16 results on '"Fitzpatrick, David"'
Search Results
2. Publisher Correction: BRD4 interacts with NIPBL and BRD4 is mutated in a Cornelia de Lange–like syndrome
- Author
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Olley, Gabrielle, Ansari, Morad, Bengani, Hemant, Grimes, Graeme R., Rhodes, James, von Kriegsheim, Alex, Blatnik, Ana, Stewart, Fiona J., Wakeling, Emma, Carroll, Nicola, Ross, Alison, Park, Soo-Mi, Deciphering Developmental Disorders Study, Bickmore, Wendy A., Pradeepa, Madapura M., and FitzPatrick, David R.
- Published
- 2019
- Full Text
- View/download PDF
3. Publisher Correction: BRD4 interacts with NIPBL and BRD4 is mutated in a Cornelia de Lange–like syndrome
- Author
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Olley, Gabrielle, Ansari, Morad, Bengani, Hemant, Grimes, Graeme R., Rhodes, James, von Kriegsheim, Alex, Blatnik, Ana, Stewart, Fiona J., Wakeling, Emma, Carroll, Nicola, Ross, Alison, Park, Soo-Mi, Bickmore, Wendy A., Pradeepa, Madapura M., FitzPatrick, David R., and Deciphering Developmental Disorders Study
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- 2018
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4. Loss-of-function mutations in SMARCE1 cause an inherited disorder of multiple spinal meningiomas.
- Author
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Smith, Miriam J, O'Sullivan, James, Bhaskar, Sanjeev S, Hadfield, Kristen D, Poke, Gemma, Caird, John, Sharif, Saba, Eccles, Diana, Fitzpatrick, David, Rawluk, Daniel, du Plessis, Daniel, Newman, William G, and Evans, D Gareth
- Subjects
SPINAL tumors ,MENINGIOMA ,NERVOUS system tumors ,NEUROFIBROMATOSIS ,CANCER genetics ,GENETIC mutation - Abstract
One-third of all primary central nervous system tumors in adults are meningiomas. Rarely, meningiomas occur at multiple sites, usually occurring in individuals with type 2 neurofibromatosis (NF2). We sequenced the exomes of three unrelated individuals with familial multiple spinal meningiomas without NF2 mutations. We identified two individuals with heterozygous loss-of-function mutations in the SWI/SNF chromatin-remodeling complex subunit gene SMARCE1. Sequencing of SMARCE1 in six further individuals with spinal meningiomas identified two additional heterozygous loss-of-function mutations. Tumors from individuals with SMARCE1 mutations were of clear-cell histological subtype, and all had loss of SMARCE1 protein, consistent with a tumor suppressor mechanism. Our findings identify multiple-spinal-meningioma disease as a new discrete entity and establish a key role for the SWI/SNF complex in the pathogenesis of both meningiomas and tumors with clear-cell histology. [ABSTRACT FROM AUTHOR]
- Published
- 2013
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5. Disruption of an AP-2α binding site in an IRF6 enhancer is associated with cleft lip.
- Author
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Rahimov, Fedik, Marazita, Mary L, Visel, Axel, Cooper, Margaret E, Hitchler, Michael J, Rubini, Michele, Domann, Frederick E, Govil, Manika, Christensen, Kaare, Bille, Camille, Melbye, Mads, Jugessur, Astanand, Lie, Rolv T, Wilcox, Allen J, Fitzpatrick, David R, Green, Eric D, Mossey, Peter A, Little, Julian, Steegers-Theunissen, Regine P, and Pennacchio, Len A
- Subjects
BINDING sites ,CLEFT lip ,INTERFERONS ,LABORATORY mice ,TRANSCRIPTION factors - Abstract
Previously we have shown that nonsyndromic cleft lip with or without cleft palate (NSCL/P) is strongly associated with SNPs in IRF6 (interferon regulatory factor 6). Here, we use multispecies sequence comparisons to identify a common SNP (rs642961, G>A) in a newly identified IRF6 enhancer. The A allele is significantly overtransmitted (P = 1 × 10
−11 ) in families with NSCL/P, in particular those with cleft lip but not cleft palate. Further, there is a dosage effect of the A allele, with a relative risk for cleft lip of 1.68 for the AG genotype and 2.40 for the AA genotype. EMSA and ChIP assays demonstrate that the risk allele disrupts the binding site of transcription factor AP-2α and expression analysis in the mouse localizes the enhancer activity to craniofacial and limb structures. Our findings place IRF6 and AP-2α in the same developmental pathway and identify a high-frequency variant in a regulatory element contributing substantially to a common, complex disorder. [ABSTRACT FROM AUTHOR]- Published
- 2008
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6. Mutations in CEP57 cause mosaic variegated aneuploidy syndrome.
