) without intellectual disability. DCC mutations result in variable dominant phenotypes with decreased penetrance, including mirror movements and ACC associated with a favorable developmental prognosis. Possible phenotypic modifiers include the type and location of mutation and the sex of the individual.

Published
2017

38. Rasmussen encephalitis tissue transfer program

Author

Kruse, Carol A., primary, Pardo, Carlos A., additional, Hartman, Adam L., additional, Jallo, George, additional, Vining, Eileen P. G., additional, Voros, Joe, additional, Gaillard, William D., additional, Liu, Judy, additional, Oluigbo, Chima, additional, Malone, Stephen, additional, Bleasel, Andrew F., additional, Dexter, Mark, additional, Micati, Alex, additional, Velasco, Tonicarlo R., additional, Machado, Helio R., additional, Martino, Anthony M., additional, Huang, Adam, additional, Wheatley, B. M., additional, Grant, Gerald A., additional, Granata, Tiziana, additional, Freri, Elena, additional, Garbelli, Rita, additional, Koh, Sookyong, additional, Nordli, Douglas R., additional, Campos, Alexandre R., additional, O'Neill, Brent, additional, Handler, Michael H., additional, Chapman, Kevin E., additional, Wilfong, Angus A., additional, Curry, Daniel J., additional, Yaun, Amanda, additional, Madsen, Joseph R., additional, Smyth, Matthew D., additional, Mercer, Deanna, additional, Bingaman, William, additional, Harvey, A. S., additional, Leventer, Richard J., additional, Lockhart, Paul J., additional, Gillies, Greta, additional, Pope, Kate, additional, Giller, Cole A., additional, Park, Yong D., additional, Rojiani, Amyn M., additional, Sharma, Suash J., additional, Jenkins, Patrick, additional, Tung, Spencer, additional, Huynh, My N., additional, Chirwa, Thabiso W., additional, Cepeda, Carlos, additional, Levine, Michael S., additional, Chang, Julia W., additional, Owens, Geoffrey C., additional, Vinters, Harry V., additional, and Mathern, Gary W., additional

Published
2016
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39. The Cockayne Syndrome Natural History (CoSyNH) study: clinical findings in 102 individuals and recommendations for care

Author

Wilson, Brian T., primary, Stark, Zornitza, additional, Sutton, Ruth E., additional, Danda, Sumita, additional, Ekbote, Alka V., additional, Elsayed, Solaf M., additional, Gibson, Louise, additional, Goodship, Judith A., additional, Jackson, Andrew P., additional, Te Keng, Wee ik, additional, King, Mary D., additional, McCann, Emma, additional, Motojima, Toshino, additional, Murray, Jennifer E., additional, Omata, Taku, additional, Pilz, Daniela, additional, Pope, Kate, additional, Sugita, Katsuo, additional, White, Susan M., additional, and Wilson, Ian J., additional

Published
2016
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40. ALPK3-deficient cardiomyocytes generated from patient-derived induced pluripotent stem cells and mutant human embryonic stem cells display abnormal calcium handling and establish that ALPK3 deficiency underlies familial cardiomyopathy

Author

Phelan, Dean G., primary, Anderson, David J., additional, Howden, Sara E., additional, Wong, Raymond C.B., additional, Hickey, Peter F., additional, Pope, Kate, additional, Wilson, Gabrielle R., additional, Pébay, Alice, additional, Davis, Andrew M., additional, Petrou, Steven, additional, Elefanty, Andrew G., additional, Stanley, Edouard G., additional, James, Paul A., additional, Macciocca, Ivan, additional, Bahlo, Melanie, additional, Cheung, Michael M., additional, Amor, David J., additional, Elliott, David A., additional, and Lockhart, Paul J., additional

Published
2016
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41. Familial cortical dysplasia caused by mutation in the mammalian target of rapamycin regulatorNPRL3

Author

Sim, Joe C., primary, Scerri, Thomas, additional, Fanjul-Fernández, Miriam, additional, Riseley, Jessica R., additional, Gillies, Greta, additional, Pope, Kate, additional, van Roozendaal, Hanna, additional, Heng, Julian I., additional, Mandelstam, Simone A., additional, McGillivray, George, additional, MacGregor, Duncan, additional, Kannan, Lakshminarayanan, additional, Maixner, Wirginia, additional, Harvey, A. Simon, additional, Amor, David J., additional, Delatycki, Martin B., additional, Crino, Peter B., additional, Bahlo, Melanie, additional, Lockhart, Paul J., additional, and Leventer, Richard J., additional

