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2. Structural and non-coding variants increase the diagnostic yield of clinical whole genome sequencing for rare diseases

Author

Pagnamenta, Alistair T., Camps, Carme, Giacopuzzi, Edoardo, Taylor, John M., Hashim, Mona, Calpena, Eduardo, Kaisaki, Pamela J., Hashimoto, Akiko, Yu, Jing, Sanders, Edward, Schwessinger, Ron, Hughes, Jim R., Lunter, Gerton, Dreau, Helene, Ferla, Matteo, Lange, Lukas, Kesim, Yesim, Ragoussis, Vassilis, Vavoulis, Dimitrios V., Allroggen, Holger, Ansorge, Olaf, Babbs, Christian, Banka, Siddharth, Baños-Piñero, Benito, Beeson, David, Ben-Ami, Tal, Bennett, David L., Bento, Celeste, Blair, Edward, Brasch-Andersen, Charlotte, Bull, Katherine R., Cario, Holger, Cilliers, Deirdre, Conti, Valerio, Davies, E. Graham, Dhalla, Fatima, Dacal, Beatriz Diez, Dong, Yin, Dunford, James E., Guerrini, Renzo, Harris, Adrian L., Hartley, Jane, Hollander, Georg, Javaid, Kassim, Kane, Maureen, Kelly, Deirdre, Kelly, Dominic, Knight, Samantha J. L., Kreins, Alexandra Y., Kvikstad, Erika M., Langman, Craig B., Lester, Tracy, Lines, Kate E., Lord, Simon R., Lu, Xin, Mansour, Sahar, Manzur, Adnan, Maroofian, Reza, Marsden, Brian, Mason, Joanne, McGowan, Simon J., Mei, Davide, Mlcochova, Hana, Murakami, Yoshiko, Németh, Andrea H., Okoli, Steven, Ormondroyd, Elizabeth, Ousager, Lilian Bomme, Palace, Jacqueline, Patel, Smita Y., Pentony, Melissa M., Pugh, Chris, Rad, Aboulfazl, Ramesh, Archana, Riva, Simone G., Roberts, Irene, Roy, Noémi, Salminen, Outi, Schilling, Kyleen D., Scott, Caroline, Sen, Arjune, Smith, Conrad, Stevenson, Mark, Thakker, Rajesh V., Twigg, Stephen R. F., Uhlig, Holm H., van Wijk, Richard, Vona, Barbara, Wall, Steven, Wang, Jing, Watkins, Hugh, Zak, Jaroslav, Schuh, Anna H., Kini, Usha, Wilkie, Andrew O. M., Popitsch, Niko, and Taylor, Jenny C.

Published
2023
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3. Personalized recurrence risk assessment following the birth of a child with a pathogenic de novo mutation

Author

Bernkopf, Marie, Abdullah, Ummi B., Bush, Stephen J., Wood, Katherine A., Ghaffari, Sahar, Giannoulatou, Eleni, Koelling, Nils, Maher, Geoffrey J., Thibaut, Loïc M., Williams, Jonathan, Blair, Edward M., Kelly, Fiona Blanco, Bloss, Angela, Burkitt-Wright, Emma, Canham, Natalie, Deng, Alexander T., Dixit, Abhijit, Eason, Jacqueline, Elmslie, Frances, Gardham, Alice, Hay, Eleanor, Holder, Muriel, Homfray, Tessa, Hurst, Jane A., Johnson, Diana, Jones, Wendy D., Kini, Usha, Kivuva, Emma, Kumar, Ajith, Lees, Melissa M., Leitch, Harry G., Morton, Jenny E. V., Németh, Andrea H., Ramachandrappa, Shwetha, Saunders, Katherine, Shears, Deborah J., Side, Lucy, Splitt, Miranda, Stewart, Alison, Stewart, Helen, Suri, Mohnish, Clouston, Penny, Davies, Robert W., Wilkie, Andrew O. M., and Goriely, Anne

Published
2023
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5. Reassessing the association: Evaluation of a polyalanine deletion variant of RUNX2 in non‐syndromic sagittal and metopic craniosynostosis.

Author

Walton, Isaac S., McCann, Emma, Weber, Astrid, Morton, Jenny E. V., Noons, Peter, Wilson, Louise C., Ching, Rosanna C., Cilliers, Deirdre, Johnson, David, Phipps, Julie M., Shears, Deborah J., Thomas, Gregory P. L., Wall, Steven A., Twigg, Stephen R. F., and Wilkie, Andrew O. M.

Subjects
TRANSCRIPTION factors, HOMINIDS, GENE frequency, GENETIC polymorphisms, NUCLEOTIDE sequencing
Abstract

The RUNT‐related transcription factor RUNX2 plays a critical role in osteoblast differentiation, and alterations to gene dosage cause distinct craniofacial anomalies. Uniquely amongst the RUNT‐related family, vertebrate RUNX2 encodes a polyglutamine/polyalanine repeat (Gln23‐Glu‐Ala17 in humans), with the length of the polyalanine component completely conserved in great apes. Surprisingly, a frequent 6‐amino acid deletion polymorphism, p.(Ala84_Ala89)del, occurs in humans (termed 11A allele), and a previous association study (Cuellar et al. Bone137:115395;2020) reported that the 11A variant was significantly more frequent in non‐syndromic sagittal craniosynostosis (nsSag; allele frequency [AF] = 0.156; 95% confidence interval [CI] 0.126–0.189) compared to non‐syndromic metopic craniosynostosis (nsMet; AF = 0.068; 95% CI 0.045–0.098). However, the gnomAD v.2.1.1 control population used by Cuellar et al. did not display Hardy–Weinberg equilibrium, hampering interpretation. To re‐examine this association, we genotyped the RUNX2 11A polymorphism in 225 individuals with sporadic nsSag as parent–child trios and 164 singletons with sporadic nsMet, restricting our analysis to individuals of European ancestry. We compared observed allele frequencies to the non‐transmitted alleles in the parent–child trios, and to the genome sequencing data from gnomAD v.4, which display Hardy–Weinberg equilibrium. Observed AFs (and 95% CI) were 0.076 (0.053–0.104) in nsSag and 0.082 (0.055–0.118) in nsMet, compared with 0.062 (0.042–0.089) in non‐transmitted parental alleles and 0.065 (0.063–0.067) in gnomAD v.4.0.0 non‐Finnish European control genomes. In summary, we observed a non‐significant excess, compared to gnomAD data, of 11A alleles in both nsSag (relative risk 1.18, 95% CI 0.83–1.67) and nsMet (relative risk 1.29, 95% CI 0.87–1.92), but we did not replicate the much higher excess of RUNX2 11A alleles in nsSag previously reported (p = 0.0001). [ABSTRACT FROM AUTHOR]

Published
2024
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6. A Comparison of Structural Variant Calling from Short-Read and Nanopore-Based Whole-Genome Sequencing Using Optical Genome Mapping as a Benchmark.

Author

Pei, Yang, Tanguy, Melanie, Giess, Adam, Dixit, Abhijit, Wilson, Louise C., Gibbons, Richard J., Twigg, Stephen R. F., Elgar, Greg, and Wilkie, Andrew O. M.