- Author
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Snape, Katie, Hanks, Sandra, Ruark, Elise, Barros-Núñez, Patricio, Elliott, Anna, Murray, Anne, Lane, Andrew H., Shannon, Nora, Callier, Patrick, Chitayat, David, Clayton-Smith, Jill, FitzPatrick, David R, Gisselsson, David, Jacquemont, Sebastien, Asakura-Hay, Keiko, Micale, Mark A., Tolmie, John, Turnpenny, Peter D., Wright, Michael, and Douglas, Jenny
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GENETIC mutation ,ANEUPLOIDY ,CENTROSOMES ,MICROTUBULES ,CELL division - Abstract
Using exome sequencing and a variant prioritization strategy that focuses on loss-of-function variants, we identified biallelic, loss-of-function CEP57 mutations as a cause of constitutional mosaic aneuploidies. CEP57 is a centrosomal protein and is involved in nucleating and stabilizing microtubules. Our findings indicate that these and/or additional functions of CEP57 are crucial for maintaining correct chromosomal number during cell division. [ABSTRACT FROM AUTHOR]
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- 2011
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7. Constitutional aneuploidy and cancer predisposition caused by biallelic mutations in BUB1B.
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Hanks, Sandra, Coleman, Kim, Reid, Sarah, Plaja, Alberto, Firth, Helen, FitzPatrick, David, Kidd, Alexa, Méhes, Károly, Nash, Richard, Robin, Nathanial, Shannon, Nora, Tolmie, John, Swansbury, John, Irrthum, Alexandre, Douglas, Jenny, and Rahman, Nazneen
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ANEUPLOIDY ,PLOIDY ,MICROCEPHALY ,HEAD abnormalities ,CHILDHOOD cancer ,RHABDOMYOSARCOMA - Abstract
Mosaic variegated aneuploidy is a rare recessive condition characterized by growth retardation, microcephaly, childhood cancer and constitutional mosaicism for chromosomal gains and losses. In five families with mosaic variegated aneuploidy, including two with embryonal rhabdomyosarcoma, we identified truncating and missense mutations of BUB1B, which encodes BUBR1, a key protein in the mitotic spindle checkpoint. These data are the first to relate germline mutations in a spindle checkpoint gene with a human disorder and strongly support a causal link between aneuploidy and cancer development. [ABSTRACT FROM AUTHOR]
- Published
- 2004
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8. Mutations in SOX2 cause anophthalmia.
- Author
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Fantes, Judy, Ragge, Nicola K., Lynch, Sally-Ann, McGill, Niolette I., Collin, J. Richard O., Howard-Peebles, Patricia N., Hayward, Caroline, Vivian, Anthony J., Williamson, Kathy, van Heyningen, Veronica, and FitzPatrick, David R.
- Subjects
GENETIC mutation ,EYE abnormalities - Abstract
A submicroscopic deletion containing SOX2 was identified at the 3q breakpoint in a child with t(3;11)(q26.3;p11.2) associated with bilateral anophthalmia. Subsequent SOX2 mutation analysis identified de novo truncating mutations ofSOX2 in 4 of 35 (11%) individuals with anophthalmia. Both eyes were affected in all cases with an identified mutation. [ABSTRACT FROM AUTHOR]
- Published
- 2003
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9. Filling in the gaps in cranial suture biology.
- Author
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FitzPatrick, David R
- Subjects
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CRANIAL sutures , *OSTEOBLASTS , *CRANIOLOGY , *PHOSPHORYLATION , *CRANIOSYNOSTOSES - Abstract
Two new loci for premature fusion of the cranial sutures in humans suggest a common endpoint in osteoblast regulation, linking upregulation of phosphorylated ERK1/2 and TWIST1 haploinsufficiency. [ABSTRACT FROM AUTHOR]
- Published
- 2013
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10. Corrigendum: SMCHD1 mutations associated with a rare muscular dystrophy can also cause isolated arhinia and Bosma arhinia microphthalmia syndrome.
