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1. Molecular, cellular and clinical characterisation of mosaic variegated aneuploidy syndrome

Author

Hanks, Sandra

Subjects
616.99, Cancer Genetics Section
Abstract

Mosaic variegated aneuploidy (MVA) syndrome is an autosomal recessive disorder characterised by mosaic aneuploidies, a variety of phenotypic abnormalities and predisposition to cancer. This study aimed to identify the genetic defect underlying MVA and to characterise the associated cellular and clinical phenotypes. Following a candidate gene screening approach, I identified biallelic BUB1B mutations as a cause of MVA. BUB1B encodes BUBR1 which has multiple, crucial roles in the mitotic spindle checkpoint. I subsequently demonstrated that BUBR1 expression was reduced in BUB1B cases. Furthermore, transfer of human chromosome 15, containing the BUB1B locus, complemented the cellular phenotype in BUB1B mutation-positive cells. As hereditary cancer genes are frequently implicated in sporadic cancers, I undertook mutational analyses of sporadic childhood tumours which confirmed that somatic BUB1B mutations are unlikely to be common in cancers of the types typically associated with MVA. To enable stratification of cases into phenotypically characterised subgroups, I evaluated the molecular, cellular and clinical features associated with MVA. Cases can be classified according to the presence (40%) or absence (60%) of BUB1B mutations. Whilst a strong phenotypic overlap of BUB1B and non-BUB1B cases renders the delineation of clinical subgroups difficult, BUB1B cases do appear to be at higher risk of developing cancer. Karyotypic analyses revealed that there was no apparent correlation between mutation status and the extent of aneuploidies. However, assessment of mitotic checkpoint function demonstrated that the checkpoint defect was profound in BUB1B cases; in contrast, most non-BUB1B cases analysed had intermediate or normal checkpoint function. Our results clearly highlight the heterogeneous nature of MVA syndrome. Furthermore, our data were the first to relate germline mutations in a mitotic checkpoint gene with a human disorder and strongly support a causal role for aneuploidy in cancer development. The aim of future work would be to identify the causative gene(s) in non-BUB1B cases.

Published
2011

2. Mosaic PPM1D mutations are associated with predisposition to breast and ovarian cancer

Author

Ruark, Elise, Snape, Katie, Humburg, Peter, Loveday, Chey, Bajrami, Ilirjana, Brough, Rachel, Rodrigues, Daniel Nava, Renwick, Anthony, Seal, Sheila, Ramsay, Emma, Duarte, Silvana Del Vecchio, Rivas, Manuel A, Warren-Perry, Margaret, Zachariou, Anna, Campion-Flora, Adriana, Hanks, Sandra, Murray, Anne, Pour, Naser Ansari, Douglas, Jenny, Gregory, Lorna, Rimmer, Andrew, Walker, Neil M, Yang, Tsun-Po, Adlard, Julian W, Barwell, Julian, Berg, Jonathan, Brady, Angela F, Brewer, Carole, Brice, Glen, Chapman, Cyril, Cook, Jackie, Davidson, Rosemarie, Donaldson, Alan, Douglas, Fiona, Eccles, Diana, Evans, D Gareth, Greenhalgh, Lynn, Henderson, Alex, Izatt, Louise, Kumar, Ajith, Lalloo, Fiona, Miedzybrodzka, Zosia, Morrison, Patrick J, Paterson, Joan, Porteous, Mary, Rogers, Mark T, Shanley, Susan, Walker, Lisa, Gore, Martin, Houlston, Richard, Brown, Matthew A, Caufield, Mark J, Deloukas, Panagiotis, McCarthy, Mark I, Todd, John A, Turnbull, Clare, Reis-Filho, Jorge S, Ashworth, Alan, Antoniou, Antonis C, Lord, Christopher J, Donnelly, Peter, and Rahman, Nazneen