Subjects
WHOLE genome sequencing, GENE mapping, DNA copy number variations, GENOMES, GENOMICS
Abstract

The identification of structural variants (SVs) in genomic data represents an ongoing challenge because of difficulties in reliable SV calling leading to reduced sensitivity and specificity. We prepared high-quality DNA from 9 parent–child trios, who had previously undergone short-read whole-genome sequencing (Illumina platform) as part of the Genomics England 100,000 Genomes Project. We reanalysed the genomes using both Bionano optical genome mapping (OGM; 8 probands and one trio) and Nanopore long-read sequencing (Oxford Nanopore Technologies [ONT] platform; all samples). To establish a "truth" dataset, we asked whether rare proband SV calls (n = 234) made by the Bionano Access (version 1.6.1)/Solve software (version 3.6.1_11162020) could be verified by individual visualisation using the Integrative Genomics Viewer with either or both of the Illumina and ONT raw sequence. Of these, 222 calls were verified, indicating that Bionano OGM calls have high precision (positive predictive value 95%). We then asked what proportion of the 222 true Bionano SVs had been identified by SV callers in the other two datasets. In the Illumina dataset, sensitivity varied according to variant type, being high for deletions (115/134; 86%) but poor for insertions (13/58; 22%). In the ONT dataset, sensitivity was generally poor using the original Sniffles variant caller (48% overall) but improved substantially with use of Sniffles2 (36/40; 90% and 17/23; 74% for deletions and insertions, respectively). In summary, we show that the precision of OGM is very high. In addition, when applying the Sniffles2 caller, the sensitivity of SV calling using ONT long-read sequence data outperforms Illumina sequencing for most SV types. [ABSTRACT FROM AUTHOR]

Published
2024
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7. BTB domain mutations perturbing KCTD15 oligomerisation cause a distinctive frontonasal dysplasia syndrome

Author

Miller, Kerry A, primary, Cruz Walma, David A, additional, Pinkas, Daniel M, additional, Tooze, Rebecca S, additional, Bufton, Joshua C, additional, Richardson, William, additional, Manning, Charlotte E, additional, Hunt, Alice E, additional, Cros, Julien, additional, Hartill, Verity, additional, Parker, Michael J, additional, McGowan, Simon J, additional, Twigg, Stephen R F, additional, Chalk, Rod, additional, Staunton, David, additional, Johnson, David, additional, Wilkie, Andrew O M, additional, and Bullock, Alex N, additional

Published
2024
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8. HomozygousSMAD6variants in two unrelated patients with craniosynostosis and radioulnar synostosis

Author

Luyckx, Ilse, primary, Walton, Isaac Scott, additional, Boeckx, Nele, additional, Van Schil, Kristof, additional, Pang, Chingyiu, additional, De Praeter, Mania, additional, Lord, Helen, additional, Watson, Christopher Mark, additional, Bonthron, David T, additional, Van Laer, Lut, additional, Wilkie, Andrew O M, additional, and Loeys, Bart, additional

Published
2024
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9. Population screening requires robust evidence—genomics is no exception

Author

Turnbull, Clare, primary, Firth, Helen V, additional, Wilkie, Andrew O M, additional, Newman, William, additional, Raymond, F Lucy, additional, Tomlinson, Ian, additional, Lachmann, Robin, additional, Wright, Caroline F, additional, Wordsworth, Sarah, additional, George, Angela, additional, McCartney, Margaret, additional, and Lucassen, Anneke, additional

Published
2023
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13. Homozygous SMAD6 variants in two unrelated patients with craniosynostosis and radioulnar synostosis.

Author

Luyckx, Ilse, Walton, Isaac Scott, Boeckx, Nele, Van Schil, Kristof, Chingyiu Pang, De Praeter, Mania, Lord, Helen, Watson, Christopher Mark, Bonthron, David T., Van Laer, Lut, Wilkie, Andrew O. M., and Loeys, Bart

Abstract

Background SMAD6 encodes an intracellular inhibitor of the bone morphogenetic protein (BMP) signalling pathway. Until now, rare heterozygous loss-of-function variants in SMAD6 were demonstrated to increase the risk of disparate clinical disorders including cardiovascular disease, craniosynostosis and radioulnar synostosis. Only two unrelated patients harbouring biallelic SMAD6 variants presenting a complex cardiovascular phenotype and facial dysmorphism have been described. Cases Here, we present the first two patients with craniosynostosis harbouring homozygous SMAD6 variants. The male probands, both born to healthy consanguineous parents, were diagnosed with metopic synostosis and bilateral or unilateral radioulnar synostosis. Additionally, one proband had global developmental delay. Echocardiographic evaluation did not reveal cardiac or outflow tract abnormalities. Molecular analyses The novel missense (c.[584T>G];[584T>G], p.[(Val195Gly)];[(Val195Gly)]) and missense/splice-site variant (c.[817G>A];[817G>A], r.[(817g>a, 817delins[a;817+2_817+228])];[(817g>a, 8 17delins[a;817+2_817+228])], p.[(Glu273Lys,Glu273Serfs* 72)];[(Glu273Lys,Glu273Serfs*72)]) both locate in the functional MH1 domain of the protein and have not been reported in gnomAD database. Functional analyses of the variants showed reduced inhibition of BMP signalling or abnormal splicing, respectively, consistent with a hypomorphic mechanism of action. Conclusion Our data expand the spectrum of variants and phenotypic spectrum associated with homozygous variants of SMAD6 to include craniosynostosis. [ABSTRACT FROM AUTHOR]

Published
2024
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14. A variant in IL6ST with a selective IL-11 signaling defect in human and mouse

Author

Schwerd, Tobias, Krause, Freia, Twigg, Stephen R. F., Aschenbrenner, Dominik, Chen, Yin-Huai, Borgmeyer, Uwe, Müller, Miryam, Manrique, Santiago, Schumacher, Neele, Wall, Steven A., Jung, Jonathan, Damm, Timo, Glüer, Claus-Christian, Scheller, Jürgen, Rose-John, Stefan, Jones, E. Yvonne, Laurence, Arian, Wilkie, Andrew O. M., Schmidt-Arras, Dirk, and Uhlig, Holm H.

Published
2020
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15. Use of genome sequencing to hunt for cryptic second-hit variants: analysis of 31 cases recruited to the 100 000 Genomes Project.

Author

Moore, A. Rachel, Jing Yu, Yang Pei, Cheng, Emily W. Y., Taylor Tavares, Ana Lisa, Walker, Woolf T., Thomas, N. Simon, Kamath, Arveen, Ibitoye, Rita, Josifova, Dragana, Wilsdon, Anna, Ross, Alison, Calder, Alistair D., Offiah, Amaka C., Wilkie, Andrew O. M., Taylor, Jenny C., and Pagnamenta, Alistair T.

Abstract

Background Current clinical testing methods used to uncover the genetic basis of rare disease have inherent limitations, which can lead to causative pathogenic variants being missed. Within the rare disease arm of the 100 000 Genomes Project (100kGP), families were recruited under the clinical indication ’single autosomal recessive mutation in rare disease’. These participants presented with strong clinical suspicion for a specific autosomal recessive disorder, but only one suspected pathogenic variant had been identified through standard-of-care testing. Whole genome sequencing (WGS) aimed to identify cryptic ’second-hit’ variants. Methods To investigate the 31 families with available data that remained unsolved following formal review within the 100kGP, SVRare was used to aggregate structural variants present in <1% of 100kGP participants. Small variants were assessed using population allele frequency data and SpliceAI. Literature searches and publicly available online tools were used for further annotation of pathogenicity. Results Using these strategies, 8/31 cases were solved, increasing the overall diagnostic yield of this cohort from 10/41 (24.4%) to 18/41 (43.9%). Exemplar cases include a patient with cystic fibrosis harbouring a novel exonic LINE1 insertion in CFTR and a patient with generalised arterial calcification of infancy with complex interlinked duplications involving exons 2–6 of ENPP1. Although ambiguous by short-read WGS, the ENPP1 variant structure was resolved using optical genome mapping and RNA analysis. Conclusion Systematic examination of cryptic variants across a multi-disease cohort successfully identifies additional pathogenic variants. WGS data analysis in autosomal recessive rare disease should consider complex structural and small intronic variants as potentially pathogenic second hits. [ABSTRACT FROM AUTHOR]

Published
2023
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16. HUWE1 variants cause dominant X-linked intellectual disability: a clinical study of 21 patients

Author

Moortgat, Stéphanie, Berland, Siren, Aukrust, Ingvild, Maystadt, Isabelle, Baker, Laura, Benoit, Valerie, Caro-Llopis, Alfonso, Cooper, Nicola S., Debray, François-Guillaume, Faivre, Laurence, Gardeitchik, Thatjana, Haukanes, Bjørn I., Houge, Gunnar, Kivuva, Emma, Martinez, Francisco, Mehta, Sarju G., Nassogne, Marie-Cécile, Powell-Hamilton, Nina, Pfundt, Rolph, Rosello, Monica, Prescott, Trine, Vasudevan, Pradeep, van Loon, Barbara, Verellen-Dumoulin, Christine, Verloes, Alain, Lippe, Charlotte von der, Wakeling, Emma, Wilkie, Andrew O. M., Wilson, Louise, Yuen, Amy, Study, DDD, Low, Karen J., and Newbury-Ecob, Ruth A.

