Publications by authors named "John Tolmie"

47 Publications

A mutation creating an upstream initiation codon in the 5' UTR causes acampomelic campomelic dysplasia.

Mol Genet Genomic Med 2017 May 21;5(3):261-268. Epub 2017 Mar 21.

Institute of Human GeneticsUniversity of FreiburgFreiburgGermany.

Background: Campomelic dysplasia (CD) is a semilethal developmental disorder caused by mutations in and around . CD is characterized by multiple skeletal malformations including bending (campomelia) of long bones. Surviving patients frequently have the acampomelic form of CD (ACD).

Methods: This is a single case report on a patient with clinical and radiological features of ACD who has no mutation in the protein-coding sequence nor a translocation with breakpoint in the regulatory domain. We include functional studies of the novel mutant protein in vitro and in cultured cells.

Results: The patient was found to have a de novo heterozygous mutation c.-185G>A in the 5'UTR. The mutation creates an upstream translation start codon, uAUG, with a much better fit of its flanking sequence to the Kozak consensus than the wild-type AUG. By in vitro transcription-translation and transient transfection into COS-7 cells, we show that the uAUG leads to translation of a short peptide from a reading frame that terminates just after the wild-type AUG start codon. This results in reduced translation of the wild-type protein, compatible with the milder phenotype of the patient.

Conclusion: Findings support the notion that more mildly affected, surviving CD/ACD patients carry mutant alleles with residual expression of SOX9 wild-type protein. Although rarely described in human genetic disease and for the first time here for CD, mutations creating upstream AUG codons may be more common than generally assumed.
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http://dx.doi.org/10.1002/mgg3.282DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5441400PMC
May 2017

B56δ-related protein phosphatase 2A dysfunction identified in patients with intellectual disability.

J Clin Invest 2015 Aug 13;125(8):3051-62. Epub 2015 Jul 13.

Here we report inherited dysregulation of protein phosphatase activity as a cause of intellectual disability (ID). De novo missense mutations in 2 subunits of serine/threonine (Ser/Thr) protein phosphatase 2A (PP2A) were identified in 16 individuals with mild to severe ID, long-lasting hypotonia, epileptic susceptibility, frontal bossing, mild hypertelorism, and downslanting palpebral fissures. PP2A comprises catalytic (C), scaffolding (A), and regulatory (B) subunits that determine subcellular anchoring, substrate specificity, and physiological function. Ten patients had mutations within a highly conserved acidic loop of the PPP2R5D-encoded B56δ regulatory subunit, with the same E198K mutation present in 6 individuals. Five patients had mutations in the PPP2R1A-encoded scaffolding Aα subunit, with the same R182W mutation in 3 individuals. Some Aα cases presented with large ventricles, causing macrocephaly and hydrocephalus suspicion, and all cases exhibited partial or complete corpus callosum agenesis. Functional evaluation revealed that mutant A and B subunits were stable and uncoupled from phosphatase activity. Mutant B56δ was A and C binding-deficient, while mutant Aα subunits bound B56δ well but were unable to bind C or bound a catalytically impaired C, suggesting a dominant-negative effect where mutant subunits hinder dephosphorylation of B56δ-anchored substrates. Moreover, mutant subunit overexpression resulted in hyperphosphorylation of GSK3β, a B56δ-regulated substrate. This effect was in line with clinical observations, supporting a correlation between the ID degree and biochemical disturbance.
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http://dx.doi.org/10.1172/JCI79860DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4623570PMC
August 2015

Haploinsufficiency of the NOTCH1 Receptor as a Cause of Adams-Oliver Syndrome With Variable Cardiac Anomalies.

Circ Cardiovasc Genet 2015 Aug 11;8(4):572-581. Epub 2015 May 11.

Barts & The London School of Medicine & Dentistry, Queen Mary University of London, London, United Kingdom.

Background: Adams-Oliver syndrome (AOS) is a rare disorder characterized by congenital limb defects and scalp cutis aplasia. In a proportion of cases, notable cardiac involvement is also apparent. Despite recent advances in the understanding of the genetic basis of AOS, for the majority of affected subjects, the underlying molecular defect remains unresolved. This study aimed to identify novel genetic determinants of AOS.