Subjects
Breast Cancer, Ovarian Cancer, Cancer, Rare Diseases, Aetiology, 2.1 Biological and endogenous factors, Alleles, Breast Neoplasms, Cluster Analysis, Exons, Female, Genetic Predisposition to Disease, Humans, Isoenzymes, Lymphocytes, Mosaicism, Mutation, Ovarian Neoplasms, Phosphoprotein Phosphatases, Protein Phosphatase 2C, Sequence Analysis, DNA, Tumor Suppressor Protein p53, Breast and Ovarian Cancer Susceptibility Collaboration, Wellcome Trust Case Control Consortium, General Science & Technology
Abstract

Improved sequencing technologies offer unprecedented opportunities for investigating the role of rare genetic variation in common disease. However, there are considerable challenges with respect to study design, data analysis and replication. Using pooled next-generation sequencing of 507 genes implicated in the repair of DNA in 1,150 samples, an analytical strategy focused on protein-truncating variants (PTVs) and a large-scale sequencing case-control replication experiment in 13,642 individuals, here we show that rare PTVs in the p53-inducible protein phosphatase PPM1D are associated with predisposition to breast cancer and ovarian cancer. PPM1D PTV mutations were present in 25 out of 7,781 cases versus 1 out of 5,861 controls (P = 1.12 × 10(-5)), including 18 mutations in 6,912 individuals with breast cancer (P = 2.42 × 10(-4)) and 12 mutations in 1,121 individuals with ovarian cancer (P = 3.10 × 10(-9)). Notably, all of the identified PPM1D PTVs were mosaic in lymphocyte DNA and clustered within a 370-base-pair region in the final exon of the gene, carboxy-terminal to the phosphatase catalytic domain. Functional studies demonstrate that the mutations result in enhanced suppression of p53 in response to ionizing radiation exposure, suggesting that the mutant alleles encode hyperactive PPM1D isoforms. Thus, although the mutations cause premature protein truncation, they do not result in the simple loss-of-function effect typically associated with this class of variant, but instead probably have a gain-of-function effect. Our results have implications for the detection and management of breast and ovarian cancer risk. More generally, these data provide new insights into the role of rare and of mosaic genetic variants in common conditions, and the use of sequencing in their identification.

Published
2013

5. Chromosomal instability by mutations in the novel minor spliceosome component CENATAC

Author

Wolf, Bas, primary, Oghabian, Ali, additional, Akinyi, Maureen V, additional, Hanks, Sandra, additional, Tromer, Eelco C, additional, Hooff, Jolien J E, additional, Voorthuijsen, Lisa, additional, Rooijen, Laura E, additional, Verbeeren, Jens, additional, Uijttewaal, Esther C H, additional, Baltissen, Marijke P A, additional, Yost, Shawn, additional, Piloquet, Philippe, additional, Vermeulen, Michiel, additional, Snel, Berend, additional, Isidor, Bertrand, additional, Rahman, Nazneen, additional, Frilander, Mikko J, additional, and Kops, Geert J P L, additional

Published
2021
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6. Chromosomal instability by mutations in the novel minor spliceosome component CENATAC

Author

Sub Bioinformatics, Theoretical Biology and Bioinformatics, de Wolf, Bas, Oghabian, Ali, Akinyi, Maureen V, Hanks, Sandra, Tromer, Eelco C, van Hooff, Jolien J E, van Voorthuijsen, Lisa, van Rooijen, Laura E, Verbeeren, Jens, Uijttewaal, Esther C H, Baltissen, Marijke P A, Yost, Shawn, Piloquet, Philippe, Vermeulen, Michiel, Snel, Berend, Isidor, Bertrand, Rahman, Nazneen, Frilander, Mikko J, Kops, Geert J P L, Sub Bioinformatics, Theoretical Biology and Bioinformatics, de Wolf, Bas, Oghabian, Ali, Akinyi, Maureen V, Hanks, Sandra, Tromer, Eelco C, van Hooff, Jolien J E, van Voorthuijsen, Lisa, van Rooijen, Laura E, Verbeeren, Jens, Uijttewaal, Esther C H, Baltissen, Marijke P A, Yost, Shawn, Piloquet, Philippe, Vermeulen, Michiel, Snel, Berend, Isidor, Bertrand, Rahman, Nazneen, Frilander, Mikko J, and Kops, Geert J P L