Published
2018
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17. Development of Erf-Mediated Craniosynostosis and Pharmacological Amelioration

Author

Vogiatzi, Angeliki, primary, Keklikoglou, Kleoniki, additional, Makris, Konstantinos, additional, Argyrou, Dionysia Stamatia, additional, Zacharopoulos, Athanasios, additional, Sotiropoulou, Varvara, additional, Parthenios, Nikolaos, additional, Gkikas, Angelos, additional, Kokkori, Maria, additional, Richardson, Melodie S. W., additional, Fenwick, Aimée L., additional, Archontidi, Sofia, additional, Arvanitidis, Christos, additional, Robertson, Jeremy, additional, Parthenios, John, additional, Zacharakis, Giannis, additional, Twigg, Stephen R. F., additional, Wilkie, Andrew O. M., additional, and Mavrothalassitis, George, additional

Published
2023
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18. Pathogenic variants in the paired-related homeobox 1 gene (PRRX1) cause craniosynostosis with incomplete penetrance

Author

Tooze, R., Miller, K.A., Swagemakers, S.M.A., Calpena, E., McGowan, Simon J., Boute, Odile, Leeuw, N. de, Ockeloen, Charlotte W., Twigg, S.R.F., Wilkie, Andrew O. M., Tooze, R., Miller, K.A., Swagemakers, S.M.A., Calpena, E., McGowan, Simon J., Boute, Odile, Leeuw, N. de, Ockeloen, Charlotte W., Twigg, S.R.F., and Wilkie, Andrew O. M.

Abstract

Item does not contain fulltext

Published
2023

20. Homozygous SMAD6variants in two unrelated patients with craniosynostosis and radioulnar synostosis

Author

Luyckx, Ilse, Walton, Isaac Scott, Boeckx, Nele, Van Schil, Kristof, Pang, Chingyiu, De Praeter, Mania, Lord, Helen, Watson, Christopher Mark, Bonthron, David T, Van Laer, Lut, Wilkie, Andrew O M, and Loeys, Bart

Abstract

BackgroundSMAD6encodes an intracellular inhibitor of the bone morphogenetic protein (BMP) signalling pathway. Until now, rare heterozygous loss-of-function variants in SMAD6were demonstrated to increase the risk of disparate clinical disorders including cardiovascular disease, craniosynostosis and radioulnar synostosis. Only two unrelated patients harbouring biallelic SMAD6variants presenting a complex cardiovascular phenotype and facial dysmorphism have been described.CasesHere, we present the first two patients with craniosynostosis harbouring homozygous SMAD6variants. The male probands, both born to healthy consanguineous parents, were diagnosed with metopic synostosis and bilateral or unilateral radioulnar synostosis. Additionally, one proband had global developmental delay. Echocardiographic evaluation did not reveal cardiac or outflow tract abnormalities.Molecular analysesThe novel missense (c.[584T>G];[584T>G], p.[(Val195Gly)];[(Val195Gly)]) and missense/splice-site variant (c.[817G>A];[817G>A], r.[(817g>a,817delins[a;817+2_817+228])];[(817g>a,817delins[a;817+2_817+228])], p.[(Glu273Lys,Glu273Serfs*72)];[(Glu273Lys,Glu273Serfs*72)]) both locate in the functional MH1 domain of the protein and have not been reported in gnomAD database. Functional analyses of the variants showed reduced inhibition of BMP signalling or abnormal splicing, respectively, consistent with a hypomorphic mechanism of action.ConclusionOur data expand the spectrum of variants and phenotypic spectrum associated with homozygous variants of SMAD6to include craniosynostosis.

Published
2024
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21. Implementation of a genomic medicine multi-disciplinary team approach for rare disease in the clinical setting: a prospective exome sequencing case series

Author

Taylor, John, Craft, Jude, Blair, Edward, Wordsworth, Sarah, Beeson, David, Chandratre, Saleel, Cossins, Judith, Lester, Tracy, Németh, Andrea H., Ormondroyd, Elizabeth, Patel, Smita Y., Pagnamenta, Alistair T., Taylor, Jenny C., Thomson, Kate L., Watkins, Hugh, Wilkie, Andrew O. M., and Knight, Julian C.

Published
2019
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25. Whole genome sequencing of ‘mutation-negative’ individuals with Cornelia de Lange Syndrome

Author

Ansari, Morad, primary, Halachev, Mihail, additional, Parry, David, additional, Campos, Jose L., additional, D’Souza, Elston N., additional, Barnett, Christopher, additional, Wilkie, Andrew O. M., additional, Barnicoat, Angela, additional, Patel, Chirag V., additional, Sukarova-Angelovska, Elena, additional, Girisha, Katta M., additional, Firth, Helen V., additional, Prescott, Katrina, additional, Wilson, Louise C., additional, McEntagart, Meriel, additional, Davidson, Rosemarie, additional, Lynch, Sally Ann, additional, Joss, Shelagh, additional, Holden, Simon T., additional, Lam, Wayne K., additional, Sisodiya, Sanjay M., additional, Green, Andrew J., additional, Poke, Gemma, additional, Whiffin, Nicola, additional, FitzPatrick, David R., additional, and Meynert, Alison, additional

Published
2022
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26. Heterozygous mutations affecting the protein kinase domain of CDK13 cause a syndromic form of developmental delay and intellectual disability

Author

Hamilton, Mark J, Caswell, Richard C, Canham, Natalie, Cole, Trevor, Firth, Helen V, Foulds, Nicola, Heimdal, Ketil, Hobson, Emma, Houge, Gunnar, Joss, Shelagh, Kumar, Dhavendra, Lampe, Anne Katrin, Maystadt, Isabelle, McKay, Victoria, Metcalfe, Kay, Newbury-Ecob, Ruth, Park, Soo-Mi, Robert, Leema, Rustad, Cecilie F, Wakeling, Emma, Wilkie, Andrew O M, Study, The Deciphering Developmental Disorders, Twigg, Stephen R F, and Suri, Mohnish

Published
2018
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27. Contributions of intrinsic mutation rate and selfish selection to levels of de novo HRAS mutations in the paternal germline

Author

Giannoulatou, Eleni, McVean, Gilean, Taylor, Indira B., McGowan, Simon J., Maher, Geoffrey J., Iqbal, Zamin, Pfeifer, Susanne P., Turner, Isaac, Wright, Emma M. M. Burkitt, Shorto, Jennifer, Itani, Aysha, Turner, Karen, Gregory, Lorna, Buck, David, Meyts, Ewa Rajpert-De, Looijenga, Leendert H. J., Kerr, Bronwyn, Wilkie, Andrew O. M., and Goriely, Anne

Published
2013

28. Craniosynostosis, inner ear, and renal anomalies in a child with complete loss of SPRY1 (sprouty homolog 1) function.

Author

Tooze, Rebecca S., Calpena, Eduardo, Twigg, Stephen R. F., D'Arco, Felice, Wakeling, Emma L., and Wilkie, Andrew O. M.

