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S Banka,
E Howard,
S Bunstone,
Ke Chandler,
B Kerr,
K Lachlan,
S McKee,
Sg Mehta,
Alt Tavares, J Tolmie,
D Donnai
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ABSTRACT: Kabuki syndrome (KS) is a rare multi-system disorder that can result in a variety of congenital malformations, typical dysmorphism and variable learning disability. It is caused by MLL2 point mutations in the majority of the cases and, rarely by deletions involving KDM6A. Nearly one third of cases remain unsolved. Here, we expand the known genetic basis of KS by presenting five typical patients with the condition, all of whom have novel MLL2 mutation types- two patients with mosaic small deletions, one with a mosaic whole-gene deletion, one with a multi-exon deletion and one with an intragenic multi-exon duplication. We recommend MLL2 dosage studies for all patients with typical KS, where traditional Sanger sequencing fails to identify mutations. The prevalence of such MLL2 mutations in KS may be comparable with deletions involving KDM6A. These findings may be helpful in understanding the mutational mechanism of MLL2 and the disease mechanism of KS.
Clinical Genetics 08/2012; · 3.13 Impact Factor
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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
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Olivier Gribouval,
Vincent Morinière,
Audrey Pawtowski,
Christelle Arrondel,
Satu-Leena Sallinen,
Carola Saloranta,
Carol Clericuzio,
Géraldine Viot,
Julia Tantau,
Sophie Blesson, [......],
Albert David,
Deborah Bartholdi,
Amir Peleg,
Damien Brackman,
Rosario Stone,
Ralph DeBerardinis,
Pierre Corvol,
Annie Michaud,
Corinne Antignac,
Marie Claire Gubler
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ABSTRACT: Autosomal recessive renal tubular dysgenesis (RTD) is a severe disorder of renal tubular development characterized by early onset and persistent fetal anuria leading to oligohydramnios and the Potter sequence, associated with skull ossification defects. Early death occurs in most cases from anuria, pulmonary hypoplasia, and refractory arterial hypotension. The disease is linked to mutations in the genes encoding several components of the renin-angiotensin system (RAS): AGT (angiotensinogen), REN (renin), ACE (angiotensin-converting enzyme), and AGTR1 (angiotensin II receptor type 1). Here, we review the series of 54 distinct mutations identified in 48 unrelated families. Most of them are novel and ACE mutations are the most frequent, observed in two-thirds of families (64.6%). The severity of the clinical course was similar whatever the mutated gene, which underlines the importance of a functional RAS in the maintenance of blood pressure and renal blood flow during the life of a human fetus. Renal hypoperfusion, whether genetic or secondary to a variety of diseases, precludes the normal development/ differentiation of proximal tubules. The identification of the disease on the basis of precise clinical and histological analyses and the characterization of the genetic defects allow genetic counseling and early prenatal diagnosis.
Human Mutation 11/2011; 33(2):316-26. · 5.69 Impact Factor
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Ruth McGowan,
Ramkumar Gulati,
Pamela McHenry,
Alexander Cooke,
Sandra Butler,
Wee Teik Keng,
Victoria Murday,
Margo Whiteford,
Frederik G Dikkers,
Brigit Sikkema-Raddatz,
Ton van Essen, John Tolmie
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ABSTRACT: We describe the clinical characteristics of 4 singleton cases, 3 males and 1 female, with Myhre Syndrome (OMIM 139210), who were born to non-consanguineous parents. Three cases had no family history of similarly affected individuals but 1 male's mother had short stature, some facial features suggestive of Myhre syndrome and evidence of skewed X-chromosome inactivation in her blood DNA. Short stature, deafness, learning difficulties, skeletal anomalies and facial dysmorphisms were evident in all cases. Arthralgia and stiff joints with limited movement were also present. The facial appearance, thickened skin, a 'muscular' habitus are memorable features. The female patient was least affected: this patient and one affected male displayed streaky skin with areas of patchy thickening, suggestive of genetic mosaicism. One patient developed sleep apnoea, a restrictive ventilatory defect and died following a choking episode. Another affected male developed recurrent, progressive, proximal, tracheal stenosis requiring partial tracheal resection, laser treatment and eventually tracheotomy. Review of Myhre syndrome patients in the literature and syndromes in the differential diagnosis, suggests heterogeneity in Myhre syndrome and clinical overlap with Laryngotracheal stenosis, Arthropathy, Prognathism and Short stature syndrome.