Published
2021

7. Chromosomal instability by mutations in the novel minor spliceosome component CENATAC

Author

de Wolf, Bas, Oghabian, Ali, Akinyi, Maureen V, Hanks, Sandra, Tromer, Eelco C, van Hooff, Jolien J E, van Voorthuijsen, Lisa, van Rooijen, Laura E, Verbeeren, Jens, Uijttewaal, Esther C H, Baltissen, Marijke P A, Yost, Shawn, Piloquet, Philippe, Vermeulen, Michiel, Snel, Berend, Isidor, Bertrand, Rahman, Nazneen, Frilander, Mikko J, Kops, Geert J P L, de Wolf, Bas, Oghabian, Ali, Akinyi, Maureen V, Hanks, Sandra, Tromer, Eelco C, van Hooff, Jolien J E, van Voorthuijsen, Lisa, van Rooijen, Laura E, Verbeeren, Jens, Uijttewaal, Esther C H, Baltissen, Marijke P A, Yost, Shawn, Piloquet, Philippe, Vermeulen, Michiel, Snel, Berend, Isidor, Bertrand, Rahman, Nazneen, Frilander, Mikko J, and Kops, Geert J P L

Abstract

Aneuploidy is the leading cause of miscarriage and congenital birth defects, and a hallmark of cancer. Despite this strong association with human disease, the genetic causes of aneuploidy remain largely unknown. Through exome sequencing of patients with constitutional mosaic aneuploidy, we identified biallelic truncating mutations in CENATAC (CCDC84). We show that CENATAC is a novel component of the minor (U12-dependent) spliceosome that promotes splicing of a specific, rare minor intron subtype. This subtype is characterized by AT-AN splice sites and relatively high basal levels of intron retention. CENATAC depletion or expression of disease mutants resulted in excessive retention of AT-AN minor introns in ˜ 100 genes enriched for nucleocytoplasmic transport and cell cycle regulators, and caused chromosome segregation errors. Our findings reveal selectivity in minor intron splicing and suggest a link between minor spliceosome defects and constitutional aneuploidy in humans.

Published
2021

8. Chromosomal instability by mutations in the novel minor spliceosome component CENATAC

Author

CMM USEQ Facility, CMM Groep Burgering, Hubrecht Institute with UMC, de Wolf, Bas, Oghabian, Ali, Akinyi, Maureen V., Hanks, Sandra, Tromer, Eelco C., van Hooff, Jolien J.E., van Voorthuijsen, Lisa, van Rooijen, Laura E., Verbeeren, Jens, Uijttewaal, Esther C.H., Baltissen, Marijke P.A., Yost, Shawn, Piloquet, Philippe, Vermeulen, Michiel, Snel, Berend, Isidor, Bertrand, Rahman, Nazneen, Frilander, Mikko J., Kops, Geert J.P.L., CMM USEQ Facility, CMM Groep Burgering, Hubrecht Institute with UMC, de Wolf, Bas, Oghabian, Ali, Akinyi, Maureen V., Hanks, Sandra, Tromer, Eelco C., van Hooff, Jolien J.E., van Voorthuijsen, Lisa, van Rooijen, Laura E., Verbeeren, Jens, Uijttewaal, Esther C.H., Baltissen, Marijke P.A., Yost, Shawn, Piloquet, Philippe, Vermeulen, Michiel, Snel, Berend, Isidor, Bertrand, Rahman, Nazneen, Frilander, Mikko J., and Kops, Geert J.P.L.