Abstract

Introduction SPRY1 encodes protein sprouty homolog 1 (Spry-1), a negative regulator of receptor tyrosine kinase signalling. Null mutant mice display kidney/urinary tract abnormalities and altered size of the skull; complete loss-of-function of Spry-1 in humans has not been reported. Methods Analysis of whole-genome sequencing data from individuals with craniosynostosis enrolled in the 100,000 Genomes Project identified a likely pathogenic variant within SPRY1. Reverse-transcriptase PCR and western blot analysis were used to investigate the effect of the variant on SPRY1 mRNA and protein, in lymphoblastoid cell lines from the patient and both parents. Results A nonsense variant in SPRY1, encoding p.(Leu27*), was confirmed to be heterozygous in the unaffected parents and homozygous in the child. The child's phenotype, which included sagittal craniosynostosis, subcutaneous cystic lesions overlying the lambdoid sutures, hearing loss associated with bilateral cochlear and vestibular dysplasia and a unilateral renal cyst, overlapped the features reported in Spry1-/- null mice. Functional studies supported escape from nonsense-mediated decay, but western blot analysis demonstrated complete absence of full-length protein in the affected child and a marked reduction in both parents. Conclusion This is the first report of complete loss of Spry-1 function in humans, associated with abnormalities of the cranial sutures, inner ear, and kidneys. [ABSTRACT FROM AUTHOR]

Published
2023
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30. The PREGCARE study: Personalized recurrence risk assessment following the birth of a child with a pathogenic de novo mutation

Author

Bernkopf, Marie, primary, Abdullah, Ummi B., additional, Bush, Stephen J., additional, Wood, Katherine, additional, Ghaffari, Sahar, additional, Giannoulatou, Eleni, additional, Koelling, Nils, additional, Maher, Geoffrey J., additional, Thibault, Loïc M., additional, Williams, Jonathan, additional, Blair, Edward M., additional, Kelly, Fiona Blanco, additional, Bloss, Angela, additional, Burkitt-Wright, Emma, additional, Canham, Natalie, additional, Deng, Alexander T., additional, Dixit, Abhijit, additional, Eason, Jacqueline, additional, Elmslie, Frances, additional, Gardham, Alice, additional, Hay, Eleanor, additional, Holder, Muriel, additional, Homfray, Tessa, additional, Hurst, Jane A., additional, Johnson, Diana, additional, Jones, Wendy D., additional, Kini, Usha, additional, Kivuva, Emma, additional, Kumar, Ajith, additional, Lees, Melissa M., additional, Leitch, Harry G., additional, Morton, Jenny E. V., additional, Németh, Andrea H., additional, Ramachandrappa, Shwetha, additional, Saunders, Katherine, additional, Shears, Deborah J., additional, Side, Lucy, additional, Splitt, Miranda, additional, Stewart, Alison, additional, Stewart, Helen, additional, Suri, Mohnish, additional, Clouston, Penny, additional, Davies, Robert W., additional, Wilkie, Andrew O. M., additional, and Goriely, Anne, additional

Published
2022
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31. Recurrent de novo missense variants across multiple histone H4 genes underlie a neurodevelopmental syndrome

Author

Tessadori, Federico, Duran, Karen, Knapp, Karen, Fellner, Matthias, Deciphering Developmental Disorders Study, Smithson, Sarah, Beleza Meireles, Ana, Elting, Mariet W, Waisfisz, Quinten, O'Donnell-Luria, Anne, Nowak, Catherine, Douglas, Jessica, Ronan, Anne, Brunet, Theresa, Kotzaeridou, Urania, Svihovec, Shayna, Saenz, Margarita S, Thiffault, Isabelle, Del Viso, Florencia, Devine, Patrick, Rego, Shannon, Tenney, Jessica, van Haeringen, Arie, Ruivenkamp, Claudia A L, Koene, Saskia, Robertson, Stephen P, Deshpande, Charulata, Pfundt, Rolph, Verbeek, Nienke, van de Kamp, Jiddeke M, Weiss, Janneke M M, Ruiz, Anna, Gabau, Elisabeth, Banne, Ehud, Pepler, Alexander, Bottani, Armand, Laurent, Sacha, Guipponi, Michel, Bijlsma, Emilia, Bruel, Ange-Line, Sorlin, Arthur, Willis, Mary, Powis, Zoe, Smol, Thomas, Vincent-Delorme, Catherine, Baralle, Diana, Colin, Estelle, Revencu, Nicole, Calpena, Eduardo, Wilkie, Andrew O M, Chopra, Maya, Cormier-Daire, Valerie, Keren, Boris, Afenjar, Alexandra, Niceta, Marcello, Terracciano, Alessandra, Specchio, Nicola, Tartaglia, Marco, Rio, Marlene, Barcia, Giulia, Rondeau, Sophie, Colson, Cindy, Bakkers, Jeroen, Mace, Peter D, Bicknell, Louise S, van Haaften, Gijs, Study, Deciphering Developmental Disorders, UCL - SSS/IREC/SLUC - Pôle St.-Luc, UCL - (SLuc) Centre de génétique médicale UCL, UCL - (SLuc) Centre de malformations vasculaires congénitales, Human genetics, Amsterdam Reproduction & Development (AR&D), Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Gastroenterology Endocrinology Metabolism, and Hubrecht Institute for Developmental Biology and Stem Cell Research

Subjects
Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], nucleosome, Histones/metabolism, DNA, Syndrome, zebrafish, neurodevelopmental disorder, Chromatin, Zebrafish/genetics, Histones, histone H4, intellectual disability, Tumours of the digestive tract Radboud Institute for Molecular Life Sciences [Radboudumc 14], Genetics, Animals, Humans, microcephaly, Zebrafish, Genetics (clinical)
Abstract

Contains fulltext : 252023.pdf (Publisher’s version ) (Open Access) Chromatin is essentially an array of nucleosomes, each of which consists of the DNA double-stranded fiber wrapped around a histone octamer. This organization supports cellular processes such as DNA replication, DNA transcription, and DNA repair in all eukaryotes. Human histone H4 is encoded by fourteen canonical histone H4 genes, all differing at the nucleotide level but encoding an invariant protein. Here, we present a cohort of 29 subjects with de novo missense variants in six H4 genes (H4C3, H4C4, H4C5, H4C6, H4C9, and H4C11) identified by whole-exome sequencing and matchmaking. All individuals present with neurodevelopmental features of intellectual disability and motor and/or gross developmental delay, while non-neurological features are more variable. Ten amino acids are affected, six recurrently, and are all located within the H4 core or C-terminal tail. These variants cluster to specific regions of the core H4 globular domain, where protein-protein interactions occur with either other histone subunits or histone chaperones. Functional consequences of the identified variants were evaluated in zebrafish embryos, which displayed abnormal general development, defective head organs, and reduced body axis length, providing compelling evidence for the causality of the reported disorder(s). While multiple developmental syndromes have been linked to chromatin-associated factors, missense-bearing histone variants (e.g., H3 oncohistones) are only recently emerging as a major cause of pathogenicity. Our findings establish a broader involvement of H4 variants in developmental syndromes.

