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Dive into the research topics where Janine Smith is active.

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Featured researches published by Janine Smith.


Nature Genetics | 2010

De novo mutations of SETBP1 cause Schinzel-Giedion syndrome

Alexander Hoischen; Bregje W.M. van Bon; Christian Gilissen; Peer Arts; Bart van Lier; Marloes Steehouwer; Petra de Vries; Rick de Reuver; Nienke Wieskamp; Geert Mortier; Koenraad Devriendt; Marta Z Amorim; Nicole Revencu; Alexa Kidd; Mafalda Barbosa; Anne Turner; Janine Smith; Christina Oley; Alex Henderson; Ian Hayes; Elizabeth Thompson; Han G. Brunner; Bert B.A. de Vries; Joris A. Veltman

Schinzel-Giedion syndrome is characterized by severe mental retardation, distinctive facial features and multiple congenital malformations; most affected individuals die before the age of ten. We sequenced the exomes of four affected individuals (cases) and found heterozygous de novo variants in SETBP1 in all four. We also identified SETBP1 mutations in eight additional cases using Sanger sequencing. All mutations clustered to a highly conserved 11-bp exonic region, suggesting a dominant-negative or gain-of-function effect.


Nature Genetics | 2005

Mutations in SIL1 cause Marinesco-Sjogren syndrome, a cerebellar ataxia with cataract and myopathy

Jan Senderek; M. Krieger; Claudia Stendel; Carsten Bergmann; Markus Moser; N. Breitbach-Faller; Sabine Rudnik-Schöneborn; A. Blaschek; N. I. Wolf; I. Harting; Kathryn N. North; Janine Smith; Francesco Muntoni; Martin Brockington; Susana Quijano-Roy; F. Renault; Ralf Herrmann; L. M. Hendershot; J. M. Schroder; Hanns Lochmüller; Haluk Topaloglu; Thomas Voit; Joachim Weis; F. Ebinger; Klaus Zerres

SIL1 (also called BAP) acts as a nucleotide exchange factor for the Hsp70 chaperone BiP (also called GRP78), which is a key regulator of the main functions of the endoplasmic reticulum. We found nine distinct mutations that would disrupt the SIL1 protein in individuals with Marinesco-Sjögren syndrome, an autosomal recessive cerebellar ataxia complicated by cataracts, developmental delay and myopathy. Identification of SIL1 mutations implicates Marinesco-Sjögren syndrome as a disease of endoplasmic reticulum dysfunction and suggests a role for this organelle in multisystem disorders.


Annals of Neurology | 2008

Brain involvement in muscular dystrophies with defective dystroglycan glycosylation

Emma Clement; Eugenio Mercuri; Caroline Godfrey; Janine Smith; S. Robb; Maria Kinali; Volker Straub; Kate Bushby; Adnan Y. Manzur; Beril Talim; Frances Cowan; R. Quinlivan; Andrea Klein; Cheryl Longman; Robert McWilliam; Haluk Topaloglu; Rachael Mein; Stephen Abbs; Kathryn N. North; A. James Barkovich; Mary A. Rutherford; Francesco Muntoni

To assess the range and severity of brain involvement, as assessed by magnetic resonance imaging, in 27 patients with mutations in POMT1 (4), POMT2 (9), POMGnT1 (7), Fukutin (4), or LARGE (3), responsible for muscular dystrophies with abnormal glycosylation of dystroglycan (dystroglycanopathies).


American Journal of Human Genetics | 2011

Whole-Exome-Sequencing Identifies Mutations in Histone Acetyltransferase Gene KAT6B in Individuals with the Say-Barber-Biesecker Variant of Ohdo Syndrome

Jill Clayton-Smith; James O'Sullivan; Sarah B. Daly; Sanjeev Bhaskar; Ruth Day; Beverley Anderson; Anne K. Voss; Tim Thomas; Leslie G. Biesecker; Philip Smith; Alan Fryer; Kate Chandler; Bronwyn Kerr; May Tassabehji; Sally Ann Lynch; Małgorzata Krajewska-Walasek; Shane McKee; Janine Smith; Elizabeth Sweeney; Sahar Mansour; Shehla Mohammed; Dian Donnai; Graeme C.M. Black