European journal of medical genetics 07/2011; 54(6):e553-9. · 1.57 Impact Factor
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Katie Snape,
Sandra Hanks,
Elise Ruark,
Patricio Barros-Núñez,
Anna Elliott,
Anne Murray,
Andrew H Lane,
Nora Shannon,
Patrick Callier,
David Chitayat, [......],
David R Fitzpatrick,
David Gisselsson,
Sebastien Jacquemont,
Keiko Asakura-Hay,
Mark A Micale, John Tolmie,
Peter D Turnpenny,
Michael Wright,
Jenny Douglas,
Nazneen Rahman
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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.
Nature Genetics 06/2011; 43(6):527-9. · 35.53 Impact Factor
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Rob Hastings,
Jan-Maarten Cobben,
Gabriele Gillessen-Kaesbach,
Judith Goodship,
Hanne Hove,
Susanne Kjaergaard,
Helena Kemp,
Helen Kingston,
Peter Lunt,
Sahar Mansour, [......],
Kay Metcalfe,
Catherine Murdoch-Davis,
Mary Ray,
Marlène Rio,
Sarah Smithson, John Tolmie,
Peter Turnpenny,
Bregje van Bon,
Dagmar Wieczorek,
Ruth Newbury-Ecob
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ABSTRACT: Bohring-Opitz syndrome (BOS) is a rare congenital disorder of unknown etiology diagnosed on the basis of distinctive clinical features. We suggest diagnostic criteria for this condition, describe ten previously unreported patients, and update the natural history of four previously reported patients. This is the largest series reported to date, providing a unique opportunity to document the key clinical features and course through childhood. Investigations undertaken to try and elucidate the underlying pathogenesis of BOS using array comparative genomic hybridization and tandem mass spectrometry of cholesterol precursors did not show any pathogenic changes responsible.
European journal of human genetics: EJHG 02/2011; 19(5):513-9. · 3.56 Impact Factor
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ABSTRACT: Ulnar Mammary syndrome (UMS) is an autosomal disorder caused by haploinsufficiency of the TBX3 gene. There is marked intrafamilial variation in expression of the syndrome. We present one three generation family in which the proband has absence of the right ulna and third, fourth and fifth rays in her right hand. Her mother and maternal grandmother have more subtle anomalies while all have a similar facial appearance with a broad nasal tip, a broad jaw, a prominent chin and a tongue frenulum. They have a single base pair insertion (c. 992dup) in TBX3. We compare faces from the handful of published UMS patients which include photographs, this family and four other cases with TBX3 mutations. All have similarities in appearance which we suggest could alert clinicians to the possibility of a TBX3 mutation if individuals present with more subtle features of UMS such as postaxial polydactyly, isolated 5th finger anomalies, delayed puberty in males, breast hypoplasia or short stature with or without growth hormone deficiency.
European journal of medical genetics 01/2011; 54(3):301-5. · 1.57 Impact Factor
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Anna Hackett,
Patrick S Tarpey,
Andrea Licata,
James Cox,
Annabel Whibley,
Jackie Boyle,
Carolyn Rogers,
John Grigg,
Michael Partington,
Roger E Stevenson, [......],
Gillian Turner,
Meredith Wilson,
Andrew P Futreal,
Mark Corbett,
Marie Shaw,
Jozef Gecz,
F Lucy Raymond,
Michael R Stratton,
Charles E Schwartz,
Fatima E Abidi
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ABSTRACT: Mutations of the calcium/calmodulin-dependent serine protein kinase (CASK) gene have recently been associated with X-linked mental retardation (XLMR) with microcephaly, optic atrophy and brainstem and cerebellar hypoplasia, as well as with an X-linked syndrome having some FG-like features. Our group has recently identified four male probands from 358 probable XLMR families with missense mutations (p.Y268H, p.P396S, p.D710G and p.W919R) in the CASK gene. Congenital nystagmus, a rare and striking feature, was present in two of these families. We screened a further 45 probands with either nystagmus or microcephaly and mental retardation (MR), and identified two further mutations, a missense mutation (p.Y728C) and a splice mutation (c.2521-2A>T) in two small families with nystagmus and MR. Detailed clinical examinations of all six families, including an ophthalmological review in four families, were undertaken to further characterise the phenotype. We report on the clinical features of 24 individuals, mostly male, from six families with CASK mutations. The phenotype was variable, ranging from non-syndromic mild MR to severe MR associated with microcephaly and dysmorphic facial features. Carrier females were variably affected. Congenital nystagmus was found in members of four of the families. Our findings reinforce the CASK gene as a relatively frequent cause of XLMR in females and males. We further define the phenotypic spectrum and demonstrate that affected males with missense mutations or in-frame deletions in CASK are frequently associated with congenital nystagmus and XLMR, a striking feature not previously reported.