Methods And Results: Whole-exome sequencing was performed for 12 probands, each with a clinical diagnosis of AOS. Analyses led to the identification of novel heterozygous truncating NOTCH1 mutations (c.1649dupA and c.6049_6050delTC) in 2 kindreds in which AOS was segregating as an autosomal dominant trait. Screening a cohort of 52 unrelated AOS subjects, we detected 8 additional unique NOTCH1 mutations, including 3 de novo amino acid substitutions, all within the ligand-binding domain. Congenital heart anomalies were noted in 47% (8/17) of NOTCH1-positive probands and affected family members. In leukocyte-derived RNA from subjects harboring NOTCH1 extracellular domain mutations, we observed significant reduction of NOTCH1 expression, suggesting instability and degradation of mutant mRNA transcripts by the cellular machinery. Transient transfection of mutagenized NOTCH1 missense constructs also revealed significant reduction in gene expression. Mutant NOTCH1 expression was associated with downregulation of the Notch target genes HEY1 and HES1, indicating that NOTCH1-related AOS arises through dysregulation of the Notch signaling pathway.

Conclusions: These findings highlight a key role for NOTCH1 across a range of developmental anomalies that include cardiac defects and implicate NOTCH1 haploinsufficiency as a likely molecular mechanism for this group of disorders.
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http://dx.doi.org/10.1161/CIRCGENETICS.115.001086DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4545518PMC
August 2015

DNA copy number variations are important in the complex genetic architecture of müllerian disorders.

Fertil Steril 2015 Apr 20;103(4):1021-1030.e1. Epub 2015 Feb 20.

School of Medicine, College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom.

Objective: To clinically and genetically investigate women with müllerian disorders, including Mayer-Rokitanksy-Kuster-Hauser (MRKH) syndrome.

Design: Two-year prospective clinical and laboratory study.

Setting: Not applicable.

Patient(s): Thirty-five women over 16 years of age with a müllerian disorder, including MRKH.

Intervention(s): Women were recruited from specialist gynecology clinics or identified from the Scottish Disorders of Sex Development Register (www.sdsd.scot.nhs.uk/index.html). Associated abnormalities were detected by clinical examination, imaging studies, and biochemical analyses. Chromosomal microduplications and microdeletions were detected by array comparative genomic hybridization (CGH) and validated by fluorescence in situ hydridization.

Main Outcome Measure(s): Identification of associated congenital and biochemical abnormalities and identification of regions of genomic imbalance using array CGH.

Result(s): Associated congenital anomalies were common, present in 25/35 (71%) of affected women, particularly renal and skeletal abnormalities, which were present in 15/35 (43%) and 17/35 (49%) women, respectively. Using array CGH, novel or recurrent regions of genomic imbalance were identified in 4/11 (36%) women with MRKH and in 5/24 (21%) women with other müllerian abnormalities.

Conclusion(s): Additional congenital abnormalities and regions of genomic imbalance are common in women with müllerian disorders, including MRKH. Recurrent microdeletions and microduplications associated with MRKH implicate specific possibly causative genes. The investigation of women with müllerian disorders should be thorough, and array CGH should be considered, given the potential highly significant familial implications of a chromosomal abnormality.
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http://dx.doi.org/10.1016/j.fertnstert.2015.01.008DOI Listing
April 2015

Diverse phenotypic consequences of mutations affecting the C-terminus of FLNA.

J Mol Med (Berl) 2015 Jul 18;93(7):773-82. Epub 2015 Feb 18.

Department of Paediatrics and Child Health, Dunedin School of Medicine, Otago University, Dunedin, New Zealand.

