Louise A Brueton

Publications (8)85.09 Total impact

• Article: CHRNG genotype-phenotype correlations in the multiple pterygium syndromes.

  Julie Vogt, Neil V Morgan, Pauline Rehal, Laurence Faivre, Louise A Brueton, Kristin Becker, Jean-Pierre Fryns, Sue Holder, Lily Islam, Emma Kivuva, Sally Ann Lynch, Renaud Touraine, Louise C Wilson, Fiona MacDonald, Eamonn R Maher
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  ABSTRACT: Germline mutations in the CHRNG gene that encodes the γ subunit of the embryonal acetylcholine receptor may cause the non-lethal Escobar variant (EVMPS) or the lethal form (LMPS) of multiple pterygium syndrome (MPS). In addition CHRNG mutations and mutations in other components of the embryonal acetylcholine receptor may present with fetal akinesia deformation sequence (FADS) without pterygia. In order to elucidate further the role of CHRNG mutations in MPS/FADS, this study evaluated the results of CHRNG mutation analysis in 100 families with a clinical diagnosis of MPS/FADS. CHRNG mutations were identified in 11/41 (27%) of families with EVMPS and 5/59 (8%) with LMPS/FADS. Most patients with a detectable CHRNG mutation (21 of 24 (87.5%)) had pterygia but no CHRNG mutations were detected in the presence of central nervous system anomalies. The mutation spectrum was similar in EVMPS and LMPS/FADS kindreds and EVMPS and LMPS phenotypes were observed in different families with the same CHRNG mutation. Despite this intrafamilial variability, it is estimated that there is a 95% chance that a subsequent sibling will have the same MPS phenotype (EVMPS or LMPS) as the proband (though concordance is less for more distant relatives). Based on these findings, a molecular genetic diagnostic pathway for the investigation of MPS/FADS is proposed.
  Journal of Medical Genetics 01/2012; 49(1):21-6. · 6.36 Impact Factor
• Article: Inactivation of IL11 signaling causes craniosynostosis, delayed tooth eruption, and supernumerary teeth.

  Pekka Nieminen, Neil V Morgan, Aimée L Fenwick, Satu Parmanen, Lotta Veistinen, Marja L Mikkola, Peter J van der Spek, Andrew Giraud, Louise Judd, Sirpa Arte, Louise A Brueton, Steven A Wall, Irene M J Mathijssen, Eamonn R Maher, Andrew O M Wilkie, Sven Kreiborg, Irma Thesleff
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  ABSTRACT: Craniosynostosis and supernumerary teeth most often occur as isolated developmental anomalies, but they are also separately manifested in several malformation syndromes. Here, we describe a human syndrome featuring craniosynostosis, maxillary hypoplasia, delayed tooth eruption, and supernumerary teeth. We performed homozygosity mapping in three unrelated consanguineous Pakistani families and localized the syndrome to a region in chromosome 9. Mutational analysis of candidate genes in the region revealed that all affected children harbored homozygous missense mutations (c.662C>G [p.Pro221Arg], c.734C>G [p.Ser245Cys], or c.886C>T [p.Arg296Trp]) in IL11RA (encoding interleukin 11 receptor, alpha) on chromosome 9p13.3. In addition, a homozygous nonsense mutation, c.475C>T (p.Gln159X), and a homozygous duplication, c.916_924dup (p.Thr306_Ser308dup), were observed in two north European families. In cell-transfection experiments, the p.Arg296Trp mutation rendered the receptor unable to mediate the IL11 signal, indicating that the mutation causes loss of IL11RA function. We also observed disturbed cranial growth and suture activity in the Il11ra null mutant mice, in which reduced size and remodeling of limb bones has been previously described. We conclude that IL11 signaling is essential for the normal development of craniofacial bones and teeth and that its function is to restrict suture fusion and tooth number. The results open up the possibility of modulation of IL11 signaling for the treatment of craniosynostosis.
  The American Journal of Human Genetics 07/2011; 89(1):67-81. · 10.60 Impact Factor
• Article: Mutations involved in Aicardi-Goutières syndrome implicate SAMHD1 as regulator of the innate immune response.