European journal of human genetics: EJHG 12/2009; 18(5):544-52. · 3.56 Impact Factor
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Clinical dysmorphology 09/2009; 18(4):236-7. · 0.47 Impact Factor
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Mohnish Suri,
Peter Kelehan,
David O'neill,
Shantala Vadeyar,
Judith Grant,
S Faisal Ahmed, John Tolmie,
Emma McCann,
Wayne Lam,
Shirley Smith,
David Fitzpatrick,
Nicholas D Hastie,
William Reardon
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ABSTRACT: Meacham syndrome is a rare sporadically occurring multiple malformation syndrome characterized by male pseudohermaphroditism with abnormal internal female genitalia comprising a uterus and double or septate vagina, complex congenital heart defect and diaphragmatic abnormalities. We report on eight new cases of this condition, two of whom were shown to have heterozygous missense mutations in the C-terminal zinc finger domains of WT1: Arg366Cys and Arg394Trp. These data represent clinical and molecular evidence that the WT1 gene plays a central role in normal development of the diaphragm and the proepicardially derived tissues. Identification of WT1 expression in the region of coelomic mesothelium which will form the proepicardium and diaphragm provides a plausible unifying patterning defect in these cases. Interestingly, the Arg366Cys mutation has been previously reported in Denys-Drash syndrome and Arg394Trp mutation has been previously reported in both isolated Wilms tumor and Denys-Drash syndrome. This phenotypic diversity with a single mutation suggests there are other factors modulating all aspects of WT1 function during human development. If genetic modifiers of WT1 can be identified in animal models these become good candidate genes for the cases with Meacham syndrome we report on here where WT1 mutations cannot be identified.
American Journal of Medical Genetics Part A 11/2007; 143A(19):2312-20. · 2.39 Impact Factor
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Asif Ali,
Paul T Christie,
Irina V Grigorieva,
Brian Harding,
Hilde Van Esch,
S Faisal Ahmed,
Maria Bitner-Glindzicz,
Eberhard Blind,
Catherine Bloch,
Patricia Christin, [......],
Christoph J Mache,
Zulf Mughal,
Albert C M Ong,
Choni Rinat,
Nicholas Shaw,
Sarah F Smithson, John Tolmie,
Jacques Weill,
M Andrew Nesbit,
Rajesh V Thakker
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ABSTRACT: The hypoparathyroidism-deafness-renal (HDR) dysplasia syndrome is an autosomal dominant disorder caused by mutations of the dual zinc finger transcription factor, GATA3. We investigated 21 HDR probands and 14 patients with isolated hypoparathyroidism for GATA3 abnormalities. Thirteen different heterozygous germline mutations were identified in patients with HDR. These consisted of three nonsense mutations, six frameshifting deletions, two frameshifting insertions, one missense (Leu348Arg) mutation and one acceptor splice site mutation. The splice site mutation was demonstrated to cause a pre-mRNA processing abnormality leading to the use of an alternative acceptor site 8 bp downstream of the normal site, resulting in a frameshift and prematurely terminated protein. Electrophoretic mobility shift assays (EMSAs) revealed three classes of GATA3 mutations: those that lead to a loss of DNA binding which represent over 90% of all mutations, and involved a loss of the carboxy-terminal zinc finger; those that resulted in a reduced DNA-binding affinity; and those (e.g. Leu348Arg) that did not alter DNA binding or the affinity but likely altered the conformational change that occurs during binding in the DNA major groove as predicted by a three-dimensional modeling. These results elucidate further the molecular mechanisms underlying the altered functions of mutants of this zinc finger transcription factor and their role in causing this developmental anomaly. No mutations were identified in patients with isolated hypoparathyroidism, thereby indicating that GATA3 abnormalities are more likely to result in two or more of the phenotypic features of the HDR syndrome and not in one, such as isolated hypoparathyroidism.