- Author
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Shaw ND, Brand H, Kupchinsky ZA, Bengani H, Plummer L, Jones TI, Erdin S, Williamson KA, Rainger J, Stortchevoi A, Samocha K, Currall BB, Dunican DS, Collins RL, Willer JR, Lek A, Lek M, Nassan M, Pereira S, Kammin T, Lucente D, Silva A, Seabra CM, Chiang C, An Y, Ansari M, Rainger JK, Joss S, Smith JC, Lippincott MF, Singh SS, Patel N, Jing JW, Law JR, Ferraro N, Verloes A, Rauch A, Steindl K, Zweier M, Scheer I, Sato D, Okamoto N, Jacobsen C, Tryggestad J, Chernausek S, Schimmenti LA, Brasseur B, Cesaretti C, García-Ortiz JE, Buitrago TP, Silva OP, Hoffman JD, Mühlbauer W, Ruprecht KW, Loeys BL, Shino M, Kaindl AM, Cho CH, Morton CC, Meehan RR, van Heyningen V, Liao EC, Balasubramanian R, Hall JE, Seminara SB, Macarthur D, Moore SA, Yoshiura KI, Gusella JF, Marsh JA, Graham JM Jr, Lin AE, Katsanis N, Jones PL, Crowley WF Jr, Davis EE, FitzPatrick DR, and Talkowski ME
- Published
- 2017
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11. Resequencing at scale in neurodevelopmental disorders.
- Author
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FitzPatrick DR
- Subjects
- Humans, Autism Spectrum Disorder genetics, Developmental Disabilities genetics, Intellectual Disability genetics
- Abstract
An international collaboration has assembled DNA samples and detailed phenotypic information from >13,000 individuals with a clinical diagnosis of either autism spectrum disorder (ASD) or intellectual disability/developmental delay (ID/DD). The application of molecular inversion probe technologies to sequence 208 candidate genes at scale in this impressive resource has identified a large set of plausibly causative mutations for these disorders.
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- 2017
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- View/download PDF
12. SMCHD1 mutations associated with a rare muscular dystrophy can also cause isolated arhinia and Bosma arhinia microphthalmia syndrome.
- Author
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Shaw ND, Brand H, Kupchinsky ZA, Bengani H, Plummer L, Jones TI, Erdin S, Williamson KA, Rainger J, Stortchevoi A, Samocha K, Currall BB, Dunican DS, Collins RL, Willer JR, Lek A, Lek M, Nassan M, Pereira S, Kammin T, Lucente D, Silva A, Seabra CM, Chiang C, An Y, Ansari M, Rainger JK, Joss S, Smith JC, Lippincott MF, Singh SS, Patel N, Jing JW, Law JR, Ferraro N, Verloes A, Rauch A, Steindl K, Zweier M, Scheer I, Sato D, Okamoto N, Jacobsen C, Tryggestad J, Chernausek S, Schimmenti LA, Brasseur B, Cesaretti C, García-Ortiz JE, Buitrago TP, Silva OP, Hoffman JD, Mühlbauer W, Ruprecht KW, Loeys BL, Shino M, Kaindl AM, Cho CH, Morton CC, Meehan RR, van Heyningen V, Liao EC, Balasubramanian R, Hall JE, Seminara SB, Macarthur D, Moore SA, Yoshiura KI, Gusella JF, Marsh JA, Graham JM Jr, Lin AE, Katsanis N, Jones PL, Crowley WF Jr, Davis EE, FitzPatrick DR, and Talkowski ME
- Subjects
- Adolescent, Child, Child, Preschool, Female, Humans, Infant, Male, Phenotype, Choanal Atresia genetics, Chromosomal Proteins, Non-Histone genetics, Genetic Predisposition to Disease genetics, Microphthalmos genetics, Muscular Dystrophies genetics, Mutation genetics, Nose abnormalities
- Abstract
Arhinia, or absence of the nose, is a rare malformation of unknown etiology that is often accompanied by ocular and reproductive defects. Sequencing of 40 people with arhinia revealed that 84% of probands harbor a missense mutation localized to a constrained region of SMCHD1 encompassing the ATPase domain. SMCHD1 mutations cause facioscapulohumeral muscular dystrophy type 2 (FSHD2) via a trans-acting loss-of-function epigenetic mechanism. We discovered shared mutations and comparable DNA hypomethylation patterning between these distinct disorders. CRISPR/Cas9-mediated alteration of smchd1 in zebrafish yielded arhinia-relevant phenotypes. Transcriptome and protein analyses in arhinia probands and controls showed no differences in SMCHD1 mRNA or protein abundance but revealed regulatory changes in genes and pathways associated with craniofacial patterning. Mutations in SMCHD1 thus contribute to distinct phenotypic spectra, from craniofacial malformation and reproductive disorders to muscular dystrophy, which we speculate to be consistent with oligogenic mechanisms resulting in pleiotropic outcomes.