  Gillian I Rice, Jacquelyn Bond, Aruna Asipu, Rebecca L Brunette, Iain W Manfield, Ian M Carr, Jonathan C Fuller, Richard M Jackson, Teresa Lamb, Tracy A Briggs, [......], Ronen Spiegel, Tiong Y Tan, Adeline Vanderver, Emma L Wakeling, Evangeline Wassmer, Elizabeth Whittaker, Pierre Lebon, Daniel B Stetson, David T Bonthron, Yanick J Crow
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  ABSTRACT: Aicardi-Goutières syndrome is a mendelian mimic of congenital infection and also shows overlap with systemic lupus erythematosus at both a clinical and biochemical level. The recent identification of mutations in TREX1 and genes encoding the RNASEH2 complex and studies of the function of TREX1 in DNA metabolism have defined a previously unknown mechanism for the initiation of autoimmunity by interferon-stimulatory nucleic acid. Here we describe mutations in SAMHD1 as the cause of AGS at the AGS5 locus and present data to show that SAMHD1 may act as a negative regulator of the cell-intrinsic antiviral response.
  Nature Genetics 08/2009; 41(7):829-32. · 35.53 Impact Factor
• Source

  Available from: Julie Mcgaughran

  Article: Further clinical and molecular delineation of the 9q subtelomeric deletion syndrome supports a major contribution of EHMT1 haploinsufficiency to the core phenotype.

  T Kleefstra, W A van Zelst-Stams, W M Nillesen, V Cormier-Daire, G Houge, N Foulds, M van Dooren, M H Willemsen, R Pfundt, A Turner, [......], R Casalone, A Weber, L A Brueton, A Delicado Navarro, M Palomares Bralo, H Venselaar, S P A Stegmann, H G Yntema, H van Bokhoven, H G Brunner
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  ABSTRACT: The 9q subtelomeric deletion syndrome (9qSTDS) is clinically characterised by moderate to severe mental retardation, childhood hypotonia and facial dysmorphisms. In addition, congenital heart defects, urogenital defects, epilepsy and behavioural problems are frequently observed. The syndrome can be either caused by a submicroscopic 9q34.3 deletion or by intragenic EHMT1 mutations leading to haploinsufficiency of the EHMT1 gene. So far it has not been established if and to what extent other genes in the 9q34.3 region contribute to the phenotype observed in deletion cases. This study reports the largest cohort of 9qSTDS cases so far. By a multiplex ligation dependent probe amplification (MLPA) approach, the authors identified and characterised 16 novel submicroscopic 9q deletions. Direct sequence analysis of the EHMT1 gene in 24 patients exhibiting the 9qSTD phenotype without such deletion identified six patients with an intragenic EHMT1 mutation. Five of these mutations predict a premature termination codon whereas one mutation gives rise to an amino acid substitution in a conserved domain of the protein. The data do not provide any evidence for phenotype-genotype correlations between size of the deletions or type of mutations and severity of clinical features. Therefore, the authors confirm the EHMT1 gene to be the major determinant of the 9qSTDS phenotype. Interestingly, five of six patients who had reached adulthood had developed severe psychiatric pathology, which may indicate that EHMT1 haploinsufficiency is associated with neurodegeneration in addition to neurodevelopmental defect.
  Journal of Medical Genetics 04/2009; 46(9):598-606. · 6.36 Impact Factor
• Article: Clinical and molecular genetic features of Beckwith-Wiedemann syndrome associated with assisted reproductive technologies.

  Derek Lim, Sarah C Bowdin, Louise Tee, Gail A Kirby, Edward Blair, Alan Fryer, Wayne Lam, Christine Oley, Trevor Cole, Louise A Brueton, Wolf Reik, Fiona Macdonald, Eamonn R Maher
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  ABSTRACT: Beckwith-Wiedemann syndrome (BWS) is a model imprinting disorder resulting from mutations or epigenetic events affecting imprinted genes at 11p15.5. Most BWS cases are sporadic and result from imprinting errors (epimutations) involving either of the two 11p15.5 imprinting control regions (IC1 and IC2). Previously, we and other reported an association between sporadic BWS and assisted reproductive technologies (ARTs). In this study, we compared the clinical phenotype and molecular features of ART (IVF and ICSI) and non-ART children with sporadic BWS. A total of 25 patients with post-ART BWS were ascertained (12 after IVF and 13 after ICSI). Molecular genetic analysis revealed an IC2 epimutations (KvDMR1 loss of methylation) in 24 of the 25 children tested. Comparison of clinical features of children with post-ART BWS to those with non-ART BWS and IC2 defects revealed a lower frequency of exomphalos (43 versus 69%, P = 0.029) and a higher risk of neoplasia (two cases, P = 0.0014). As loss of methylation at imprinting control regions other than 11p15.5 might modify the phenotype of BWS patients with IC2 epimutations, we investigated differentially methylated regions (DMRs) at 6q24, 7q32 and 15q13 in post-ART and non-ART BWS IC2 cases (n = 55). Loss of maternal allele methylation at these DMRs occurred in 37.5% of ART and 6.4% of non-ART BWS IC2 defect cases. Thus, more generalized DMR hypomethylation is more frequent, but not exclusive to post-ART BWS. These findings provide further evidence that ART may be associated with disturbed normal genomic imprinting in a subset of children.
  Human Reproduction 01/2009; 24(3):741-7. · 4.47 Impact Factor
• Article: Clinical and molecular phenotype of Aicardi-Goutieres syndrome.