Published
2015
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42. Complete callosal agenesis, pontocerebellar hypoplasia, and axonal neuropathy due to AMPD2 loss

Author

Marsh, Ashley P.L., primary, Lukic, Vesna, additional, Pope, Kate, additional, Bromhead, Catherine, additional, Tankard, Rick, additional, Ryan, Monique M., additional, Yiu, Eppie M., additional, Sim, Joe C.H., additional, Delatycki, Martin B., additional, Amor, David J., additional, McGillivray, George, additional, Sherr, Elliott H., additional, Bahlo, Melanie, additional, Leventer, Richard J., additional, and Lockhart, Paul J., additional

Published
2015
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43. Familial cortical dysplasia type IIA caused by a germline mutation inDEPDC 5

Author

Scerri, Thomas, primary, Riseley, Jessica R., additional, Gillies, Greta, additional, Pope, Kate, additional, Burgess, Rosemary, additional, Mandelstam, Simone A., additional, Dibbens, Leanne, additional, Chow, Chung W., additional, Maixner, Wirginia, additional, Harvey, Anthony Simon, additional, Jackson, Graeme D., additional, Amor, David J., additional, Delatycki, Martin B., additional, Crino, Peter B., additional, Berkovic, Samuel F., additional, Scheffer, Ingrid E., additional, Bahlo, Melanie, additional, Lockhart, Paul J., additional, and Leventer, Richard J., additional

Published
2015
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44. Mutations in SPRTN cause early onset hepatocellular carcinoma, genomic instability and progeroid features

Author

Lessel, Davor, Vaz, Bruno, Halder, Swagata, Lockhart, Paul J., Marinovic-Terzic, Ivana, Lopez-Mosqueda, Jaime, Philipp, Melanie, Sim, Joe C. H., Smith, Katherine R., Oehler, Judith, Cabrera, Elisa, Freire, Raimundo, Pope, Kate, Nahid, Amsha, Norris, Fiona, Leventer, Richard J., Delatycki, Martin B., Barbi, Gotthold, von Ameln, Simon, Hoegel, Josef, Degoricija, Marina, Fertig, Regina, Burkhalter, Martin D., Hofmann, Kay, Thiele, Holger, Altmueller, Janine, Nuernberg, Gudrun, Nuernberg, Peter, Bahlo, Melanie, Martin, George M., Aalfs, Cora M., Oshima, Junko, Terzic, Janos, Amor, David J., Dikic, Ivan, Ramadan, Kristijan, Kubisch, Christian, Lessel, Davor, Vaz, Bruno, Halder, Swagata, Lockhart, Paul J., Marinovic-Terzic, Ivana, Lopez-Mosqueda, Jaime, Philipp, Melanie, Sim, Joe C. H., Smith, Katherine R., Oehler, Judith, Cabrera, Elisa, Freire, Raimundo, Pope, Kate, Nahid, Amsha, Norris, Fiona, Leventer, Richard J., Delatycki, Martin B., Barbi, Gotthold, von Ameln, Simon, Hoegel, Josef, Degoricija, Marina, Fertig, Regina, Burkhalter, Martin D., Hofmann, Kay, Thiele, Holger, Altmueller, Janine, Nuernberg, Gudrun, Nuernberg, Peter, Bahlo, Melanie, Martin, George M., Aalfs, Cora M., Oshima, Junko, Terzic, Janos, Amor, David J., Dikic, Ivan, Ramadan, Kristijan, and Kubisch, Christian

Abstract

Age-related degenerative and malignant diseases represent major challenges for health care systems. Elucidation of the molecular mechanisms underlying carcinogenesis and age-associated pathologies is thus of growing biomedical relevance. We identified biallelic germline mutations in SPRTN (also called C1orf124 or DVC1)(1-7) in three patients from two unrelated families. All three patients are affected by a new segmental progeroid syndrome characterized by genomic instability and susceptibility toward early onset hepatocellular carcinoma. SPRTN was recently proposed to have a function in translesional DNA synthesis and the prevention of mutagenesis(1-7). Our in vivo and in vitro characterization of identified mutations has uncovered an essential role for SPRTN in the prevention of DNA replication stress during general DNA replication and in replication-related G2/M-checkpoint regulation. In addition to demonstrating the pathogenicity of identified SPRTN mutations, our findings provide a molecular explanation of how SPRTN dysfunction causes accelerated aging and susceptibility toward carcinoma.