Human Molecular Genetics 03/2007; 16(3):265-75. · 7.64 Impact Factor
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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
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Sandra Hanks,
Kim Coleman,
Sarah Reid,
Alberto Plaja,
Helen Firth,
David Fitzpatrick,
Alexa Kidd,
Károly Méhes,
Richard Nash,
Nathanial Robin,
Nora Shannon, John Tolmie,
John Swansbury,
Alexandre Irrthum,
Jenny Douglas,
Nazneen Rahman
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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.
Nature Genetics 12/2004; 36(11):1159-61. · 35.53 Impact Factor
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ABSTRACT: Genomewide linkage searches aimed at identifying disease susceptibility loci are generally conducted using 300-400 microsatellite markers. Genotyping bi-allelic single nucleotide polymorphisms (SNPs) provides an alternative strategy. The availability of dense SNP maps coupled with recent technological developments in highly paralleled SNP genotyping makes it practical to now consider the use of these markers for whole-genome genetic linkage analyses. Here, we report the findings from three successful genomewide linkage analyses of families segregating autosomal recessively inherited neonatal diabetes, craniosynostosis and dominantly inherited renal dysplasia using the Affymetrix 10K SNP array. A single locus was identified for each disease state, two of which are novel. The performance of the SNP array, both in terms of efficiency and precision, indicates that such platforms will become the dominant technology for performing genomewide linkage searches.
Nucleic Acids Research 02/2004; 32(20):e164. · 8.03 Impact Factor
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ABSTRACT: We report three siblings who were variably affected by craniosynostosis, calcification of the basal ganglia, and mild facial dysmorphism comprising prominent eyes and a prominent nasal bridge. The children are of normal intelligence and have no limb abnormalities. Their parents are first cousins and are phenotypically normal. We propose that this combination of clinical findings represents a recognizable, autosomal recessive craniosynostosis syndrome.
Clinical Dysmorphology 11/2003; 12(4):215-20. · 0.54 Impact Factor
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ABSTRACT: We describe two sisters with a PEHO-like syndrome. The first-born had early epileptic spasms with hypsarrhythmia, visual inattention with optic atrophy, progressive microcephaly and absence of development. Cranial magnetic resonance imaging revealed periventricular white matter changes. Cerebellar hypoplasia, characteristic of true PEHO syndrome, was absent. The MRI changes were interpreted as periventricular leucomalacia due to prenatal ischaemia, and a low recurrence risk was suggested. Subsequently, the younger sister was born similarly affected. The PEHO syndrome (progressive encephalopathy, hypsarrhythmia and optic atrophy) is a rare, autosomal recessive, encephalopathy of infancy. Diagnosis is clinical but cerebellar hypoplasia on neuroimaging is regarded as an additional necessary criterion. A heterogeneous group of PEHO-like patients, who lack cerebellar hypoplasia but have varying supratentorial abnormalities, have been reported. This is the second report of siblings with a PEHO-like syndrome, and supports the existence of a distinct, autosomal recessive condition in which neuroimaging abnormalities may be misinterpreted.
Clinical Dysmorphology 05/2003; 12(2):133-6. · 0.54 Impact Factor
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Anna Hackett,
Patrick S Tarpey,
Andrea Licata,
James Cox,
Annabel Whibley,
Jackie Boyle,
Carolyn Rogers,
John Grigg,
Michael Partington,
Roger E Stevenson, [......],
Gillian Turner,
Meredith Wilson,
Andrew P Futreal,
Mark Corbett,
Marie Shaw,
Jozef Gecz,
F Lucy Raymond,
Michael R Stratton,
Charles E Schwartz,
Fatima E Abidi