- Published
- 2017
- Full Text
- View/download PDF
13. The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies.
- Author
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Redin C, Brand H, Collins RL, Kammin T, Mitchell E, Hodge JC, Hanscom C, Pillalamarri V, Seabra CM, Abbott MA, Abdul-Rahman OA, Aberg E, Adley R, Alcaraz-Estrada SL, Alkuraya FS, An Y, Anderson MA, Antolik C, Anyane-Yeboa K, Atkin JF, Bartell T, Bernstein JA, Beyer E, Blumenthal I, Bongers EM, Brilstra EH, Brown CW, Brüggenwirth HT, Callewaert B, Chiang C, Corning K, Cox H, Cuppen E, Currall BB, Cushing T, David D, Deardorff MA, Dheedene A, D'Hooghe M, de Vries BB, Earl DL, Ferguson HL, Fisher H, FitzPatrick DR, Gerrol P, Giachino D, Glessner JT, Gliem T, Grady M, Graham BH, Griffis C, Gripp KW, Gropman AL, Hanson-Kahn A, Harris DJ, Hayden MA, Hill R, Hochstenbach R, Hoffman JD, Hopkin RJ, Hubshman MW, Innes AM, Irons M, Irving M, Jacobsen JC, Janssens S, Jewett T, Johnson JP, Jongmans MC, Kahler SG, Koolen DA, Korzelius J, Kroisel PM, Lacassie Y, Lawless W, Lemyre E, Leppig K, Levin AV, Li H, Li H, Liao EC, Lim C, Lose EJ, Lucente D, Macera MJ, Manavalan P, Mandrile G, Marcelis CL, Margolin L, Mason T, Masser-Frye D, McClellan MW, Mendoza CJ, Menten B, Middelkamp S, Mikami LR, Moe E, Mohammed S, Mononen T, Mortenson ME, Moya G, Nieuwint AW, Ordulu Z, Parkash S, Pauker SP, Pereira S, Perrin D, Phelan K, Aguilar RE, Poddighe PJ, Pregno G, Raskin S, Reis L, Rhead W, Rita D, Renkens I, Roelens F, Ruliera J, Rump P, Schilit SL, Shaheen R, Sparkes R, Spiegel E, Stevens B, Stone MR, Tagoe J, Thakuria JV, van Bon BW, van de Kamp J, van Der Burgt I, van Essen T, van Ravenswaaij-Arts CM, van Roosmalen MJ, Vergult S, Volker-Touw CM, Warburton DP, Waterman MJ, Wiley S, Wilson A, Yerena-de Vega MC, Zori RT, Levy B, Brunner HG, de Leeuw N, Kloosterman WP, Thorland EC, Morton CC, Gusella JF, and Talkowski ME
- Subjects
- Female, Humans, Male, Chromosome Aberrations, Congenital Abnormalities genetics, Gene Rearrangement, Genetic Markers genetics, Genetic Predisposition to Disease, Genome-Wide Association Study
- Abstract
Despite the clinical significance of balanced chromosomal abnormalities (BCAs), their characterization has largely been restricted to cytogenetic resolution. We explored the landscape of BCAs at nucleotide resolution in 273 subjects with a spectrum of congenital anomalies. Whole-genome sequencing revised 93% of karyotypes and demonstrated complexity that was cryptic to karyotyping in 21% of BCAs, highlighting the limitations of conventional cytogenetic approaches. At least 33.9% of BCAs resulted in gene disruption that likely contributed to the developmental phenotype, 5.2% were associated with pathogenic genomic imbalances, and 7.3% disrupted topologically associated domains (TADs) encompassing known syndromic loci. Remarkably, BCA breakpoints in eight subjects altered a single TAD encompassing MEF2C, a known driver of 5q14.3 microdeletion syndrome, resulting in decreased MEF2C expression. We propose that sequence-level resolution dramatically improves prediction of clinical outcomes for balanced rearrangements and provides insight into new pathogenic mechanisms, such as altered regulation due to changes in chromosome topology., Competing Interests: The authors have none to declare.