Published
2014

45. Mutations in RAB39B Cause X-Linked Intellectual Disability and Early-Onset Parkinson Disease with α-Synuclein Pathology

Author

Wilson, Gabrielle R., primary, Sim, Joe C.H., additional, McLean, Catriona, additional, Giannandrea, Maila, additional, Galea, Charles A., additional, Riseley, Jessica R., additional, Stephenson, Sarah E.M., additional, Fitzpatrick, Elizabeth, additional, Haas, Stefan A., additional, Pope, Kate, additional, Hogan, Kirk J., additional, Gregg, Ronald G., additional, Bromhead, Catherine J., additional, Wargowski, David S., additional, Lawrence, Christopher H., additional, James, Paul A., additional, Churchyard, Andrew, additional, Gao, Yujing, additional, Phelan, Dean G., additional, Gillies, Greta, additional, Salce, Nicholas, additional, Stanford, Lynn, additional, Marsh, Ashley P.L., additional, Mignogna, Maria L., additional, Hayflick, Susan J., additional, Leventer, Richard J., additional, Delatycki, Martin B., additional, Mellick, George D., additional, Kalscheuer, Vera M., additional, D’Adamo, Patrizia, additional, Bahlo, Melanie, additional, Amor, David J., additional, and Lockhart, Paul J., additional

Published
2014
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46. Diagnostic and cost utility of whole exome sequencing in peripheral neuropathy.

Author

Walsh, Maie, Bell, Katrina M., Chong, Belinda, Creed, Emma, Brett, Gemma R., Pope, Kate, Thorne, Natalie P., Sadedin, Simon, Georgeson, Peter, Phelan, Dean G., Day, Timothy, Taylor, Jessica A., Sexton, Adrienne, Lockhart, Paul J., Kiers, Lynette, Fahey, Michael, Macciocca, Ivan, Gaff, Clara L., Oshlack, Alicia, and Yiu, Eppie M.

Subjects
NUCLEOTIDE sequencing, PERIPHERAL neuropathy, PHENOTYPES, SINGLE nucleotide polymorphisms, GENE expression
Abstract

Objective To explore the diagnostic utility and cost effectiveness of whole exome sequencing ( WES) in a cohort of individuals with peripheral neuropathy. Methods Singleton WES was performed in individuals recruited though one pediatric and one adult tertiary center between February 2014 and December 2015. Initial analysis was restricted to a virtual panel of 55 genes associated with peripheral neuropathies. Patients with uninformative results underwent expanded analysis of the WES data. Data on the cost of prior investigations and assessments performed for diagnostic purposes in each patient was collected. Results Fifty patients with a peripheral neuropathy were recruited (median age 18 years; range 2-68 years). The median time from initial presentation to study enrollment was 6 years 9 months (range 2 months-62 years), and the average cost of prior investigations and assessments for diagnostic purposes AU$4013 per patient. Eleven individuals received a diagnosis from the virtual panel. Eight individuals received a diagnosis following expanded analysis of the WES data, increasing the overall diagnostic yield to 38%. Two additional individuals were diagnosed with pathogenic copy number variants through SNP microarray. Conclusions This study provides evidence that WES has a high diagnostic utility and is cost effective in patients with a peripheral neuropathy. Expanded analysis of WES data significantly improves the diagnostic yield in patients in whom a diagnosis is not found on the initial targeted analysis. This is primarily due to diagnosis of conditions caused by newly discovered genes and the resolution of complex and atypical phenotypes. [ABSTRACT FROM AUTHOR]

Published
2017
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47. Mutations in SPRTN cause early onset hepatocellular carcinoma, genomic instability and progeroid features