Unlabelled: Filamin A, the filamentous protein encoded by the X-linked gene FLNA, cross-links cytoskeletal actin into three-dimensional networks, facilitating its role as a signalling scaffold and a mechanosensor of extrinsic shear forces. Central to these functions is the ability of FLNA to form V-shaped homodimers through its C-terminal located filamin repeat 24. Additionally, many proteins that interact with FLNA have a binding site that includes the C-terminus of the protein. Here, a cohort of patients with mutations affecting this region of the protein is studied, with particular emphasis on the phenotype of male hemizygotes. Seven unrelated families are reported, with five exhibiting a typical female presentation of periventricular heterotopia (PH), a neuronal migration disorder typically caused by loss-of-function mutations in FLNA. One male presents with widespread PH consistent with previous male phenotypes attributable to hypomorphic mutations in FLNA. In stark contrast, two brothers are described with a mild PH presentation, due to a missense mutation (p.Gly2593Glu) inserting a large negatively charged amino acid into the hydrophobic dimerisation interface of FLNA. Co-immunoprecipitation, in vitro cross-linking studies and gel filtration chromatography all demonstrated that homodimerisation of isolated FLNA repeat 24 is abolished by this p.Gly2593Glu substitution but that extended FLNA(Gly2593Glu) repeat 16-24 constructs exhibit dimerisation. These observations imply that other interactions apart from those mediated by the canonical repeat 24 dimerisation interface contribute to FLNA homodimerisation and that mutations affecting this region of the protein can have broad phenotypic effects.

Key Messages: • Mutations in the X-linked gene FLNA cause a spectrum of syndromes. • Genotype-phenotype correlations are emerging but still remain unclear. • C-term mutations can confer male lethality, survival or connective tissue defects. • Mutations leading to the latter affect filamin dimerisation. • This deficit is compensated for by remotely acting domains elsewhere in FLNA.
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http://dx.doi.org/10.1007/s00109-015-1261-7DOI Listing
July 2015

Mosaic structural variation in children with developmental disorders.

Hum Mol Genet 2015 May 29;24(10):2733-45. Epub 2015 Jan 29.

MRC Integrative Epidemiology Unit, University of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, UK.

Delineating the genetic causes of developmental disorders is an area of active investigation. Mosaic structural abnormalities, defined as copy number or loss of heterozygosity events that are large and present in only a subset of cells, have been detected in 0.2-1.0% of children ascertained for clinical genetic testing. However, the frequency among healthy children in the community is not well characterized, which, if known, could inform better interpretation of the pathogenic burden of this mutational category in children with developmental disorders. In a case-control analysis, we compared the rate of large-scale mosaicism between 1303 children with developmental disorders and 5094 children lacking developmental disorders, using an analytical pipeline we developed, and identified a substantial enrichment in cases (odds ratio = 39.4, P-value 1.073e - 6). A meta-analysis that included frequency estimates among an additional 7000 children with congenital diseases yielded an even stronger statistical enrichment (P-value 1.784e - 11). In addition, to maximize the detection of low-clonality events in probands, we applied a trio-based mosaic detection algorithm, which detected two additional events in probands, including an individual with genome-wide suspected chimerism. In total, we detected 12 structural mosaic abnormalities among 1303 children (0.9%). Given the burden of mosaicism detected in cases, we suspected that many of the events detected in probands were pathogenic. Scrutiny of the genotypic-phenotypic relationship of each detected variant assessed that the majority of events are very likely pathogenic. This work quantifies the burden of structural mosaicism as a cause of developmental disorders.
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http://dx.doi.org/10.1093/hmg/ddv033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4406290PMC
May 2015

Chromosomal microarray analysis for looked after children: a double-edged sword?

Arch Dis Child 2015 Feb 26;100(2):206-7. Epub 2014 Sep 26.

School of Medicine, University of Glasgow, Glasgow, UK.

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http://dx.doi.org/10.1136/archdischild-2014-307189DOI Listing
February 2015

How to use… microarray comparative genomic hybridisation to investigate developmental disorders.

Arch Dis Child Educ Pract Ed 2015 Feb 4;100(1):24-9. Epub 2014 Sep 4.

West of Scotland Department of Clinical Genetics, Level 2A, Southern General Hospital, Glasgow, UK.

