Bruce Castle

Publications (4)10.55 Total impact

• Article: How genetically heterogeneous is Kabuki syndrome?: MLL2 testing in 116 patients, review and analyses of mutation and phenotypic spectrum.

  Siddharth Banka, Ratna Veeramachaneni, William Reardon, Emma Howard, Sancha Bunstone, Nicola Ragge, Michael J Parker, Yanick J Crow, Bronwyn Kerr, Helen Kingston, [......], Deepthi C de Silva, I Karen Temple, Amanda L Collins, Katherine Lachlan, Frances Elmslie, Meriel McEntagart, Bruce Castle, Jill Clayton-Smith, Graeme C Black, Dian Donnai
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  ABSTRACT: MLL2 mutations are detected in 55 to 80% of patients with Kabuki syndrome (KS). In 20 to 45% patients with KS, the genetic basis remains unknown, suggesting possible genetic heterogeneity. Here, we present the largest yet reported cohort of 116 patients with KS. We identified MLL2 variants in 74 patients, of which 47 are novel and a majority are truncating. We show that pathogenic missense mutations were commonly located in exon 48. We undertook a systematic facial KS morphology study of patients with KS at our regional dysmorphology meeting. Our data suggest that nearly all patients with typical KS facial features have pathogenic MLL2 mutations, although KS can be phenotypically variable. Furthermore, we show that MLL2 mutation-positive KS patients are more likely to have feeding problems, kidney anomalies, early breast bud development, joint dislocations and palatal malformations in comparison with MLL2 mutation-negative patients. Our work expands the mutation spectrum of MLL2 that may help in better understanding of this molecule, which is important in gene expression, epigenetic control of active chromatin states, embryonic development and cancer. Our analyses of the phenotype indicates that MLL2 mutation-positive and -negative patients differ systematically, and genetic heterogeneity of KS is not as extensive as previously suggested. Moreover, phenotypic variability of KS suggests that MLL2 testing should be considered even in atypical patients.
  European journal of human genetics: EJHG 11/2011; 20(4):381-8. · 3.56 Impact Factor
• Source

  Available from: PubMed Central

  Article: ABCC6 mutations in pseudoxanthoma elasticum: an update including eight novel ones.

  Astrid S Plomp, Ralph J Florijn, Jacoline Ten Brink, Bruce Castle, Helen Kingston, Ana Martín-Santiago, Theo G M F Gorgels, Paulus T V M de Jong, Arthur A B Bergen
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  ABSTRACT: Pseudoxanthoma elasticum (PXE) is an autosomal recessive disorder of connective tissue, affecting the retina, the skin, and the cardiovascular system. PXE is caused by mutations in ABCC6. Up to now, the literature reports that there are 180 different ABCC6 mutations in PXE. The purpose of this paper is to report eight novel mutations in ABCC6 and to update the spectrum and frequency of ABCC6 mutations in PXE patients. Eye, skin, and DNA examinations were performed using standard methodologies. We newly investigated the gene in 90 probands by denaturing high-performance liquid chromatography (dHPLC) and direct sequencing. We examined a total of 166 probands. Eight novel ABCC6 mutations (c.1685T>C, p.Met562Thr; c.2477T>C, p.Leu826Pro; c.2891G>C, p.Arg964Pro; c.3207C>A, p.Tyr1069X; c.3364delT, p.Ser1122fs; c.3717T>G, p.Tyr1293X; c.3871G>A, p.Ala1291Thr; c.4306_4312del, p.Thr1436fs) were found in seven unrelated patients. Currently, our mutation detection score is at least one ABCC6 mutation in 87% of patients with a clinical diagnosis of PXE. Our results support that ABCC6 is the most important, and probably the only, causative gene of PXE. In total, 188 different ABCC6 mutations have now been reported in PXE in the literature.
  Molecular vision 01/2008; 14:118-24. · 2.20 Impact Factor
• Article: Transmitted duplication of 12q21.32-12q22 includes 48 genes and has no apparent phenotypic consequences.

  John C K Barber, Viv K Maloney, Maria Kirchhoff, N Simon Thomas, Tracy A Boyle, Bruce Castle
  American Journal of Medical Genetics Part A 04/2007; 143(6):615-8. · 2.39 Impact Factor
• Source

  Available from: Viv K Maloney

  Article: SHOX mutations in a family and a fetus with Langer mesomelic dwarfism.

  N Simon Thomas, Viv Maloney, Paul Bass, Varsha Mulik, Diana Wellesley, Bruce Castle
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  ABSTRACT: Léri-Weill dyschondrosteosis (LWD) and Langer mesomelic dysplasia (LMD) are caused by mutations in the SHOX gene. LWD results from haploinsufficiency and is dominantly inherited, while the more severe LMD results from the homozygous loss of SHOX. We describe a family and fetus with two SHOX mutations. Several relatives carry an approximately 200 kb interstitial deletion that includes the whole SHOX gene. Their condition is mild, with no Madelung deformity, and was originally diagnosed as hypochondroplasia (HCH). This deletion was also transmitted to a female fetus. However, unlike her carrier relatives, the ultrasound scan of the fetus and subsequent autopsy were consistent with LMD. The fetus inherited an additional Xp deletion (Xpter-Xp22.12) that also included the SHOX gene from her chromosomally normal father. This represents a unique molecular condition for LMD: the fetus is a compound heterozygote with two independent deletions, one inherited and one arising from a de novo event.
  American Journal of Medical Genetics Part A 08/2004; 128A(2):179-84. · 2.39 Impact Factor