Say-Barber-Biesecker-Young-Simpson syndrome (SBBYSS or Ohdo syndrome) is a multiple anomaly syndrome characterized by severe intellectual disability, blepharophimosis, and a mask-like facial appearance. A number of individuals with SBBYSS also have thyroid abnormalities and cleft palate. The condition usually occurs sporadically and is therefore presumed to be due in most cases to new dominant mutations. In individuals with SBBYSS, a whole-exome sequencing approach was used to demonstrate de novo protein-truncating mutations in the highly conserved histone acetyltransferase gene KAT6B (MYST4/MORF)) in three out of four individuals sequenced. Sanger sequencing was used to confirm truncating mutations of KAT6B, clustering in the final exon of the gene in all four individuals and in a further nine persons with typical SBBYSS. Where parental samples were available, the mutations were shown to have occurred de novo. During mammalian development KAT6B is upregulated specifically in the developing central nervous system, facial structures, and limb buds. The phenotypic features seen in the Qkf mouse, a hypomorphic Kat6b mutant, include small eyes, ventrally placed ears and long first digits that mirror the human phenotype. This is a further example of how perturbation of a protein involved in chromatin modification might give rise to a multisystem developmental disorder.


Journal of Medical Genetics | 2002

Germline mutation of the tumour suppressor PTEN in Proteus syndrome

Janine Smith; Edwin P. Kirk; George Theodosopoulos; Glenn M. Marshall; Jan L Walker; M Rogers; Michael Field; J J Brereton; Deborah J. Marsh

Proteus syndrome (PS, OMIM 176920) is a hamartomatous disorder characterised by overgrowth of multiple tissues, connective tissue and epidermal naevi, and vascular malformations.1 These presentations are usually apparent at birth or soon after and continue to develop as the patient ages. It is named after the Greek god Proteus who, legend has it, could change his shape at will to avoid capture. It is probably the disease suffered by the Elephant Man.2 Tumours, mostly benign but some malignant, have also been reported in PS, generally presenting by the age of 20 years and including papillary adenocarcinoma of the testis, meningioma, and cystadenoma of the ovaries.3 Given the predominantly sporadic nature of this syndrome and the mosaic distribution of lesions, it has been suggested that PS may be caused by somatic mosaicism for a genetic change that is lethal in the non-mosaic state.4 Clinical overlap, in the form of tissue overgrowth, macrocephaly, and the presence of lipomas, exists between PS and another hamartoma syndrome, Bannayan-Riley-Ruvalcaba syndrome (BRR, OMIM 153480),5 in which up to 60% of affected subjects are known to carry a germline mutation of the tumour suppressor gene PTEN .6 BRR also shows partial clinical overlap with Cowden syndrome (CS, OMIM 158350), in which affected subjects are at risk of developing hamartomas in multiple organs including the breast, thyroid, central nervous system, skin, and gastrointestinal tract, as well as malignant tumours of the breast, thyroid, and endometrium. PTEN is mutated in the germline in up to 80% of patients with CS.6 Two recent reports have shown germline, and probably germline mosaic, PTEN mutations in a subset of patients with PS or a PS-like disorder,7,8 although other studies of patients with PS have been unable to confirm these findings.9,10 PTEN …


Human Mutation | 2008

A multicenter study on the prevalence and spectrum of mutations in the otoferlin gene (OTOF) in subjects with nonsyndromic hearing impairment and auditory neuropathy

Montserrat Rodríguez-Ballesteros; Rául A Reynoso; Margarita Olarte; Manuela Villamar; Constantino Morera; Rosamaria Santarelli; Edoardo Arslan; Carme Medá; Carlos Curet; Christiane Völter; Manuel Sainz-Quevedo; Pierangela Castorina; Umberto Ambrosetti; Stefano Berrettini; Klemens Frei; Socorro Tedín; Janine Smith; M. Cruz Tapia; Laura Cavallé; Nancy Gelvez; Paola Primignani; Elena Gómez-Rosas; Mirta Martín; Miguel A. Moreno-Pelayo; Martalucía Tamayo; José Moreno-Barral; Felipe Moreno; Ignacio del Castillo