Array-comparative genomic hybridisation (array-CGH) is a relatively new test that permits close scrutiny of chromosomal structure to detect genomic microdeletions and microduplications that are invisible in a conventional karyotype. Array-CGH is now the 'first-line' genetic test in the investigation of early developmental impairments and learning difficulties, especially if the clinical picture includes dysmorphism, abnormal growth, congenital anomalies, epilepsy and autism, alone or in combination. However, due to the array-CGH report's technical content and the uncertain clinical significance of many genomic findings, the results of array-CGH studies need careful interpretation. Array-CGH trebles the frequency of diagnosis compared with conventional karyotyping, but collaborative working, involving paediatricians, clinical geneticists and clinical scientists, is most important for interpretation of the results of new genomic investigations in everyday clinical practice.
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http://dx.doi.org/10.1136/archdischild-2014-306022DOI Listing
February 2015

Genetic heterogeneity in Cornelia de Lange syndrome (CdLS) and CdLS-like phenotypes with observed and predicted levels of mosaicism.

J Med Genet 2014 Oct 14;51(10):659-68. Epub 2014 Aug 14.

MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.

Background: Cornelia de Lange syndrome (CdLS) is a multisystem disorder with distinctive facial appearance, intellectual disability and growth failure as prominent features. Most individuals with typical CdLS have de novo heterozygous loss-of-function mutations in NIPBL with mosaic individuals representing a significant proportion. Mutations in other cohesin components, SMC1A, SMC3, HDAC8 and RAD21 cause less typical CdLS.

Methods: We screened 163 affected individuals for coding region mutations in the known genes, 90 for genomic rearrangements, 19 for deep intronic variants in NIPBL and 5 had whole-exome sequencing.

Results: Pathogenic mutations [including mosaic changes] were identified in: NIPBL 46 [3] (28.2%); SMC1A 5 [1] (3.1%); SMC3 5 [1] (3.1%); HDAC8 6 [0] (3.6%) and RAD21 1 [0] (0.6%). One individual had a de novo 1.3 Mb deletion of 1p36.3. Another had a 520 kb duplication of 12q13.13 encompassing ESPL1, encoding separase, an enzyme that cleaves the cohesin ring. Three de novo mutations were identified in ANKRD11 demonstrating a phenotypic overlap with KBG syndrome. To estimate the number of undetected mosaic cases we used recursive partitioning to identify discriminating features in the NIPBL-positive subgroup. Filtering of the mutation-negative group on these features classified at least 18% as 'NIPBL-like'. A computer composition of the average face of this NIPBL-like subgroup was also more typical in appearance than that of all others in the mutation-negative group supporting the existence of undetected mosaic cases.

Conclusions: Future diagnostic testing in 'mutation-negative' CdLS thus merits deeper sequencing of multiple DNA samples derived from different tissues.
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http://dx.doi.org/10.1136/jmedgenet-2014-102573DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4173748PMC
October 2014

The phenotype of congenital insensitivity to pain due to the NaV1.9 variant p.L811P.

Eur J Hum Genet 2015 May 13;23(5):561-3. Epub 2014 Aug 13.

Institute of Human Genetics, Jena University Hospital, Jena, Germany.

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http://dx.doi.org/10.1038/ejhg.2014.166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4402639PMC
May 2015

Gain-of-function mutations in IFIH1 cause a spectrum of human disease phenotypes associated with upregulated type I interferon signaling.

Nat Genet 2014 May 30;46(5):503-509. Epub 2014 Mar 30.

Manchester Academic Health Science Centre, University of Manchester, Genetic Medicine, Manchester, UK.

The type I interferon system is integral to human antiviral immunity. However, inappropriate stimulation or defective negative regulation of this system can lead to inflammatory disease. We sought to determine the molecular basis of genetically uncharacterized cases of the type I interferonopathy Aicardi-Goutières syndrome and of other undefined neurological and immunological phenotypes also demonstrating an upregulated type I interferon response. We found that heterozygous mutations in the cytosolic double-stranded RNA receptor gene IFIH1 (also called MDA5) cause a spectrum of neuroimmunological features consistently associated with an enhanced interferon state. Cellular and biochemical assays indicate that these mutations confer gain of function such that mutant IFIH1 binds RNA more avidly, leading to increased baseline and ligand-induced interferon signaling. Our results demonstrate that aberrant sensing of nucleic acids can cause immune upregulation.
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http://dx.doi.org/10.1038/ng.2933DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4004585PMC
May 2014

Myhre and LAPS syndromes: clinical and molecular review of 32 patients.

Eur J Hum Genet 2014 Nov 15;22(11):1272-7. Epub 2014 Jan 15.