Published
2021

9. Mutations in the gene encoding capillary morphogenesis protein 2 cause juvenile hyaline fibromatosis and infantile systemic hyalinosis

Author

Hanks, Sandra, Adams, Sarah, Douglas, Jenny, Arbour, Laura, Atherton, David J., Balci, Sevim, Bode, Harald, Campbell, Mary E., Feingold, Murray, Keser, Gokhan, Kleijer, Wim, Mancini, Grazia, McGrath, John A., Muntoni, Francesco, Nanda, Arti, Teare, M. Dawn, Warman, Matthew, Pope, F. Michael, Superti-Furga, Andrea, Futreal, P. Andrew, and Rahman, Nazneen

Subjects
Gene mutations -- Research, Chromosome abnormalities -- Research, Hyaline membrane disease -- Genetic aspects, Biological sciences
Published
2003

10. Ehlers-Danlos syndrome with severe early-onset periodontal disease (EDS-VIII) is a distinct, heterogeneous disorder with one predisposition gene at chromosome 12p13. (Report)

Author

Rahman, Nazneen, Dunstan, Melanie, Teare, M. Dawn, Hanks, Sandra, Douglas, Jenny, Coleman, Kim, Bottomly, William E., Campbell, Mary E., Berglund, Britta, Nordenskjold, Magnus, Forssell, Bengt, Burrows, Nigel, Lunt, Peter, Young, Ian, Williams, Nigel, Bignell, Graham R., Futreal, P. Andrew, and Pope, F. Michael

Subjects
Ehlers-Danlos syndrome -- Research, Ehlers-Danlos syndrome -- Genetic aspects, Biological sciences
Published
2003

11. NSD1 mutations are the major cause of sotos syndrome and occur in some cases of weaver syndrome but are rare in other overgrowth phenotypes

Author

Douglas, Jenny, Hanks, Sandra, Temple, I. Karen, Davies, Sally, Murray, Alexandra, Upadhyaya, Meena, Tomkins, Susan, Hughes, Helen E., Cole, Trevor R.P., and Rahman, Nazneen

Subjects
Gene mutations -- Physiological aspects, Human chromosome abnormalities -- Physiological aspects, Human chromosome abnormalities -- Genetic aspects, Biological sciences
Published
2003

12. The gene for juvenile hyaline fibromatosis maps to chromosome 4q21. (Report)

Author

Rahman, Nazneen, Dunstan, Melanie, Teare, M. Dawn, Hanks, Sandra, Edkins, Sarah J., Hughes, Jaime, Bignell, Graham R., Mancini, Grazia, Kleijer, Wim, Campbell, Mary, Keser, Gokhan, Black, Carol, Williams, Nigel, Arbour, Laura, Warman, Matthew, Superti-Furga, Andrea, Futreal, P. Andrew, and Pope, F. Michael

Subjects
Human genetics, Genetic disorders -- Health aspects, Genetic disorders -- Research, Genetic disorders -- Demographic aspects, Cells -- Genetic aspects, Skin lesions -- Genetic aspects, Glycoproteins -- Genetic aspects, Glycosaminoglycans -- Genetic aspects, Biological sciences
Published
2002

13. DICER1 syndrome: clarifying the diagnosis, clinical features and management implications of a pleiotropic tumour predisposition syndrome

Author

Slade, Ingrid, Bacchelli, Chiara, Davies, Helen, Murray, Anne, Abbaszadeh, Fatemeh, Hanks, Sandra, Barfoot, Rita, Burke, Amos, Chisholm, Julia, Hewitt, Martin, Jenkinson, Helen, King, Derek, Morland, Bruce, Pizer, Barry, Prescott, Katrina, Saggar, Anand, Side, Lucy, Traunecker, Heidi, Vaidya, Sucheta, Ward, Paul, Futreal, P Andrew, Vujanic, Gordan, Nicholson, Andrew G, Sebire, Neil, Turnbull, Clare, Priest, John R, Pritchard-Jones, Kathryn, Houlston, Richard, Stiller, Charles, Stratton, Michael R, Douglas, Jenny, and Rahman, Nazneen

Published
2011
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15. Biallelic TRIP13 mutations predispose to Wilms tumor and chromosome missegregation