Published
2022

32. Recurrent de novo missense variants across multiple histone H4 genes underlie a neurodevelopmental syndrome.

Author

UCL - SSS/IREC/SLUC - Pôle St.-Luc, UCL - (SLuc) Centre de génétique médicale UCL, UCL - (SLuc) Centre de malformations vasculaires congénitales, Tessadori, Federico, Duran, Karen, Knapp, Karen, Fellner, Matthias, Deciphering Developmental Disorders Study, Smithson, Sarah, Beleza Meireles, Ana, Elting, Mariet W, Waisfisz, Quinten, O'Donnell-Luria, Anne, Nowak, Catherine, Douglas, Jessica, Ronan, Anne, Brunet, Theresa, Kotzaeridou, Urania, Svihovec, Shayna, Saenz, Margarita S, Thiffault, Isabelle, Del Viso, Florencia, Devine, Patrick, Rego, Shannon, Tenney, Jessica, van Haeringen, Arie, Ruivenkamp, Claudia A L, Koene, Saskia, Robertson, Stephen P, Deshpande, Charulata, Pfundt, Rolph, Verbeek, Nienke, van de Kamp, Jiddeke M, Weiss, Janneke M M, Ruiz, Anna, Gabau, Elisabeth, Banne, Ehud, Pepler, Alexander, Bottani, Armand, Laurent, Sacha, Guipponi, Michel, Bijlsma, Emilia, Bruel, Ange-Line, Sorlin, Arthur, Willis, Mary, Powis, Zoe, Smol, Thomas, Vincent-Delorme, Catherine, Baralle, Diana, Colin, Estelle, Revencu, Nicole, Calpena, Eduardo, Wilkie, Andrew O M, Chopra, Maya, Cormier-Daire, Valerie, Keren, Boris, Afenjar, Alexandra, Niceta, Marcello, Terracciano, Alessandra, Specchio, Nicola, Tartaglia, Marco, Rio, Marlene, Barcia, Giulia, Rondeau, Sophie, Colson, Cindy, Bakkers, Jeroen, Mace, Peter D, Bicknell, Louise S, van Haaften, Gijs, UCL - SSS/IREC/SLUC - Pôle St.-Luc, UCL - (SLuc) Centre de génétique médicale UCL, UCL - (SLuc) Centre de malformations vasculaires congénitales, Tessadori, Federico, Duran, Karen, Knapp, Karen, Fellner, Matthias, Deciphering Developmental Disorders Study, Smithson, Sarah, Beleza Meireles, Ana, Elting, Mariet W, Waisfisz, Quinten, O'Donnell-Luria, Anne, Nowak, Catherine, Douglas, Jessica, Ronan, Anne, Brunet, Theresa, Kotzaeridou, Urania, Svihovec, Shayna, Saenz, Margarita S, Thiffault, Isabelle, Del Viso, Florencia, Devine, Patrick, Rego, Shannon, Tenney, Jessica, van Haeringen, Arie, Ruivenkamp, Claudia A L, Koene, Saskia, Robertson, Stephen P, Deshpande, Charulata, Pfundt, Rolph, Verbeek, Nienke, van de Kamp, Jiddeke M, Weiss, Janneke M M, Ruiz, Anna, Gabau, Elisabeth, Banne, Ehud, Pepler, Alexander, Bottani, Armand, Laurent, Sacha, Guipponi, Michel, Bijlsma, Emilia, Bruel, Ange-Line, Sorlin, Arthur, Willis, Mary, Powis, Zoe, Smol, Thomas, Vincent-Delorme, Catherine, Baralle, Diana, Colin, Estelle, Revencu, Nicole, Calpena, Eduardo, Wilkie, Andrew O M, Chopra, Maya, Cormier-Daire, Valerie, Keren, Boris, Afenjar, Alexandra, Niceta, Marcello, Terracciano, Alessandra, Specchio, Nicola, Tartaglia, Marco, Rio, Marlene, Barcia, Giulia, Rondeau, Sophie, Colson, Cindy, Bakkers, Jeroen, Mace, Peter D, Bicknell, Louise S, and van Haaften, Gijs

Abstract

Chromatin is essentially an array of nucleosomes, each of which consists of the DNA double-stranded fiber wrapped around a histone octamer. This organization supports cellular processes such as DNA replication, DNA transcription, and DNA repair in all eukaryotes. Human histone H4 is encoded by fourteen canonical histone H4 genes, all differing at the nucleotide level but encoding an invariant protein. Here, we present a cohort of 29 subjects with de novo missense variants in six H4 genes (H4C3, H4C4, H4C5, H4C6, H4C9, and H4C11) identified by whole-exome sequencing and matchmaking. All individuals present with neurodevelopmental features of intellectual disability and motor and/or gross developmental delay, while non-neurological features are more variable. Ten amino acids are affected, six recurrently, and are all located within the H4 core or C-terminal tail. These variants cluster to specific regions of the core H4 globular domain, where protein-protein interactions occur with either other histone subunits or histone chaperones. Functional consequences of the identified variants were evaluated in zebrafish embryos, which displayed abnormal general development, defective head organs, and reduced body axis length, providing compelling evidence for the causality of the reported disorder(s). While multiple developmental syndromes have been linked to chromatin-associated factors, missense-bearing histone variants (e.g., H3 oncohistones) are only recently emerging as a major cause of pathogenicity. Our findings establish a broader involvement of H4 variants in developmental syndromes.

Published
2022

34. Targeted Sequencing of Candidate Regions Associated with Sagittal and Metopic Nonsyndromic Craniosynostosis

Author

Justice, Cristina M., primary, Musolf, Anthony M., additional, Cuellar, Araceli, additional, Lattanzi, Wanda, additional, Simeonov, Emil, additional, Kaneva, Radka, additional, Paschall, Justin, additional, Cunningham, Michael, additional, Wilkie, Andrew O. M., additional, Wilson, Alexander F., additional, Romitti, Paul A., additional, and Boyadjiev, Simeon A., additional

Published
2022
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37. Whole-genome sequencing of patients with rare diseases in a national health system