INSERM U781 Unit, Department of Genetics, Institut Imagine, Paris Descartes University-Sorbonne Paris Cité, Necker Enfants-Malades Hospital, Paris, France.

Myhre syndrome is characterized by short stature, brachydactyly, facial features, pseudomuscular hypertrophy, joint limitation and hearing loss. We identified SMAD4 mutations as the cause of Myhre syndrome. SMAD4 mutations have also been identified in laryngotracheal stenosis, arthropathy, prognathism and short stature syndrome (LAPS). This study aimed to review the features of Myhre and LAPS patients to define the clinical spectrum of SMAD4 mutations. We included 17 females and 15 males ranging in age from 8 to 48 years. Thirty were diagnosed with Myhre syndrome and two with LAPS. SMAD4 coding sequence was analyzed by Sanger sequencing. Clinical and radiological features were collected from a questionnaire completed by the referring physicians. All patients displayed a typical facial gestalt, thickened skin, joint limitation and muscular pseudohypertrophy. Growth retardation was common (68.7%) and was variable in severity (from -5.5 to -2 SD), as was mild-to-moderate intellectual deficiency (87.5%) with additional behavioral problems in 56.2% of the patients. Significant health concerns like obesity, arterial hypertension, bronchopulmonary insufficiency, laryngotracheal stenosis, pericarditis and early death occurred in four. Twenty-nine patients had a de novo heterozygous SMAD4 mutation, including both patients with LAPS. In 27 cases mutation affected Ile500 and in two cases Arg496. The three patients without SMAD4 mutations had typical findings of Myhre syndrome. Myhre-LAPS syndrome is a clinically homogenous condition with life threatening complications in the course of the disease. Our identification of SMAD4 mutations in 29/32 cases confirms that SMAD4 is the major gene responsible for Myhre syndrome.
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http://dx.doi.org/10.1038/ejhg.2013.288DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4200423PMC
November 2014

SMAD4 mutations causing Myhre syndrome result in disorganization of extracellular matrix improved by losartan.

Eur J Hum Genet 2014 Aug 8;22(8):988-94. Epub 2014 Jan 8.

1] Telethon Institute of Genetics and Medicine, Naples, Italy [2] Department of Translational Medicine, Federico II University of Naples, Naples, Italy.

Myhre syndrome (MS, MIM 139210) is a connective tissue disorder that presents with short stature, short hands and feet, facial dysmorphic features, muscle hypertrophy, thickened skin, and deafness. Recurrent missense mutations in SMAD4 encoding for a transducer mediating transforming growth factor β (TGF-β) signaling are responsible for MS. We found that MS fibroblasts showed increased SMAD4 protein levels, impaired matrix deposition, and altered expression of genes encoding matrix metalloproteinases and related inhibitors. Increased TGF-β signaling and progression of aortic root dilation in Marfan syndrome can be prevented by the antihypertensive drug losartan, a TGF-β antagonists and angiotensin-II type 1 receptor blocker. Herein, we showed that losartan normalizes metalloproteinase and related inhibitor transcript levels and corrects the extracellular matrix deposition defect in fibroblasts from MS patients. The results of this study may pave the way toward therapeutic applications of losartan in MS.
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http://dx.doi.org/10.1038/ejhg.2013.283DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3984901PMC
August 2014

Next generation sequencing for molecular diagnosis of neurological disorders using ataxias as a model.

Brain 2013 Oct 11;136(Pt 10):3106-18. Epub 2013 Sep 11.

1 Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford OX3 9DU, UK.