Autosomal recessive nonsyndromic hearing impairment (NSHI) is a heterogeneous condition, for which 53 genetic loci have been reported, and 29 genes have been identified to date. One of these, OTOF, encodes otoferlin, a membrane‐anchored calcium‐binding protein that plays a role in the exocytosis of synaptic vesicles at the auditory inner hair cell ribbon synapse. We have investigated the prevalence and spectrum of deafness‐causing mutations in the OTOF gene. Cohorts of 708 Spanish, 83 Colombian, and 30 Argentinean unrelated subjects with autosomal recessive NSHI were screened for the common p.Gln829X mutation. In compound heterozygotes, the second mutant allele was identified by DNA sequencing. In total, 23 Spanish, two Colombian and two Argentinean subjects were shown to carry two mutant alleles of OTOF. Of these, one Colombian and 13 Spanish subjects presented with auditory neuropathy. In addition, a cohort of 20 unrelated subjects with a diagnosis of auditory neuropathy, from several countries, was screened for mutations in OTOF by DNA sequencing. A total of 11 of these subjects were shown to carry two mutant alleles of OTOF. In total, 18 pathogenic and four neutral novel alleles of the OTOF gene were identified. Haplotype analysis for markers close to OTOF suggests a common founder for the novel c.2905_2923delinsCTCCGAGCGCA mutation, frequently found in Argentina. Our results confirm that mutation of the OTOF gene correlates with a phenotype of prelingual, profound NSHI, and indicate that OTOF mutations are a major cause of inherited auditory neuropathy. Hum Mutat 29(6), 823–831, 2008.


Human Mutation | 2013

RASA1 mutations and associated phenotypes in 68 families with capillary malformation-arteriovenous malformation

Nicole Revencu; Laurence M. Boon; Antonella Mendola; Maria R. Cordisco; Josée Dubois; Philippe Clapuyt; Frank Hammer; David J. Amor; Alan D. Irvine; Eulalia Baselga; Anne Dompmartin; Samira Syed; Ana Martin-Santiago; Lesley C. Adès; Felicity Collins; Janine Smith; Sarah A. Sandaradura; Victoria R. Barrio; Patricia E. Burrows; Francine Blei; Mariarosaria Cozzolino; Nicola Brunetti-Pierri; Asunción Vicente; Marc Abramowicz; Julie Désir; Catheline Vilain; Wendy K. Chung; Ashley Wilson; Carol Gardiner; Yim Dwight

Capillary malformation–arteriovenous malformation (CM–AVM) is an autosomal‐dominant disorder, caused by heterozygous RASA1 mutations, and manifesting multifocal CMs and high risk for fast‐flow lesions. A limited number of patients have been reported, raising the question of the phenotypic borders. We identified new patients with a clinical diagnosis of CM–AVM, and patients with overlapping phenotypes. RASA1 was screened in 261 index patients with: CM–AVM (n = 100), common CM(s) (port‐wine stain; n = 100), Sturge–Weber syndrome (n = 37), or isolated AVM(s) (n = 24). Fifty‐eight distinct RASA1 mutations (43 novel) were identified in 68 index patients with CM–AVM and none in patients with other phenotypes. A novel clinical feature was identified: cutaneous zones of numerous small white pale halos with a central red spot. An additional question addressed in this study was the “second‐hit” hypothesis as a pathophysiological mechanism for CM–AVM. One tissue from a patient with a germline RASA1 mutation was available. The analysis of the tissue showed loss of the wild‐type RASA1 allele. In conclusion, mutations in RASA1 underscore the specific CM–AVM phenotype and the clinical diagnosis is based on identifying the characteristic CMs. The high incidence of fast‐flow lesions warrants careful clinical and radiologic examination, and regular follow‐up.


Neurology | 2008

Diagnosis and etiology of congenital muscular dystrophy

Rachel A. Peat; Janine Smith; Alison G. Compton; Naomi L. Baker; Rishika A. Pace; D. J. Burkin; S. J. Kaufman; Shireen R. Lamandé; Kathryn N. North

Objective: We aimed to determine the frequency of all known forms of congenital muscular dystrophy (CMD) in a large Australasian cohort. Methods: We screened 101 patients with CMD with a combination of immunofluorescence, Western blotting, and DNA sequencing to identify disease-associated abnormalities in glycosylated α-dystroglycan, collagen VI, laminin α2, α7-integrin, and selenoprotein. Results: A total of 45% of the CMD cohort were assigned to an immunofluorescent subgroup based on their abnormal staining pattern. Abnormal staining for glycosylated α-dystroglycan was present in 25% of patients, and approximately half of these had reduced glycosylated α-dystroglycan by Western blot. Sequencing of the FKRP, fukutin, POMGnT1, and POMT1 genes in all patients with abnormal α-dystroglycan immunofluorescence identified mutations in one patient for each of these genes and two patients had mutations in POMT2. Twelve percent of patients had abnormalities in collagen VI immunofluorescence, and we identified disease-causing COL6 mutations in eight of nine patients in whom the genes were sequenced. Laminin α2 deficiency accounted for only 8% of CMD. α7-Integrin staining was absent in 12 of 45 patients studied, and ITGA7 gene mutations were excluded in all of these patients. Conclusions: We define the distribution of different forms of congenital muscular dystrophy in a large cohort of mixed ethnicity and demonstrate the utility and limitations of current diagnostic techniques.