Author

Turro, Ernest, Astle, William J., Megy, Karyn, Gräf, Stefan, Greene, Daniel, Shamardina, Olga, Allen, Hana Lango, Sanchis-Juan, Alba, Frontini, Mattia, Thys, Chantal, Stephens, Jonathan, Mapeta, Rutendo, Burren, Oliver S., Downes, Kate, Haimel, Matthias, Tuna, Salih, Deevi, Sri V.V., Aitman, Timothy J., Bennett, David L., Calleja, Paul, Carss, Keren, Caulfield, Mark J., Chinnery, Patrick F., Dixon, Peter H., Gale, Daniel P., James, Roger, Koziell, Ania, Laffan, Michael A., Levine, Adam P., Maher, Eamonn R., Markus, Hugh S., Morales, Joannella, Morrell, Nicholas W., Mumford, Andrew D., Ormondroyd, Elizabeth, Rankin, Stuart, Rendon, Augusto, Richardson, Sylvia, Roberts, Irene, Roy, Noemi B.A., Saleem, Moin A., Smith, Kenneth G.C., Stark, Hannah, Tan, Rhea Y.Y., Themistocleous, Andreas C., Thrasher, Adrian J., Watkins, Hugh, Webster, Andrew R., Wilkins, Martin R., Williamson, Catherine, Whitworth, James, Humphray, Sean, Bentley, David R., Abbs, Stephen, Abulhoul, Lara, Adlard, Julian, Ahmed, Munaza, Alachkar, Hana, Allsup, David J., Almeida-King, Jeff, Ancliff, Philip, Antrobus, Richard, Armstrong, Ruth, Arno, Gavin, Ashford, Sofie, Attwood, Anthony, Aurora, Paul, Babbs, Christian, Bacchelli, Chiara, Bakchoul, Tamam, Banka, Siddharth, Bariana, Tadbir, Barwell, Julian, Batista, Joana, Baxendale, Helen E., Beales, Phil L., Bierzynska, Agnieszka, Biss, Tina, Bitner-Glindzicz, Maria A.K., Black, Graeme C., Bleda, Marta, Blesneac, Iulia, Bockenhauer, Detlef, Bogaard, Harm, Bourne, Christian J., Boyce, Sara, Bradley, John R., Bragin, Eugene, Breen, Gerome, Brennan, Paul, Brewer, Carole, Brown, Matthew, Browning, Andrew C., Browning, Michael J., Buchan, Rachel J., Buckland, Matthew S., Bueser, Teofila, Diz, Carmen Bugarin, Burn, John, Burns, Siobhan O., Burrows, Nigel, Campbell, Carolyn, Carr-White, Gerald, Casey, Ruth, Chambers, Jenny, Chambers, John, Chan, Melanie M.Y., Cheah, Calvin, Cheng, Floria, Chitre, Manali, Christian, Martin T., Church, Colin, Clayton-Smith, Jill, Cleary, Maureen, Brod, Naomi Clements, Coghlan, Gerry, Colby, Elizabeth, Cole, Trevor R.P., Collins, Janine, Collins, Peter W., Colombo, Camilla, Compton, Cecilia J., Condliffe, Robin, Cook, Stuart, Cook, H. Terence, Cooper, Nichola, Corris, Paul A A., Furnell, Abigail, Cunningham, Fiona, Curry, Nicola S., Cutler, Antony J., Daniels, Matthew J., Dattani, Mehul, Daugherty, Louise C., Davis, John, De Soyza, Anthony, Dent, Timothy, Deshpande, Charu, Dewhurst, Eleanor F., Douzgou, Sofia, Drazyk, Anna M., Drewe, Elizabeth, Duarte, Daniel, Dutt, Tina, Edgar, J. David M., Edwards, Karen, Egner, William, Ekani, Melanie N., Elliott, Perry, Erber, Wendy N., Erwood, Marie, Estiu, Maria C., Evans, Dafydd Gareth, Evans, Gillian, Everington, Tamara, Eyries, Mélanie, Fassihi, Hiva, Favier, Remi, Findhammer, Jack, Fletcher, Debra, Flinter, Frances A., Floto, R. Andres, Fowler, Tom, Fox, James, Frary, Amy J., French, Courtney E., Freson, Kathleen, Gall, Henning, Ganesan, Vijeya, Gattens, Michael, Geoghegan, Claire, Gerighty, Terence S.A., Gharavi, Ali G., Ghio, Stefano, Ghofrani, Hossein Ardeschir, Gibbs, J. Simon R., Gibson, Kate, Gilmour, Kimberly C., Girerd, Barbara, Gleadall, Nicholas S., Goddard, Sarah, Goldstein, David B., Gomez, Keith, Gordins, Pavels, Gosal, David, Graham, Jodie, Grassi, Luigi, Greenhalgh, Lynn, Greinacher, Andreas, Gresele, Paolo, Griffiths, Philip, Grigoriadou, Sofia, Grocock, Russell J., Grozeva, Detelina, Gurnell, Mark, Hackett, Scott, Hadinnapola, Charaka, Hague, William M., Hague, Rosie, Hall, Matthew, Hanson, Helen L., Haque, Eshika, Harkness, Kirsty, Harper, Andrew R., Harris, Claire L L., Hart, Daniel, Hassan, Ahamad, Hayman, Grant, Henderson, Alex, Herwadkar, Archana, Hoffman, Jonathan, Holden, Simon, Horvath, Rita, Houlden, Henry, Houweling, Arjan C C., Howard, Luke S., Hu, Fengyuan, Hudson, Gavin, Hughes, Joseph, Huissoon, Aarnoud P., Humbert, Marc, Hunter, Sarah, Hurles, Matthew, Irving, Melita, Izatt, Louise, Johnson, Sally A., Jolles, Stephen, Jolley, Jennifer, Josifova, Dragana, Jurkute, Neringa, Karten, Tim, Karten, Johannes, Kasanicki, Mary A., Kazkaz, Hanadi, Kazmi, Rashid, Kelleher, Peter, Kelly, Anne M., Kelsall, Wilf, Kempster, Carly, Kiely, David G., Kingston, Nathalie, Klima, Robert, Koelling, Nils, Kostadima, Myrto, Kovacs, Gabor, Kreuzhuber, Roman, Kuijpers, Taco W., Kumar, Ajith, Kumararatne, Dinakantha, Kurian, Manju A., Lalloo, Fiona, Lambert, Michele, Lawrie, Allan, Layton, D. Mark, Lench, Nick, Lentaigne, Claire, Lester, Tracy, Linger, Rachel, Longhurst, Hilary, Lorenzo, Lorena E., Louka, Eleni, Lyons, Paul A., Machado, Rajiv D., MacKenzie Ross, Robert V., Madan, Bella, Maimaris, Jesmeen, Malka, Samantha, Mangles, Sarah, Marchbank, Kevin J., Marks, Stephen, Marschall, Hanns Ulrich, Marshall, Andrew, Martin, Jennifer, Mathias, Mary, Matthews, Emma, Maxwell, Heather, McAlinden, Paul, McCarthy, Mark I., McKinney, Harriet, McMahon, Aoife, Meacham, Stuart, Mead, Adam J., Castello, Ignacio Medina, Mehta, Sarju G G., Michaelides, Michel, Millar, Carolyn, Mohammed, Shehla N., Moledina, Shahin, Montani, David, Moore, Anthony T., Mozere, Monika, Muir, Keith W., Nemeth, Andrea H., Newman, William G., Newnham, Michael, Noorani, Sadia, Nurden, Paquita, O’Sullivan, Jennifer, Obaji, Samya, Odhams, Chris, Okoli, Steven, Olschewski, Andrea, Olschewski, Horst, Ong, Kai Ren, Oram, S. Helen, Ouwehand, Willem H., Palles, Claire, Papadia, Sofia, Park, Soo Mi, Parry, David, Patel, Smita, Paterson, Joan, Peacock, Andrew, Pearce, Simon H H., Peden, John, Peerlinck, Kathelijne, Penkett, Christopher J., Pepke-Zaba, Joanna, Petersen, Romina, Pilkington, Clarissa, Poole, Kenneth E.S., Prathalingam, Radhika, Psaila, Bethan, Pyle, Angela, Quinton, Richard, Rahman, Shamima, Rao, Anupama, Raymond, F. Lucy, Rayner-Matthews, Paula J., Rees, Christine, Renton, Tara, Rhodes, Christopher J., Rice, Andrew S.C., Richter, Alex, Robert, Leema, Rogers, Anthony, Rose, Sarah J., Ross-Russell, Robert, Roughley, Catherine, Roy, Noemi B. A, Ruddy, Deborah M., Sadeghi-Alavijeh, Omid, Samani, Nilesh, Samarghitean, Crina, Sargur, Ravishankar B., Sarkany, Robert N., Satchell, Simon, Savic, Sinisa, Sayer, John A., Sayer, Genevieve, Scelsi, Laura, Schaefer, Andrew M., Schulman, Sol, Scott, Richard, Scully, Marie, Searle, Claire, Seeger, Werner, Sen, Arjune, Sewell, W. A.Carrock, Seyres, Denis, Shah, Neil, Shapiro, Susan E., Shaw, Adam C., Short, Patrick J., Sibson, Keith, Side, Lucy, Simeoni, Ilenia, Simpson, Michael A A., Sims, Matthew C., Sivapalaratnam, Suthesh, Smedley, Damian, Smith, Katherine R., Snape, Katie, Soranzo, Nicole, Soubrier, Florent, Southgate, Laura, Spasic-Boskovic, Olivera, Staines, Simon, Staples, Emily, Steward, Charles, Stirrups, Kathleen E., Stuckey, Alex, Suntharalingam, Jay, Swietlik, Emilia M., Syrris, Petros, Tait, R. Campbell, Talks, Kate, Tate, Katie, Taylor, John M., Taylor, Jenny C., Thaventhiran, James E., Thomas, Ellen, Thomas, David, Thomas, Moira J., Thomas, Patrick, Thomson, Kate, Threadgold, Glen, Tilly, Tobias, Tischkowitz, Marc, Titterton, Catherine, Todd, John A., Toh, Cheng Hock, Tolhuis, Bas, Tomlinson, Ian P., Toshner, Mark, Traylor, Matthew, Treacy, Carmen, Treadaway, Paul, Trembath, Richard, Turek, Wojciech, Twiss, Philip, Vale, Tom, Geet, Chris Van, Zuydam, Natalie van, Vandekuilen, Maarten, Vandersteen, Anthony M., Vazquez-Lopez, Marta, von Ziegenweidt, Julie, Vonk Noordegraaf, Anton, Wagner, Annette, Waisfisz, Quinten, Walker, Suellen M., Walker, Neil, Walter, Klaudia, Ware, James S., Watt, Christopher, Wedderburn, Lucy, Wei, Wei, Welch, Steven B., Wessels, Julie, Westbury, Sarah K., Westwood, John Paul, Wharton, John, Whitehorn, Deborah, Wilkie, Andrew O. M, Wilson, Brian T., Wong, Edwin K.S., Wood, Nicholas, Wood, Yvette, Woods, Christopher Geoffrey, Woodward, Emma R R., Wort, Stephen J., Worth, Austen, Wright, Michael, Yates, Katherine, Yong, Patrick F.K., Young, Timothy, Yu, Ping, Yu-Wai-Man, Patrick, Zlamalova, Eliska, University of Cambridge [UK] (CAM), John Wyeth & Brother Limited, Medical Research Council (MRC), Wellcome Trust, Pulmonary medicine, ACS - Pulmonary hypertension & thrombosis, Human genetics, ACS - Atherosclerosis & ischemic syndromes, Landsteiner Laboratory, Paediatric Infectious Diseases / Rheumatology / Immunology, ARD - Amsterdam Reproduction and Development, and Project, NIHR BioResource for the 100,000 Genomes