- Published
- 2017
- Full Text
- View/download PDF
14. Distinct genetic architectures for syndromic and nonsyndromic congenital heart defects identified by exome sequencing.
- Author
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Sifrim A, Hitz MP, Wilsdon A, Breckpot J, Turki SH, Thienpont B, McRae J, Fitzgerald TW, Singh T, Swaminathan GJ, Prigmore E, Rajan D, Abdul-Khaliq H, Banka S, Bauer UM, Bentham J, Berger F, Bhattacharya S, Bu'Lock F, Canham N, Colgiu IG, Cosgrove C, Cox H, Daehnert I, Daly A, Danesh J, Fryer A, Gewillig M, Hobson E, Hoff K, Homfray T, Kahlert AK, Ketley A, Kramer HH, Lachlan K, Lampe AK, Louw JJ, Manickara AK, Manase D, McCarthy KP, Metcalfe K, Moore C, Newbury-Ecob R, Omer SO, Ouwehand WH, Park SM, Parker MJ, Pickardt T, Pollard MO, Robert L, Roberts DJ, Sambrook J, Setchfield K, Stiller B, Thornborough C, Toka O, Watkins H, Williams D, Wright M, Mital S, Daubeney PE, Keavney B, Goodship J, Abu-Sulaiman RM, Klaassen S, Wright CF, Firth HV, Barrett JC, Devriendt K, FitzPatrick DR, Brook JD, and Hurles ME
- Subjects
- CDC2 Protein Kinase chemistry, Exome genetics, Female, Humans, Male, Protein Conformation, Sequence Deletion, Syndrome, Autoantigens genetics, CDC2 Protein Kinase genetics, Heart Defects, Congenital genetics, Mi-2 Nucleosome Remodeling and Deacetylase Complex genetics, Mutation genetics, Protein Kinase C genetics
- Abstract
Congenital heart defects (CHDs) have a neonatal incidence of 0.8-1% (refs. 1,2). Despite abundant examples of monogenic CHD in humans and mice, CHD has a low absolute sibling recurrence risk (∼2.7%), suggesting a considerable role for de novo mutations (DNMs) and/or incomplete penetrance. De novo protein-truncating variants (PTVs) have been shown to be enriched among the 10% of 'syndromic' patients with extra-cardiac manifestations. We exome sequenced 1,891 probands, including both syndromic CHD (S-CHD, n = 610) and nonsyndromic CHD (NS-CHD, n = 1,281). In S-CHD, we confirmed a significant enrichment of de novo PTVs but not inherited PTVs in known CHD-associated genes, consistent with recent findings. Conversely, in NS-CHD we observed significant enrichment of PTVs inherited from unaffected parents in CHD-associated genes. We identified three genome-wide significant S-CHD disorders caused by DNMs in CHD4, CDK13 and PRKD1. Our study finds evidence for distinct genetic architectures underlying the low sibling recurrence risk in S-CHD and NS-CHD.
- Published
- 2016
- Full Text
- View/download PDF
15. Discovery of four recessive developmental disorders using probabilistic genotype and phenotype matching among 4,125 families.