Author

Lessel, Davor, primary, Vaz, Bruno, additional, Halder, Swagata, additional, Lockhart, Paul J, additional, Marinovic-Terzic, Ivana, additional, Lopez-Mosqueda, Jaime, additional, Philipp, Melanie, additional, Sim, Joe C H, additional, Smith, Katherine R, additional, Oehler, Judith, additional, Cabrera, Elisa, additional, Freire, Raimundo, additional, Pope, Kate, additional, Nahid, Amsha, additional, Norris, Fiona, additional, Leventer, Richard J, additional, Delatycki, Martin B, additional, Barbi, Gotthold, additional, von Ameln, Simon, additional, Högel, Josef, additional, Degoricija, Marina, additional, Fertig, Regina, additional, Burkhalter, Martin D, additional, Hofmann, Kay, additional, Thiele, Holger, additional, Altmüller, Janine, additional, Nürnberg, Gudrun, additional, Nürnberg, Peter, additional, Bahlo, Melanie, additional, Martin, George M, additional, Aalfs, Cora M, additional, Oshima, Junko, additional, Terzic, Janos, additional, Amor, David J, additional, Dikic, Ivan, additional, Ramadan, Kristijan, additional, and Kubisch, Christian, additional

Published
2014
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48. Expanding the phenotypic spectrum of ARID1B-mediated disorders and identification of altered cell-cycle dynamics due to ARID1B haploinsufficiency

Author

Sim, Joe C H, primary, White, Susan M, additional, Fitzpatrick, Elizabeth, additional, Wilson, Gabrielle R, additional, Gillies, Greta, additional, Pope, Kate, additional, Mountford, Hayley S, additional, Torring, Pernille M, additional, McKee, Shane, additional, Vulto-van Silfhout, Anneke T, additional, Jhangiani, Shalini N, additional, Muzny, Donna M, additional, Leventer, Richard J, additional, Delatycki, Martin B, additional, Amor, David J, additional, and Lockhart, Paul J, additional

Published
2014
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49. Identification and characterisation of a novel gene for cardiomyopathy

Author

Phelan, Dean, primary, Wilson, Gabrielle, additional, Pope, Kate, additional, Gillies, Greta, additional, Sim, Joe, additional, Bahlo, Melanie, additional, Hickey, Peter, additional, Bromhead, Catherine, additional, James, Paul, additional, du Sart, Desirée, additional, Delatyki, Martin, additional, Leventer, Rick, additional, Amor, David, additional, and Lockhart, Paul J., additional

Published
2014
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50. Cauli: a mouse strain with an Ift140 mutation that results in a skeletal ciliopathy modelling jeune syndrome

Author

Miller, Kerry A, Ah-Cann, Casey J, Welfare, Megan F, Tan, Tiong Y, Pope, Kate, Caruana, Georgina, Freckmann, Mary-Louise, Savarirayan, Ravi, Bertram, John F, Dobbie, Michael S, Bateman, John F, Farlie, Peter G, Miller, Kerry A, Ah-Cann, Casey J, Welfare, Megan F, Tan, Tiong Y, Pope, Kate, Caruana, Georgina, Freckmann, Mary-Louise, Savarirayan, Ravi, Bertram, John F, Dobbie, Michael S, Bateman, John F, and Farlie, Peter G

Abstract

Cilia are architecturally complex organelles that protrude from the cell membrane and have signalling, sensory and motility functions that are central to normal tissue development and homeostasis. There are two broad categories of cilia; motile and non-motile, or primary, cilia. The central role of primary cilia in health and disease has become prominent in the past decade with the recognition of a number of human syndromes that result from defects in the formation or function of primary cilia. This rapidly growing class of conditions, now known as ciliopathies, impact the development of a diverse range of tissues including the neural axis, craniofacial structures, skeleton, kidneys, eyes and lungs. The broad impact of cilia dysfunction on development reflects the pivotal position of the primary cilia within a signalling nexus involving a growing number of growth factor systems including Hedgehog, Pdgf, Fgf, Hippo, Notch and both canonical Wnt and planar cell polarity. We have identified a novel ENU mutant allele of Ift140, which causes a mid-gestation embryonic lethal phenotype in homozygous mutant mice. Mutant embryos exhibit a range of phenotypes including exencephaly and spina bifida, craniofacial dysmorphism, digit anomalies, cardiac anomalies and somite patterning defects. A number of these phenotypes can be attributed to alterations in Hedgehog signalling, although additional signalling systems are also likely to be involved. We also report the identification of a homozygous recessive mutation in IFT140 in a Jeune syndrome patient. This ENU-induced Jeune syndrome model will be useful in delineating the origins of dysmorphology in human ciliopathies.

Published
2013

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