Many neurological conditions are caused by immensely heterogeneous gene mutations. The diagnostic process is often long and complex with most patients undergoing multiple invasive and costly investigations without ever reaching a conclusive molecular diagnosis. The advent of massively parallel, next-generation sequencing promises to revolutionize genetic testing and shorten the 'diagnostic odyssey' for many of these patients. We performed a pilot study using heterogeneous ataxias as a model neurogenetic disorder to assess the introduction of next-generation sequencing into clinical practice. We captured 58 known human ataxia genes followed by Illumina Next-Generation Sequencing in 50 highly heterogeneous patients with ataxia who had been extensively investigated and were refractory to diagnosis. All cases had been tested for spinocerebellar ataxia 1-3, 6, 7 and Friedrich's ataxia and had multiple other biochemical, genetic and invasive tests. In those cases where we identified the genetic mutation, we determined the time to diagnosis. Pathogenicity was assessed using a bioinformatics pipeline and novel variants were validated using functional experiments. The overall detection rate in our heterogeneous cohort was 18% and varied from 8.3% in those with an adult onset progressive disorder to 40% in those with a childhood or adolescent onset progressive disorder. The highest detection rate was in those with an adolescent onset and a family history (75%). The majority of cases with detectable mutations had a childhood onset but most are now adults, reflecting the long delay in diagnosis. The delays were primarily related to lack of easily available clinical testing, but other factors included the presence of atypical phenotypes and the use of indirect testing. In the cases where we made an eventual diagnosis, the delay was 3-35 years (mean 18.1 years). Alignment and coverage metrics indicated that the capture and sequencing was highly efficient and the consumable cost was ∼£400 (€460 or US$620). Our pathogenicity interpretation pathway predicted 13 different mutations in eight different genes: PRKCG, TTBK2, SETX, SPTBN2, SACS, MRE11, KCNC3 and DARS2 of which nine were novel including one causing a newly described recessive ataxia syndrome. Genetic testing using targeted capture followed by next-generation sequencing was efficient, cost-effective, and enabled a molecular diagnosis in many refractory cases. A specific challenge of next-generation sequencing data is pathogenicity interpretation, but functional analysis confirmed the pathogenicity of novel variants showing that the pipeline was robust. Our results have broad implications for clinical neurology practice and the approach to diagnostic testing.
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http://dx.doi.org/10.1093/brain/awt236DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3784284PMC
October 2013

Situs inversus totalis and congenital hypoglossia associated with atrial ectopic bradycardia and normal neurodevelopmental outcome.

Clin Dysmorphol 2013 Jan;22(1):36-8

Neonatal Unit, Princess Royal Maternity, Yorkhill Hospitals, Glasgow, Scotland, UK.

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http://dx.doi.org/10.1097/MCD.0b013e3283590aacDOI Listing
January 2013

Results of Duchenne muscular dystrophy family screening in practice: leaks rather than cascades?

Clin Genet 2013 Feb 9;83(2):187-90. Epub 2012 Apr 9.

North Scotland Regional Genetics Service, Clinical Genetics Centre, Ashgrove House, Foresterhill, Aberdeen, UK.

Duchenne muscular dystrophy (DMD) is a progressive neuromuscular disease caused by mutations in the gene that encodes the protein dystrophin. Approximately 2 of 3 affected boys inherit their mutation from their carrier mother whereupon other female relatives are at risk of carrying the mutation. Female carriers are also at risk of developing cardiomyopathy and regular cardiac screening is recommended. Clinical genetics services offer genetic counselling and carrier tests for consenting relatives of DMD patients known as 'cascade screening'. We retrospectively analysed data from two genetics centres, West of Scotland and South East Thames where the latter centre operated a computer-held DMD register. Over the period, 1971-2008, a total of 843 potential carriers, in 195 West of Scotland families, were tested: 16% of 1st degree relatives and 48% of 2nd degree and more distant relatives were not tested. In South East Thames, a total of 1223 potential carriers in 349 families were tested: 49% of 1st degree and 65% of 2nd degree and more distant relatives were not tested. These data are similar to Becker muscular dystrophy/DMD carrier screening results recently reported from the Netherlands. Retrospective results from three countries indicate that despite efforts to offer extended cascade screening, significant numbers of potential carriers of DMD remain unaware of their reproductive and health risks.
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http://dx.doi.org/10.1111/j.1399-0004.2012.01876.xDOI Listing
February 2013

Mutations in CTC1, encoding conserved telomere maintenance component 1, cause Coats plus.

Nat Genet 2012 Jan 22;44(3):338-42. Epub 2012 Jan 22.

Manchester Academic Health Science Centre, University of Manchester, Genetic Medicine, UK.