Author

Yost, Shawn, De Wolf, Bas, Hanks, Sandra, Zachariou, Anna, Marcozzi, Chiara, Clarke, Matthew, de Voer, Richarda M, Etemad, Banafsheh, Uijttewaal, Esther, Ramsay, Emma, Wylie, Harriet, Elliott, Anna, Picton, Susan, Smith, Audrey, Smithson, Sarah F., Seal, Sheila, Ruark, Elise, Houge, Gunnar, Pines, Jonathon, Kops, Geert J.P.L., Rahman, Nazneen, Yost, Shawn, De Wolf, Bas, Hanks, Sandra, Zachariou, Anna, Marcozzi, Chiara, Clarke, Matthew, de Voer, Richarda M, Etemad, Banafsheh, Uijttewaal, Esther, Ramsay, Emma, Wylie, Harriet, Elliott, Anna, Picton, Susan, Smith, Audrey, Smithson, Sarah F., Seal, Sheila, Ruark, Elise, Houge, Gunnar, Pines, Jonathon, Kops, Geert J.P.L., and Rahman, Nazneen

Published
2017

16. Biallelic TRIP13 mutations predispose to Wilms tumor and chromosome missegregation

Author

CMM, CMM USEQ Facility, Hubrecht Institute with UMC, Cancer, Yost, Shawn, De Wolf, Bas, Hanks, Sandra, Zachariou, Anna, Marcozzi, Chiara, Clarke, Matthew, de Voer, Richarda M, Etemad, Banafsheh, Uijttewaal, Esther, Ramsay, Emma, Wylie, Harriet, Elliott, Anna, Picton, Susan, Smith, Audrey, Smithson, Sarah F., Seal, Sheila, Ruark, Elise, Houge, Gunnar, Pines, Jonathon, Kops, Geert J.P.L., Rahman, Nazneen, CMM, CMM USEQ Facility, Hubrecht Institute with UMC, Cancer, Yost, Shawn, De Wolf, Bas, Hanks, Sandra, Zachariou, Anna, Marcozzi, Chiara, Clarke, Matthew, de Voer, Richarda M, Etemad, Banafsheh, Uijttewaal, Esther, Ramsay, Emma, Wylie, Harriet, Elliott, Anna, Picton, Susan, Smith, Audrey, Smithson, Sarah F., Seal, Sheila, Ruark, Elise, Houge, Gunnar, Pines, Jonathon, Kops, Geert J.P.L., and Rahman, Nazneen

Published
2017

19. Germline mutations in the PAF1 complex gene CTR9 predispose to Wilms tumour

Author

Hanks, Sandra, primary, Perdeaux, Elizabeth R., additional, Seal, Sheila, additional, Ruark, Elise, additional, Mahamdallie, Shazia S., additional, Murray, Anne, additional, Ramsay, Emma, additional, Del Vecchio Duarte, Silvana, additional, Zachariou, Anna, additional, de Souza, Bianca, additional, Warren-Perry, Margaret, additional, Elliott, Anna, additional, Davidson, Alan, additional, Price, Helen, additional, Stiller, Charles, additional, Pritchard-Jones, Kathy, additional, and Rahman, Nazneen, additional

Published
2014
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20. Weaver syndrome and EZH2 mutations: Clarifying the clinical phenotype

Author

Tatton-Brown, Katrina, Murray, Anne, Hanks, Sandra, Douglas, Jenny, Armstrong, Ruth, Banka, Siddharth, Bird, Lynne M, Clericuzio, Carol L, Cormier-Daire, Valerie, Cushing, Tom, Flinter, Frances, Jacquemont, Marie-Line, Joss, Shelagh, Kinning, Esther, Lynch, Sally Ann, Magee, Alex, McConnell, Vivienne, Medeira, Ana, Ozono, Keiichi, Patton, Michael, Rankin, Julia, Shears, Debbie, Simon, Marleen, Splitt, Miranda, Strenger, Volker, Stuurman, Kyra, Taylor, Clare, Titheradge, Hannah, Van Maldergem, Lionel, Temple, I Karen, Cole, Trevor, Seal, Sheila, Rahman, Nazneen, Tatton-Brown, Katrina, Murray, Anne, Hanks, Sandra, Douglas, Jenny, Armstrong, Ruth, Banka, Siddharth, Bird, Lynne M, Clericuzio, Carol L, Cormier-Daire, Valerie, Cushing, Tom, Flinter, Frances, Jacquemont, Marie-Line, Joss, Shelagh, Kinning, Esther, Lynch, Sally Ann, Magee, Alex, McConnell, Vivienne, Medeira, Ana, Ozono, Keiichi, Patton, Michael, Rankin, Julia, Shears, Debbie, Simon, Marleen, Splitt, Miranda, Strenger, Volker, Stuurman, Kyra, Taylor, Clare, Titheradge, Hannah, Van Maldergem, Lionel, Temple, I Karen, Cole, Trevor, Seal, Sheila, and Rahman, Nazneen