  Gillian Rice, Teresa Patrick, Rekha Parmar, Claire F Taylor, Alec Aeby, Jean Aicardi, Rafael Artuch, Simon Attard Montalto, Carlos A Bacino, Bruno Barroso, [......], Evangeline Wassmer, Bernhard Weschke, Margo L Whiteford, Michel A A Willemsen, Andreas Zankl, Sameer M Zuberi, Simona Orcesi, Elisa Fazzi, Pierre Lebon, Yanick J Crow
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  ABSTRACT: Aicardi-Goutieres syndrome (AGS) is a genetic encephalopathy whose clinical features mimic those of acquired in utero viral infection. AGS exhibits locus heterogeneity, with mutations identified in genes encoding the 3'-->5' exonuclease TREX1 and the three subunits of the RNASEH2 endonuclease complex. To define the molecular spectrum of AGS, we performed mutation screening in patients, from 127 pedigrees, with a clinical diagnosis of the disease. Biallelic mutations in TREX1, RNASEH2A, RNASEH2B, and RNASEH2C were observed in 31, 3, 47, and 18 families, respectively. In five families, we identified an RNASEH2A or RNASEH2B mutation on one allele only. In one child, the disease occurred because of a de novo heterozygous TREX1 mutation. In 22 families, no mutations were found. Null mutations were common in TREX1, although a specific missense mutation was observed frequently in patients from northern Europe. Almost all mutations in RNASEH2A, RNASEH2B, and RNASEH2C were missense. We identified an RNASEH2C founder mutation in 13 Pakistani families. We also collected clinical data from 123 mutation-positive patients. Two clinical presentations could be delineated: an early-onset neonatal form, highly reminiscent of congenital infection seen particularly with TREX1 mutations, and a later-onset presentation, sometimes occurring after several months of normal development and occasionally associated with remarkably preserved neurological function, most frequently due to RNASEH2B mutations. Mortality was correlated with genotype; 34.3% of patients with TREX1, RNASEH2A, and RNASEH2C mutations versus 8.0% RNASEH2B mutation-positive patients were known to have died (P=.001). Our analysis defines the phenotypic spectrum of AGS and suggests a coherent mutation-screening strategy in this heterogeneous disorder. Additionally, our data indicate that at least one further AGS-causing gene remains to be identified.
  The American Journal of Human Genetics 10/2007; 81(4):713-25. · 10.60 Impact Factor
• Source

  Available from: ncbi.nlm.nih.gov

  Article: Mutations in the embryonal subunit of the acetylcholine receptor (CHRNG) cause lethal and Escobar variants of multiple pterygium syndrome.

  Neil V Morgan, Louise A Brueton, Phillip Cox, Marie T Greally, John Tolmie, Shanaz Pasha, Irene A Aligianis, Hans van Bokhoven, Tamas Marton, Lihadh Al-Gazali, Jenny E V Morton, Christine Oley, Colin A Johnson, Richard C Trembath, Han G Brunner, Eamonn R Maher
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  ABSTRACT: Multiple pterygium syndromes (MPSs) comprise a group of multiple-congenital-anomaly disorders characterized by webbing (pterygia) of the neck, elbows, and/or knees and joint contractures (arthrogryposis). In addition, a variety of developmental defects (e.g., vertebral anomalies) may occur. MPSs are phenotypically and genetically heterogeneous but are traditionally divided into prenatally lethal and nonlethal (Escobar) types. To elucidate the pathogenesis of MPS, we undertook a genomewide linkage scan of a large consanguineous family and mapped a locus to 2q36-37. We then identified germline-inactivating mutations in the embryonal acetylcholine receptor gamma subunit (CHRNG) in families with both lethal and nonlethal MPSs. These findings extend the role of acetylcholine receptor dysfunction in human disease and provide new insights into the pathogenesis and management of fetal akinesia syndromes.
  The American Journal of Human Genetics 09/2006; 79(2):390-5. · 10.60 Impact Factor
• Article: The tale of a nail sign in chromosome 4q34 deletion syndrome.

  Julie Vogt, Ethel Ryan, Marc D Tischkowitz, William Reardon, Louise A Brueton
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  ABSTRACT: Relatively, few reports of deletions involving the distal long arm of chromosome 4 (4q) exist. Five further cases are described and the findings are compared with those in previous literature reports. Distal 4q deletions may be recognized by the distinctive appearance of the fifth finger, which is stiff with a hypoplastic distal phalanx and a hooked or volar nail. All cases with this characteristic fifth finger anomaly appear to have deletions involving 4q34.
  Clinical Dysmorphology 08/2006; 15(3):127-32. · 0.54 Impact Factor