- Author
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Akawi N, McRae J, Ansari M, Balasubramanian M, Blyth M, Brady AF, Clayton S, Cole T, Deshpande C, Fitzgerald TW, Foulds N, Francis R, Gabriel G, Gerety SS, Goodship J, Hobson E, Jones WD, Joss S, King D, Klena N, Kumar A, Lees M, Lelliott C, Lord J, McMullan D, O'Regan M, Osio D, Piombo V, Prigmore E, Rajan D, Rosser E, Sifrim A, Smith A, Swaminathan GJ, Turnpenny P, Whitworth J, Wright CF, Firth HV, Barrett JC, Lo CW, FitzPatrick DR, and Hurles ME
- Subjects
- Cell Cycle Proteins genetics, Developmental Disabilities classification, Exome genetics, Family Health, Female, Genetic Variation, Genotype, Humans, Male, Matrix Metalloproteinases, Secreted genetics, Pedigree, Phenotype, Protein-Arginine N-Methyltransferases genetics, Sequence Analysis, DNA methods, Ubiquitin-Protein Ligases genetics, United Kingdom, Developmental Disabilities genetics, Genes, Recessive, Genetic Association Studies methods, Genetic Predisposition to Disease genetics
- Abstract
Discovery of most autosomal recessive disease-associated genes has involved analysis of large, often consanguineous multiplex families or small cohorts of unrelated individuals with a well-defined clinical condition. Discovery of new dominant causes of rare, genetically heterogeneous developmental disorders has been revolutionized by exome analysis of large cohorts of phenotypically diverse parent-offspring trios. Here we analyzed 4,125 families with diverse, rare and genetically heterogeneous developmental disorders and identified four new autosomal recessive disorders. These four disorders were identified by integrating Mendelian filtering (selecting probands with rare, biallelic and putatively damaging variants in the same gene) with statistical assessments of (i) the likelihood of sampling the observed genotypes from the general population and (ii) the phenotypic similarity of patients with recessive variants in the same candidate gene. This new paradigm promises to catalyze the discovery of novel recessive disorders, especially those with less consistent or nonspecific clinical presentations and those caused predominantly by compound heterozygous genotypes.
- Published
- 2015
- Full Text
- View/download PDF
16. Highly conserved non-coding elements on either side of SOX9 associated with Pierre Robin sequence.
- Author
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Benko S, Fantes JA, Amiel J, Kleinjan DJ, Thomas S, Ramsay J, Jamshidi N, Essafi A, Heaney S, Gordon CT, McBride D, Golzio C, Fisher M, Perry P, Abadie V, Ayuso C, Holder-Espinasse M, Kilpatrick N, Lees MM, Picard A, Temple IK, Thomas P, Vazquez MP, Vekemans M, Roest Crollius H, Hastie ND, Munnich A, Etchevers HC, Pelet A, Farlie PG, Fitzpatrick DR, and Lyonnet S
- Subjects
- Animals, Base Sequence, Chromosome Mapping, Chromosomes, Human, Pair 17, Conserved Sequence, Family, Gene Expression Regulation, Developmental, Humans, Mice, Mice, Transgenic, Molecular Sequence Data, Pedigree, Polymorphism, Genetic physiology, Regulatory Elements, Transcriptional genetics, Pierre Robin Syndrome genetics, SOX9 Transcription Factor genetics, Untranslated Regions genetics
- Abstract
Pierre Robin sequence (PRS) is an important subgroup of cleft palate. We report several lines of evidence for the existence of a 17q24 locus underlying PRS, including linkage analysis results, a clustering of translocation breakpoints 1.06-1.23 Mb upstream of SOX9, and microdeletions both approximately 1.5 Mb centromeric and approximately 1.5 Mb telomeric of SOX9. We have also identified a heterozygous point mutation in an evolutionarily conserved region of DNA with in vitro and in vivo features of a developmental enhancer. This enhancer is centromeric to the breakpoint cluster and maps within one of the microdeletion regions. The mutation abrogates the in vitro enhancer function and alters binding of the transcription factor MSX1 as compared to the wild-type sequence. In the developing mouse mandible, the 3-Mb region bounded by the microdeletions shows a regionally specific chromatin decompaction in cells expressing Sox9. Some cases of PRS may thus result from developmental misexpression of SOX9 due to disruption of very-long-range cis-regulatory elements.
- Published
- 2009
- Full Text
- View/download PDF
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