Publications (13)75.33 Total impact
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Article: Epigenotype-phenotype correlations in Silver-Russell syndrome.
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ABSTRACT: Silver-Russell syndrome (SRS) is characterised by intrauterine growth restriction, poor postnatal growth, relative macrocephaly, triangular face and asymmetry. Maternal uniparental disomy (mUPD) of chromosome 7 and hypomethylation of the imprinting control region (ICR) 1 on chromosome 11p15 are found in 5-10% and up to 60% of patients with SRS, respectively. As many features are non-specific, diagnosis of SRS remains difficult. Studies of patients in whom the molecular diagnosis is confirmed therefore provide valuable clinical information on the condition. A detailed, prospective study of 64 patients with mUPD7 (n=20) or ICR1 hypomethylation (n=44) was undertaken. The considerable overlap in clinical phenotype makes it difficult to distinguish these two molecular subgroups reliably. ICR1 hypomethylation was more likely to be scored as 'classical' SRS. Asymmetry, fifth finger clinodactyly and congenital anomalies were more commonly seen with ICR1 hypomethylation, whereas learning difficulties and referral for speech therapy were more likely with mUPD7. Myoclonus-dystonia has been reported previously in one mUPD7 patient. The authors report mild movement disorders in three further cases. No correlation was found between clinical severity and level of ICR1 hypomethylation. Use of assisted reproductive technology in association with ICR1 hypomethylation seems increased compared with the general population. ICR1 hypomethylation was also observed in affected siblings, although recurrence risk remains low in the majority of cases. Overall, a wide range of severity was observed, particularly with ICR1 hypomethylation. A low threshold for investigation of patients with features suggestive, but not typical, of SRS is therefore recommended.Journal of Medical Genetics 11/2010; 47(11):760-8. · 6.36 Impact Factor -
Article: Phenotype and genotype in 17 patients with Goltz-Gorlin syndrome.
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ABSTRACT: Goltz-Gorlin syndrome or focal dermal hypoplasia is a highly variable, X-linked dominant syndrome with abnormalities of ectodermal and mesodermal origin. In 2007, mutations in the PORCN gene were found to be causative in Goltz-Gorlin syndrome. A series of 17 patients with Goltz-Gorlin syndrome is reported on, and their phenotype and genotype are described. In 14 patients (13 females and one male), a PORCN mutation was found. Mutations included nonsense (n = 5), frameshift (n = 2), aberrant splicing (n = 2) and missense (n = 5) mutations. No genotype-phenotype correlation was found. All patients with the classical features of the syndrome had a detectable mutation. In three females with atypical signs, no mutation was found. The male patient had classical features and showed mosaicism for a PORCN nonsense mutation in fibroblasts. Two affected sisters had a mutation not detectable in their parents, supporting germline mosaicism. Their father had undergone radiation for testicular cancer in the past. Two classically affected females had three severely affected female fetuses which all had midline thoracic and abdominal wall defects, resembling the pentalogy of Cantrell and the limb-body wall complex. Thoracic and abdominal wall defects were also present in two surviving patients. PORCN mutations can possibly cause pentalogy of Cantrell and limb-body wall complexes as well. Therefore, particularly in cases with limb defects, it seems useful to search for these. PORCN mutations can be found in all classically affected cases of Goltz-Gorlin syndrome, including males. Somatic and germline mosaicism occur. There is no evident genotype-phenotype correlation.Journal of Medical Genetics 08/2009; 46(10):716-20. · 6.36 Impact Factor -
Article: Mosaic maternal uniparental disomy of chromosome 11 in a patient with Silver-Russell syndrome.