Abstract

Weaver syndrome, first described in 1974, is characterized by tall stature, a typical facial appearance, and variable intellectual disability. In 2011, mutations in the histone methyltransferase, EZH2, were shown to cause Weaver syndrome. To date, we have identified 48 individuals with EZH2 mutations. The mutations were primarily missense mutations occurring throughout the gene, with some clustering in the SET domain (12/48). Truncating mutations were uncommon (4/48) and only identified in the final exon, after the SET domain. Through analyses of clinical data and facial photographs of EZH2 mutation-positive individuals, we have shown that the facial features can be subtle and the clinical diagnosis of Weaver syndrome is thus challenging, especially in older individuals. However, tall stature is very common, reported in >90% of affected individuals. Intellectual disability is also common, present in ~80%, but is highly variable and frequently mild. Additional clinical features which may help in stratifying individuals to EZH2 mutation testing include camptodactyly, soft, doughy skin, umbilical hernia, and a low, hoarse cry. Considerable phenotypic overlap between Sotos and Weaver syndromes is also evident. The identification of an EZH2 mutation can therefore provide an objective means of confirming a subtle presentation of Weaver syndrome and/or distinguishing Weaver and Sotos syndromes. As mutation testing becomes increasingly accessible and larger numbers of EZH2 mutation-positive individuals are identified, knowledge of the clinical spectrum and prognostic implications of EZH2 mutations should improve.

Published
2013

21. Generation of trisomies in cancer cells by multipolar mitosis and incomplete cytokinesis.

Author

Gisselsson Nord, David, Jin, Yuesheng, Lindgren, David, Persson, Johan, Gisselsson, Lennart, Hanks, Sandra, Sehic, Daniel, Holmquist Mengelbier, Linda, Øra, Ingrid, Rahman, Nazneen, Mertens, Fredrik, Mitelman, Felix, Mandahl, Nils, Gisselsson Nord, David, Jin, Yuesheng, Lindgren, David, Persson, Johan, Gisselsson, Lennart, Hanks, Sandra, Sehic, Daniel, Holmquist Mengelbier, Linda, Øra, Ingrid, Rahman, Nazneen, Mertens, Fredrik, Mitelman, Felix, and Mandahl, Nils

Abstract

One extra chromosome copy (i.e., trisomy) is the most common type of chromosome aberration in cancer cells. The mechanisms behind the generation of trisomies in tumor cells are largely unknown, although it has been suggested that dysfunction of the spindle assembly checkpoint (SAC) leads to an accumulation of trisomies through failure to correctly segregate sister chromatids in successive cell divisions. By using Wilms tumor as a model for cancers with trisomies, we now show that trisomic cells can form even in the presence of a functional SAC through tripolar cell divisions in which sister chromatid separation proceeds in a regular fashion, but cytokinesis failure nevertheless leads to an asymmetrical segregation of chromosomes into two daughter cells. A model for the generation of trisomies by such asymmetrical cell division accurately predicted several features of clones having extra chromosomes in vivo, including the ratio between trisomies and tetrasomies and the observation that different trisomies found in the same tumor occupy identical proportions of cells and colocalize in tumor tissue. Our findings provide an experimentally validated model explaining how multiple trisomies can occur in tumor cells that still maintain accurate sister chromatid separation at metaphase-anaphase transition and thereby physiologically satisfy the SAC.