Subjects
0301 basic medicine, Erythrocytes, Internationality, Databases, Factual, National Health Programs, [SDV]Life Sciences [q-bio], Disease, VARIANTS, Genome, State Medicine, NIHR BioResource for the 100,000 Genomes Project, 0302 clinical medicine, Medicine, GATA1 Transcription Factor, Genetics, Multidisciplinary, Translational bioinformatics, ASSOCIATION, 3. Good health, Multidisciplinary Sciences, Phenotype, 030220 oncology & carcinogenesis, disease genetics, Medical genetics, Science & Technology - Other Topics, Receptors, Thrombopoietin, medicine.medical_specialty, General Science & Technology, Quantitative Trait Loci, Genomics, Computational biology, Biology, DIAGNOSIS, computational biology and bioinformatics, Actin-Related Protein 2-3 Complex, Article, LRBA, LINKS, 03 medical and health sciences, Rare Diseases, Humans, Alleles, Adaptor Proteins, Signal Transducing, Whole genome sequencing, National health, Science & Technology, Whole Genome Sequencing, MUTATIONS, business.industry, THROMBOCYTOPENIA, United Kingdom, MACROTHROMBOCYTOPENIA, genetics research, 030104 developmental biology, business, Rare disease
Abstract

Most patients with rare diseases do not receive a molecular diagnosis and the aetiological variants and causative genes for more than half such disorders remain to be discovered1. Here we used whole-genome sequencing (WGS) in a national health system to streamline diagnosis and to discover unknown aetiological variants in the coding and non-coding regions of the genome. We generated WGS data for 13,037 participants, of whom 9,802 had a rare disease, and provided a genetic diagnosis to 1,138 of the 7,065 extensively phenotyped participants. We identified 95 Mendelian associations between genes and rare diseases, of which 11 have been discovered since 2015 and at least 79 are confirmed to be aetiological. By generating WGS data of UK Biobank participants2, we found that rare alleles can explain the presence of some individuals in the tails of a quantitative trait for red blood cells. Finally, we identified four novel non-coding variants that cause disease through the disruption of transcription of ARPC1B, GATA1, LRBA and MPL. Our study demonstrates a synergy by using WGS for diagnosis and aetiological discovery in routine healthcare.

Published
2021

38. Selective loss of function variants in IL6ST cause Hyper-IgE syndrome with distinct impairments of T-cell phenotype and function

Author

Shahin, Tala, Aschenbrenner, Dominik, Cagdas, Deniz, Bal, Sevgi Köstel, Conde, Cecilia Domínguez, Garncarz, Wojciech, Medgyesi, David, Schwerd, Tobias, Karaatmaca, Betül, Cetinkaya, Pınar Gur, Esenboga, Saliha, Twigg, Stephen R. F., Cant, Andrew, Wilkie, Andrew O. M., Tezcan, Ilhan, Uhlig, Holm H., and Boztug, Kaan

Subjects
Male, Models, Molecular, Protein Conformation, DNA Mutational Analysis, Cell Differentiation, Lymphocyte Activation, Article, Immunodeficiencies, Immunophenotyping, Pedigree, Radiography, Phenotype, Loss of Function Mutation, T-Lymphocyte Subsets, Child, Preschool, Cytokine Receptor gp130, Humans, Disease Susceptibility, Child, Job Syndrome, Biomarkers, Genetic Association Studies
Abstract

Hyper-IgE syndromes comprise a group of inborn errors of immunity. STAT3-deficient hyper-IgE syndrome is characterized by elevated serum IgE levels, recurrent infections and eczema, and characteristic skeletal anomalies. A loss-of-function biallelic mutation in IL6ST encoding the GP130 receptor subunit (p.N404Y) has very recently been identified in a singleton patient (herein referred to as PN404Y) as a novel etiology of hyper-IgE syndrome. Here, we studied a patient with hyper-IgE syndrome caused by a novel homozygous mutation in IL6ST (p.P498L; patient herein referred to as PP498L) leading to abrogated GP130 signaling after stimulation with IL-6 and IL-27 in peripheral blood mononuclear cells as well as IL-6 and IL-11 in fibroblasts. Extending the initial identification of selective GP130 deficiency, we aimed to dissect the effects of aberrant cytokine signaling on T-helper cell differentiation in both patients. Our results reveal the importance of IL-6 signaling for the development of CCR6-expressing memory CD4+ T cells (including T-helper 17-enriched subsets) and non-conventional CD8+T cells which were reduced in both patients. Downstream functional analysis of the GP130 mutants (p.N404Y and p.P498L) have shown differences in response to IL-27, with the p.P498L mutation having a more severe effect that is reflected by reduced T-helper 1 cells in this patient (PP498L) only. Collectively, our data suggest that characteristic features of GP130-deficient hyper-IgE syndrome phenotype are IL-6 and IL-11 dominated, and indicate selective roles of aberrant IL-6 and IL-27 signaling on the differentiation of T-cell subsets.

Published
2019

42. TAOK1 is associated with neurodevelopmental disorder and essential for neuronal maturation and cortical development

Author

Genetica Klinische Genetica, van Woerden, Geeske M, Bos, Melanie, de Konink, Charlotte, Distel, Ben, Avagliano Trezza, Rossella, Shur, Natasha E, Barañano, Kristin, Mahida, Sonal, Chassevent, Anna, Schreiber, Allison, Erwin, Angelika L, Gripp, Karen W, Rehman, Fatima, Brulleman, Saskia, McCormack, Róisín, de Geus, Gwynna, Kalsner, Louisa, Sorlin, Arthur, Bruel, Ange-Line, Koolen, David A, Gabriel, Melissa K, Rossi, Mari, Fitzpatrick, David R, Wilkie, Andrew O M, Calpena, Eduardo, Johnson, David, Brooks, Alice, van Slegtenhorst, Marjon, Fleischer, Julie, Groepper, Daniel, Lindstrom, Kristin, Innes, A Micheil, Goodwin, Allison, Humberson, Jennifer, Noyes, Amanda, Langley, Katherine G, Telegrafi, Aida, Blevins, Amy, Hoffman, Jessica, Guillen Sacoto, Maria J, Juusola, Jane, Monaghan, Kristin G, Punj, Sumit, Simon, Marleen, Pfundt, Rolph, Elgersma, Ype, Kleefstra, Tjitske, Genetica Klinische Genetica, van Woerden, Geeske M, Bos, Melanie, de Konink, Charlotte, Distel, Ben, Avagliano Trezza, Rossella, Shur, Natasha E, Barañano, Kristin, Mahida, Sonal, Chassevent, Anna, Schreiber, Allison, Erwin, Angelika L, Gripp, Karen W, Rehman, Fatima, Brulleman, Saskia, McCormack, Róisín, de Geus, Gwynna, Kalsner, Louisa, Sorlin, Arthur, Bruel, Ange-Line, Koolen, David A, Gabriel, Melissa K, Rossi, Mari, Fitzpatrick, David R, Wilkie, Andrew O M, Calpena, Eduardo, Johnson, David, Brooks, Alice, van Slegtenhorst, Marjon, Fleischer, Julie, Groepper, Daniel, Lindstrom, Kristin, Innes, A Micheil, Goodwin, Allison, Humberson, Jennifer, Noyes, Amanda, Langley, Katherine G, Telegrafi, Aida, Blevins, Amy, Hoffman, Jessica, Guillen Sacoto, Maria J, Juusola, Jane, Monaghan, Kristin G, Punj, Sumit, Simon, Marleen, Pfundt, Rolph, Elgersma, Ype, and Kleefstra, Tjitske

Published
2021

44. The Human Phenotype Ontology project: linking molecular biology and disease through phenotype data

Author

Köhler, Sebastian, Doelken, Sandra C., Mungall, Christopher J., Bauer, Sebastian, Firth, Helen V., Bailleul-Forestier, Isabelle, Black, Graeme C. M., Brown, Danielle L., Brudno, Michael, Campbell, Jennifer, FitzPatrick, David R., Eppig, Janan T., Jackson, Andrew P., Freson, Kathleen, Girdea, Marta, Helbig, Ingo, Hurst, Jane A., Jähn, Johanna, Jackson, Laird G., Kelly, Anne M., Ledbetter, David H., Mansour, Sahar, Martin, Christa L., Moss, Celia, Mumford, Andrew, Ouwehand, Willem H., Park, Soo-Mi, Riggs, Erin Rooney, Scott, Richard H., Sisodiya, Sanjay, Van Vooren, Steven, Wapner, Ronald J., Wilkie, Andrew O. M., Wright, Caroline F., Vulto-van Silfhout, Anneke T., de Leeuw, Nicole, de Vries, Bert B. A., Washingthon, Nicole L., Smith, Cynthia L., Westerfield, Monte, Schofield, Paul, Ruef, Barbara J., Gkoutos, Georgios V., Haendel, Melissa, Smedley, Damian, Lewis, Suzanna E., and Robinson, Peter N.