Genome Biology | 2016

Disorders of sex development: Insights from targeted gene sequencing of a large international patient cohort

Stefanie Eggers; Simon Sadedin; Jocelyn A. van den Bergen; Gorjana Robevska; Thomas Ohnesorg; Jacqueline K. Hewitt; Luke S. Lambeth; Aurore Bouty; Ingrid M. Knarston; Tiong Yang Tan; Fergus J. Cameron; George A. Werther; John M. Hutson; Michele O’Connell; Sonia Grover; Yves Heloury; Margaret Zacharin; Philip Bergman; Chris Kimber; Justin Brown; Nathalie Webb; Matthew Hunter; Shubha Srinivasan; Angela Titmuss; Charles F. Verge; David Mowat; Grahame Smith; Janine Smith; Lisa Ewans; Carolyn Shalhoub

BackgroundDisorders of sex development (DSD) are congenital conditions in which chromosomal, gonadal, or phenotypic sex is atypical. Clinical management of DSD is often difficult and currently only 13% of patients receive an accurate clinical genetic diagnosis. To address this we have developed a massively parallel sequencing targeted DSD gene panel which allows us to sequence all 64 known diagnostic DSD genes and candidate genes simultaneously.ResultsWe analyzed DNA from the largest reported international cohort of patients with DSD (278 patients with 46,XY DSD and 48 with 46,XX DSD). Our targeted gene panel compares favorably with other sequencing platforms. We found a total of 28 diagnostic genes that are implicated in DSD, highlighting the genetic spectrum of this disorder. Sequencing revealed 93 previously unreported DSD gene variants. Overall, we identified a likely genetic diagnosis in 43% of patients with 46,XY DSD. In patients with 46,XY disorders of androgen synthesis and action the genetic diagnosis rate reached 60%. Surprisingly, little difference in diagnostic rate was observed between singletons and trios. In many cases our findings are informative as to the likely cause of the DSD, which will facilitate clinical management.ConclusionsOur massively parallel sequencing targeted DSD gene panel represents an economical means of improving the genetic diagnostic capability for patients affected by DSD. Implementation of this panel in a large cohort of patients has expanded our understanding of the underlying genetic etiology of DSD. The inclusion of research candidate genes also provides an invaluable resource for future identification of novel genes.


Pediatrics | 2005

Congenital Central Hypoventilation Syndrome and Hirschsprung’s Disease in an Extremely Preterm Infant

Ramesh Bajaj; Janine Smith; Delphine Trochet; John Pitkin; Robert Ouvrier; Nicole Graf; David Sillence; Martin Kluckow

Congenital central hypoventilation syndrome with Hirschsprung’s disease, also known as Haddad syndrome, is a rare disorder with a variable phenotypic severity. The underlying cause is thought to be an abnormality of neural crest development and/or migration. Surviving neonates can have generalized autonomic nervous system dysfunction. Recent reports have identified mutations in the PHOX2B gene in a significant number of patients with this disorder. Diagnosis and management of this disorder in the setting of extreme prematurity is difficult as the manifestations of failure to maintain breathing effort and failure to establish feeds overlap with the complications of prematurity. We describe an infant who had congenital central hypoventilation syndrome with Hirschsprung’s disease and was delivered at 26 weeks’ gestational age and had total aganglionosis of the bowel, failure to wean from ventilation, and a mutation in the PHOX2B gene.

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Deborah J. Marsh

Kolling Institute of Medical Research

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David Sillence

Children's Hospital at Westmead

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Felicity Collins

Children's Hospital at Westmead

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David Mowat

Boston Children's Hospital

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Edwin P. Kirk

Boston Children's Hospital

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Bruce G. Robinson

Kolling Institute of Medical Research

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Diana E. Benn

Kolling Institute of Medical Research

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