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ABSTRACT: Silver-Russell syndrome (SRS) is a clinically heterogeneous disorder characterised mainly by intrauterine and postnatal growth retardation. While maternal uniparental disomy of chromosome 7 is found in 5-10% of SRS patients, recently genetic and epigenetic mutations affecting the imprinting centres on chromosome 11p15 have been reported in up to 64% of patients. Chromosome 11p15 abnormalities reported in SRS include methylation defects in the imprinting centre 1 (ICR1) and maternally inherited duplications involving all or part of the imprinted region of 11p15. Here we report the first published case of SRS with mosaic maternal uniparental disomy of chromosome 11.Journal of Medical Genetics 07/2008; 45(6):396-9. · 6.36 Impact Factor -
Article: Arterial tortuosity syndrome: clinical and molecular findings in 12 newly identified families.
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ABSTRACT: Arterial tortuosity syndrome (ATS) is a rare autosomal recessive connective tissue disease, characterized by widespread arterial involvement with elongation, tortuosity, and aneurysms of the large and middle-sized arteries. Recently, SLC2A10 mutations were identified in this condition. This gene encodes the glucose transporter GLUT10 and was previously suggested as a candidate gene for diabetes mellitus type 2. A total of 12 newly identified ATS families with 16 affected individuals were clinically and molecularly characterized. In addition, extensive cardiovascular imaging and glucose tolerance tests were performed in both patients and heterozygous carriers. All 16 patients harbor biallelic SLC2A10 mutations of which nine are novel (six missense, three truncating mutations, including a large deletion). Haplotype analysis suggests founder effects for all five recurrent mutations. Remarkably, patients were significantly older than those previously reported in the literature (P=0.04). Only one affected relative died, most likely of an unrelated cause. Although the natural history of ATS in this series was less severe than previously reported, it does indicate a risk for ischemic events. Two patients initially presented with stroke, respectively at age 8 months and 23 years. Tortuosity of the aorta or large arteries was invariably present. Two adult probands (aged 23 and 35 years) had aortic root dilation, seven patients had localized arterial stenoses, and five had long stenotic stretches of the aorta. Heterozygous carriers did not show any vascular anomalies. Glucose metabolism was normal in six patients and eight heterozygous individuals of five families. As such, overt diabetes is not related to SLC2A10 mutations associated with ATS.Human Mutation 02/2008; 29(1):150-8. · 5.69 Impact Factor -
Article: Arterial tortuosity syndrome: clinical and molecular findings in 12 newly identified families
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ABSTRACT: Arterial tortuosity syndrome (ATS) is a rare autosomal recessive connective tissue disease, characterized by widespread arterial involvement with elongation, tortuosity, and aneurysms of the large and middle-sized arteries. Recently, SLC2A10 mutations were identified in this condition. This gene encodes the glucose transporter GLUT10 and was previously suggested as a candidate gene for diabetes mellitus type 2. A total of 12 newly identified ATS families with 16 affected individuals were clinically and molecularly characterized. In addition, extensive cardiovascular imaging and glucose tolerance tests were performed in both patients and heterozygous carriers. All 16 patients harbor biallelic SLC2A10 mutations of which nine are novel (six missense, three truncating mutations, including a large deletion). Haplotype analysis suggests founder effects for all five recurrent mutations. Remarkably, patients were significantly older than those previously reported in the literature (P=0.04). Only one affected relative died, most likely of an unrelated cause. Although the natural history of ATS in this series was less severe than previously reported, it does indicate a risk for ischemic events. Two patients initially presented with stroke, respectively at age 8 months and 23 years. Tortuosity of the aorta or large arteries was invariably present. Two adult probands (aged 23 and 35 years) had aortic root dilation, seven patients had localized arterial stenoses, and five had long stenotic stretches of the aorta. Heterozygous carriers did not show any vascular anomalies. Glucose metabolism was normal in six patients and eight heterozygous individuals of five families. As such, overt diabetes is not related to SLC2A10 mutations associated with ATS. Hum Mutat 29(1), 150–158, 2008. © 2007 Wiley-Liss, Inc.Human Mutation 12/2007; 29(1):150 - 158. · 5.69 Impact Factor -
Article: Evidence that insulin is imprinted in the human yolk sac.