Coats plus is a highly pleiotropic disorder particularly affecting the eye, brain, bone and gastrointestinal tract. Here, we show that Coats plus results from mutations in CTC1, encoding conserved telomere maintenance component 1, a member of the mammalian homolog of the yeast heterotrimeric CST telomeric capping complex. Consistent with the observation of shortened telomeres in an Arabidopsis CTC1 mutant and the phenotypic overlap of Coats plus with the telomeric maintenance disorders comprising dyskeratosis congenita, we observed shortened telomeres in three individuals with Coats plus and an increase in spontaneous γH2AX-positive cells in cell lines derived from two affected individuals. CTC1 is also a subunit of the α-accessory factor (AAF) complex, stimulating the activity of DNA polymerase-α primase, the only enzyme known to initiate DNA replication in eukaryotic cells. Thus, CTC1 may have a function in DNA metabolism that is necessary for but not specific to telomeric integrity.
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http://dx.doi.org/10.1038/ng.1084DOI Listing
January 2012

Mutations at a single codon in Mad homology 2 domain of SMAD4 cause Myhre syndrome.

Nat Genet 2011 Dec 11;44(1):85-8. Epub 2011 Dec 11.

Département de Génétique, Unité INSERM U781, Université Paris Descartes, Sorbonne Paris Cité, Hôpital Necker Enfants Malades, Paris, France.

Myhre syndrome (MIM 139210) is a developmental disorder characterized by short stature, short hands and feet, facial dysmorphism, muscular hypertrophy, deafness and cognitive delay. Using exome sequencing of individuals with Myhre syndrome, we identified SMAD4 as a candidate gene that contributes to this syndrome on the basis of its pivotal role in the bone morphogenetic pathway (BMP) and transforming growth factor (TGF)-β signaling. We identified three distinct heterozygous missense SMAD4 mutations affecting the codon for Ile500 in 11 individuals with Myhre syndrome. All three mutations are located in the region of SMAD4 encoding the Mad homology 2 (MH2) domain near the site of monoubiquitination at Lys519, and we found a defect in SMAD4 ubiquitination in fibroblasts from affected individuals. We also observed decreased expression of downstream TGF-β target genes, supporting the idea of impaired TGF-β-mediated transcriptional control in individuals with Myhre syndrome.
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http://dx.doi.org/10.1038/ng.1016DOI Listing
December 2011

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

Eur J Hum Genet 2012 Apr 30;20(4):381-8. Epub 2011 Nov 30.

Department of Genetic Medicine, St Mary's Hospital, Manchester Academic Health Sciences Centre (MAHSC), University of Manchester, Manchester, UK.

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.
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http://dx.doi.org/10.1038/ejhg.2011.220DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3306863PMC
April 2012

Spectrum of mutations in the renin-angiotensin system genes in autosomal recessive renal tubular dysgenesis.

Hum Mutat 2012 Feb 22;33(2):316-26. Epub 2011 Dec 22.

Inserm U983, Faculté de Médecine Paris Descartes, Université Paris Descartes, Paris, France.

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.
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http://dx.doi.org/10.1002/humu.21661DOI Listing
February 2012

Clinical features and respiratory complications in Myhre syndrome.

Eur J Med Genet 2011 Nov-Dec;54(6):e553-9. Epub 2011 Jul 21.

Ferguson-Smith Dept. of Clinical Genetics, Yorkhill Hospital, Glasgow, UK.

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.
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http://dx.doi.org/10.1016/j.ejmg.2011.07.001DOI Listing
January 2012

Mutations in CEP57 cause mosaic variegated aneuploidy syndrome.

Nat Genet 2011 Jun 8;43(6):527-9. Epub 2011 May 8.

Section of Cancer Genetics, Institute of Cancer Research, Sutton, UK.

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.
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http://dx.doi.org/10.1038/ng.822DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3508359PMC
June 2011

Bohring-Opitz (Oberklaid-Danks) syndrome: clinical study, review of the literature, and discussion of possible pathogenesis.

Eur J Hum Genet 2011 May 2;19(5):513-9. Epub 2011 Feb 2.

Clinical Genetics Department, Univerity Hospitals NHS Foundation Trust, St Michael's Hospital, Bristol, UK.

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.
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http://dx.doi.org/10.1038/ejhg.2010.234DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3083618PMC
May 2011

The face of Ulnar Mammary syndrome?