Published
2010

23. Chromosomal instability by mutations in the novel minor spliceosome component CENATAC.

Author

de Wolf B, Oghabian A, Akinyi MV, Hanks S, Tromer EC, van Hooff JJE, van Voorthuijsen L, van Rooijen LE, Verbeeren J, Uijttewaal ECH, Baltissen MPA, Yost S, Piloquet P, Vermeulen M, Snel B, Isidor B, Rahman N, Frilander MJ, and Kops GJPL

Subjects
Amino Acid Sequence, Cell Cycle genetics, Cell Line, Cell Line, Tumor, HeLa Cells, Humans, Introns genetics, Chromosomal Instability genetics, Chromosomes genetics, Mutation genetics, Spliceosomes genetics
Abstract

Aneuploidy is the leading cause of miscarriage and congenital birth defects, and a hallmark of cancer. Despite this strong association with human disease, the genetic causes of aneuploidy remain largely unknown. Through exome sequencing of patients with constitutional mosaic aneuploidy, we identified biallelic truncating mutations in CENATAC (CCDC84). We show that CENATAC is a novel component of the minor (U12-dependent) spliceosome that promotes splicing of a specific, rare minor intron subtype. This subtype is characterized by AT-AN splice sites and relatively high basal levels of intron retention. CENATAC depletion or expression of disease mutants resulted in excessive retention of AT-AN minor introns in ˜ 100 genes enriched for nucleocytoplasmic transport and cell cycle regulators, and caused chromosome segregation errors. Our findings reveal selectivity in minor intron splicing and suggest a link between minor spliceosome defects and constitutional aneuploidy in humans., (© 2021 The Authors. Published under the terms of the CC BY 4.0 license.)

Published
2021
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24. Correction: Germline mutations in the oncogene EZH2 cause Weaver syndrome and increased human height.

Author

Tatton-Brown K, Hanks S, Ruark E, Zachariou A, Del Vecchio Duarte S, Ramsay E, Snape K, Murray A, Perdeaux ER, Seal S, Loveday C, Banka S, Clericuzio C, Flinter F, Magee A, McConnell V, Patton M, Raith W, Rankin J, Splitt M, Strenger V, Taylor C, Wheeler P, Temple IK, Cole T, Douglas J, and Rahman N

Abstract

[This corrects the article DOI: 10.18632/oncotarget.385.].

Published
2018
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25. Germline mutations in the oncogene EZH2 cause Weaver syndrome and increased human height.

Author

Tatton-Brown K, Hanks S, Ruark E, Zachariou A, Duarte Sdel V, Ramsay E, Snape K, Murray A, Perdeaux ER, Seal S, Loveday C, Banka S, Clericuzio C, Flinter F, Magee A, McConnell V, Patton M, Raith W, Rankin J, Splitt M, Strenger V, Taylor C, Wheeler P, Temple KI, Cole T, Douglas J, and Rahman N

Subjects
Amino Acid Sequence, Body Height, Enhancer of Zeste Homolog 2 Protein, Facies, Female, Growth Disorders genetics, Histone Methyltransferases, Histone-Lysine N-Methyltransferase genetics, Histones genetics, Humans, Male, Polycomb Repressive Complex 2, Sequence Analysis, DNA, Abnormalities, Multiple genetics, Congenital Hypothyroidism genetics, Craniofacial Abnormalities genetics, DNA-Binding Proteins genetics, Germ-Line Mutation, Hand Deformities, Congenital genetics, Transcription Factors genetics
Abstract

The biological processes controlling human growth are diverse, complex and poorly understood. Genetic factors are important and human height has been shown to be a highly polygenic trait to which common and rare genetic variation contributes. Weaver syndrome is a human overgrowth condition characterised by tall stature, dysmorphic facial features, learning disability and variable additional features. We performed exome sequencing in four individuals with Weaver syndrome, identifying a mutation in the histone methyltransferase, EZH2, in each case. Sequencing of EZH2 in additional individuals with overgrowth identified a further 15 mutations. The EZH2 mutation spectrum in Weaver syndrome shows considerable overlap with the inactivating somatic EZH2 mutations recently reported in myeloid malignancies. Our data establish EZH2 mutations as the cause of Weaver syndrome and provide further links between histone modifications and regulation of human growth.

Published
2011
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