Published
2014
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45. Craniosynostosis, inner ear, and renal anomalies in a child with complete loss of SPRY1(sprouty homolog 1) function

Author

Tooze, Rebecca S, Calpena, Eduardo, Twigg, Stephen R F, D’Arco, Felice, Wakeling, Emma L, and Wilkie, Andrew O M

Abstract

IntroductionSPRY1encodes protein sprouty homolog 1 (Spry-1), a negative regulator of receptor tyrosine kinase signalling. Null mutant mice display kidney/urinary tract abnormalities and altered size of the skull; complete loss-of-function of Spry-1 in humans has not been reported.MethodsAnalysis of whole-genome sequencing data from individuals with craniosynostosis enrolled in the 100,000 Genomes Project identified a likely pathogenic variant within SPRY1. Reverse-transcriptase PCR and western blot analysis were used to investigate the effect of the variant on SPRY1mRNA and protein, in lymphoblastoid cell lines from the patient and both parents.ResultsA nonsense variant in SPRY1,encoding p.(Leu27*), was confirmed to be heterozygous in the unaffected parents and homozygous in the child. The child’s phenotype, which included sagittal craniosynostosis, subcutaneous cystic lesions overlying the lambdoid sutures, hearing loss associated with bilateral cochlear and vestibular dysplasia and a unilateral renal cyst, overlapped the features reported in Spry1−/−null mice. Functional studies supported escape from nonsense-mediated decay, but western blot analysis demonstrated complete absence of full-length protein in the affected child and a marked reduction in both parents.ConclusionThis is the first report of complete loss of Spry-1 function in humans, associated with abnormalities of the cranial sutures, inner ear, and kidneys.

Published
2023
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46. Biallelic GINS2 variant p.(Arg114Leu) causes Meier-Gorlin syndrome with craniosynostosis.

Author

NabaisSá, Maria J., Miller, Kerry A., McQuaid, Mary, Koelling, Nils, Wilkie, Andrew O. M., Wurtele, Hugo, de Brouwer, Arjan P. M., and Oliveira, Jorge

Abstract

Introduction Replication of the nuclear genome is an essential step for cell division. Pathogenic variants in genes coding for highly conserved components of the DNA replication machinery cause Meier-Gorlin syndrome (MGORS). Objective Identification of novel genes associated with MGORS. Methods Exome sequencing was performed to investigate the genotype of an individual presenting with prenatal and postnatal growth restriction, a craniofacial gestalt of MGORS and coronal craniosynostosis. The analysis of the candidate variants employed bioinformatic tools, in silico structural protein analysis and modelling in budding yeast. Results A novel homozygous missense variant NM_016095.2:c.341G>T, p.(Arg114Leu), in GINS2 was identified. Both non-consanguineous healthy parents carried this variant. Bioinformatic analysis supports its classification as pathogenic. Functional analyses using yeast showed that this variant increases sensitivity to nicotinamide, a compound that interferes with DNA replication processes. The phylogenetically highly conserved residue p.Arg114 localises at the docking site of CDC45 and MCM5 at GINS2. Moreover, the missense change possibly disrupts the effective interaction between the GINS complex and CDC45, which is necessary for the CMG helicase complex (Cdc45/MCM2-7/GINS) to accurately operate. Interestingly, our patient's phenotype is strikingly similar to the phenotype of patients with CDC45-related MGORS, particularly those with craniosynostosis, mild short stature and patellar hypoplasia. Conclusion GINS2 is a new disease-associated gene, expanding the genetic aetiology of MGORS. [ABSTRACT FROM AUTHOR]

Published
2022
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48. Introduction: Professor Gillian Morriss‐Kay DSc.

Author

Iseki, Sachiko and Wilkie, Andrew O. M.

Subjects
*CRANIAL sutures, *HUMAN anatomy, *MOLECULAR pathology, *FRONTAL bone, *BRANCHIAL arch, *VITAMIN A
Abstract

The article introduces Emeritus Professor Gillian Morriss-Kay as a guest speaker for a symposium on craniosynostosis. Gillian's expertise in developmental anatomy and molecular pathology of craniosynostosis has been instrumental in advancing the field. Her work has led to significant discoveries, including the distinct developmental origins of the frontal and parietal bones. Gillian's dedication to research and collaboration has been recognized with prestigious awards, highlighting her contributions to the field. [Extracted from the article]

Published
2024
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49. SMAD6 variants in craniosynostosis: genotype and phenotype evaluation

Author

Calpena, Eduardo, Cuellar, Araceli, Bala, Krithi, Swagemakers, Sigrid M. A., Koelling, Nil, Mcgowan, Simon J., Phipps, Julie M., Balasubramanian, Meena, Cunningham, Michael L., Douzgou, Sofia, Lattanzi, Wanda, Morton, Jenny E. V., Shears, Deborah, Weber, Astrid, Wilson, Louise C., Lord, Helen, Lester, Tracy, Johnson, David, Wall, Steven A., Twigg, Stephen R. F., Mathijssen, Irene M. J., England Research Consortium, Genomic, Boyadjiev, Simeon A., Wilkie, Andrew O. M., Wanda Lattanzi (ORCID:0000-0003-3092-4936), Calpena, Eduardo, Cuellar, Araceli, Bala, Krithi, Swagemakers, Sigrid M. A., Koelling, Nil, Mcgowan, Simon J., Phipps, Julie M., Balasubramanian, Meena, Cunningham, Michael L., Douzgou, Sofia, Lattanzi, Wanda, Morton, Jenny E. V., Shears, Deborah, Weber, Astrid, Wilson, Louise C., Lord, Helen, Lester, Tracy, Johnson, David, Wall, Steven A., Twigg, Stephen R. F., Mathijssen, Irene M. J., England Research Consortium, Genomic, Boyadjiev, Simeon A., Wilkie, Andrew O. M., and Wanda Lattanzi (ORCID:0000-0003-3092-4936)

Abstract

Purpose: Enrichment of heterozygous missense and truncating SMAD6 variants was previously reported in non-syndromic sagittal and metopic synostosis, and interaction of SMAD6 variants with a common polymorphism near BMP2 (rs1884302) was proposed to contribute to inconsistent penetrance. We determined the occurrence of SMAD6 variants in all types of craniosynostosis, evaluated the impact of different missense variants on SMAD6 function, and tested independently whether rs1884302 genotype significantly modifies the phenotype. Methods: We performed resequencing of SMAD6 in 795 unsolved patients with any type of craniosynostosis and genotyped rs1884302 in SMAD6-positive individuals and relatives. We examined the inhibitory activity and stability of SMAD6 missense variants. Results: We found 18 (2.3%) different rare damaging SMAD6 variants, with the highest prevalence in metopic synostosis (5.8%) and an 18.3-fold enrichment of loss-of-function variants compared to gnomAD data (P<10-7). Combined with eight additional variants, ≥20/26 were transmitted from an unaffected parent but rs1884302 genotype did not predict phenotype. Conclusion: Pathogenic SMAD6 variants substantially increase the risk of both nonsyndromic and syndromic presentations of craniosynostosis, especially metopic synostosis. Functional analysis is important to evaluate missense variants. Genotyping of rs1884302 is not clinically useful. Mechanisms to explain the remarkable diversity of phenotypes associated with SMAD6 variants remain obscure.

Published
2020

50. The developing mouse coronal suture at single-cell resolution

Author

Farmer, D’Juan T., primary, Mlcochova, Hana, additional, Zhou, Yan, additional, Koelling, Nils, additional, Wang, Guanlin, additional, Ashley, Neil, additional, Maxson, Robert E, additional, Wilkie, Andrew O. M., additional, Crump, J Gage, additional, and Twigg, Stephen R.F., additional

Published
2021
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