Eur J Med Genet 2011 May-Jun;54(3):301-5. Epub 2011 Jan 1.

Yorkshire Regional Genetics Centre, Ward 10, Chapel Allerton Hospital, Chapeltown Road, Leeds LS7 9TF, England, UK.

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.
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http://dx.doi.org/10.1016/j.ejmg.2010.12.010DOI Listing
September 2011

Focal segmental glomerulosclerosis, Coats'-like retinopathy, sensorineural deafness and chromosome 4 duplication: a new association.

Pediatr Nephrol 2010 Aug 27;25(8):1551-4. Epub 2010 Feb 27.

Renal Unit, Royal Hospital for Sick Children, Glasgow, G3 8SJ, UK.

We describe the novel association in a girl of nephrotic syndrome due to focal segmental glomerulosclerosis, bilateral sensorineural deafness, basal ganglia calcification, bilateral retinopathy similar to that seen in Coats' disease, with de novo duplication of a subtelomeric region of chromosome 4q35. The chromosomal duplication was identified during investigation of a possible association with features of fascio-scapulo-humeral dystrophy (FSHD). This duplication has not previously been reported with FSGS and adds to the expanding number of genetic associations with steroid-resistant nephrotic syndrome.
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http://dx.doi.org/10.1007/s00467-010-1474-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2887537PMC
August 2010

CASK mutations are frequent in males and cause X-linked nystagmus and variable XLMR phenotypes.

Eur J Hum Genet 2010 May 23;18(5):544-52. Epub 2009 Dec 23.

Genetics of Learning Disability Service, Hunter Genetics, Waratah, New South Wales, Australia.

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.
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http://dx.doi.org/10.1038/ejhg.2009.220DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2987321PMC
May 2010

Pyruvate dehydrogenase E2 deficiency: a potentially treatable cause of episodic dystonia.

Eur J Paediatr Neurol 2010 Jul 21;14(4):349-53. Epub 2009 Dec 21.

Ferguson Smith Centre for Clinical Genetics, Yorkhill Hospital, Dalnair Street, Glasgow, G3 8SJ, UK.

The association of progressive episodic dystonia and learning disability with distinctive neuroimaging findings may lead to consideration of atypical Pantothenate Kinase Associated Neurodegeneration (PKAN) and investigations directed towards that diagnosis. Recent reports indicate that deficiency of dihydrolipoamide acetyltransferase, the E2 component of the pyruvate dehydrogenase complex, may present similarly, and that this disorder should also be considered in the differential diagnosis. We describe two sisters with early onset episodic dystonia and pyruvate dehydrogenase deficiency caused by defects in the E2 subunit. Both have neuroimaging features similar to previously described patients and have mutations in the DLAT gene. As this condition is potentially treatable with a ketogenic diet, the possibility of this diagnosis should be considered in similar cases.
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http://dx.doi.org/10.1016/j.ejpn.2009.11.001DOI Listing
July 2010

Roberts syndrome: facial dysmorphology in a mildly affected case.

Clin Dysmorphol 2009 Oct;18(4):236-7

Ferguson Smith Centre for Clinical Genetics, Royal Hospital for Sick Children, Glasgow, UK.

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http://dx.doi.org/10.1097/MCD.0b013e328330209bDOI Listing
October 2009

A systematic, large-scale resequencing screen of X-chromosome coding exons in mental retardation.

Nat Genet 2009 May 19;41(5):535-43. Epub 2009 Apr 19.

Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.

Large-scale systematic resequencing has been proposed as the key future strategy for the discovery of rare, disease-causing sequence variants across the spectrum of human complex disease. We have sequenced the coding exons of the X chromosome in 208 families with X-linked mental retardation (XLMR), the largest direct screen for constitutional disease-causing mutations thus far reported. The screen has discovered nine genes implicated in XLMR, including SYP, ZNF711 and CASK reported here, confirming the power of this strategy. The study has, however, also highlighted issues confronting whole-genome sequencing screens, including the observation that loss of function of 1% or more of X-chromosome genes is compatible with apparently normal existence.
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http://dx.doi.org/10.1038/ng.367DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2872007PMC
May 2009