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ABSTRACT: Allelic variation in the size of the insulin (INS) variable number tandem repeat (VNTR) correlates with the expression of both INS in the pancreas and thymus and IGF2 (the gene downstream of INS) in the placenta. In addition, the shorter, class I alleles are associated with type 1 diabetes, whereas the longer, class III alleles are associated with type 2 diabetes, polycystic ovary syndrome (PCOS), and size at birth. Parent-of-origin effects have been reported for type 2 diabetes and PCOS, thus implicating a role for genomic imprinting in these phenotypes. In mice, Ins2 is imprinted and paternally expressed in the yolk sac. In humans, evidence for the imprinting of INS is circumstantial, with occasional monoallelic expression in the thymus. In the present study, we found evidence for the imprinted paternal expression of INS in the human yolk sac. Two other imprinted genes from the same cluster are also expressed monoallelically in the human yolk sac. IGF2 was expressed solely from the paternal allele, and H19 was expressed solely from the maternal allele. These data suggest not only further functional roles for the human yolk sac in early fetal growth, but also evidence for a potential causal link between the control of insulin expression during development and insulin/growth-related diseases in later life.Diabetes 02/2001; 50(1):199-203. · 8.29 Impact Factor -
Article: Silver-Russell syndrome and ring chromosome 7.
Journal of Medical Genetics 06/2000; 37(5):380. · 6.36 Impact Factor -
Article: Duplication of 7p11.2-p13, including GRB10, in Silver-Russell syndrome.
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ABSTRACT: Silver-Russell syndrome (SRS) is characterized by pre- and postnatal growth failure and other dysmorphic features. The syndrome is genetically heterogeneous, but maternal uniparental disomy of chromosome 7 has been demonstrated in approximately 7% of cases. This suggests that at least one gene on chromosome 7 is imprinted and involved in the pathogenesis of SRS. We have identified a de novo duplication of 7p11.2-p13 in a proband with features characteristic of SRS. FISH confirmed the presence of a tandem duplication encompassing the genes for growth factor receptor-binding protein 10 (GRB10) and insulin-like growth factor-binding proteins 1 and 3 (IGFBP1 and -3) but not that for epidermal growth factor-receptor (EGFR). Microsatellite markers showed that the duplication was of maternal origin. These findings provide the first evidence that SRS may result from overexpression of a maternally expressed imprinted gene, rather than from absent expression of a paternally expressed gene. GRB10 lies within the duplicated region and is a strong candidate, since it is a known growth suppressor. Furthermore, the mouse homologue (Grb10/Meg1) is reported to be maternally expressed and maps to the imprinted region of proximal mouse chromosome 11 that demonstrates prenatal growth failure when it is maternally disomic. We have demonstrated that the GRB10 genomic interval replicates asynchronously in human lymphocytes, suggestive of imprinting. An additional 36 SRS probands were investigated for duplication of GRB10, but none were found. However, it remains possible that GRB10 and/or other genes within 7p11.2-p13 are responsible for some cases of SRS.The American Journal of Human Genetics 02/2000; 66(1):36-46. · 10.60 Impact Factor -
Article: Biallelic expression of IGFBP1 and IGFBP3, two candidate genes for the Silver-Russell syndrome.
Journal of Medical Genetics 02/2000; 37(1):65-7. · 6.36 Impact Factor -
Article: An analysis of the distribution of hetero- and isodisomic regions of chromosome 7 in five mUPD7 Silver-Russell syndrome probands.
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ABSTRACT: Silver-Russell syndrome (SRS) shares common features of intrauterine growth retardation (IUGR) and a number of dysmorphic features including lateral asymmetry in about 50% of subjects. Its genetic aetiology is complex and most probably heterogeneous. Approximately 7% of patients with SRS have been found to have maternal uniparental disomy of chromosome 7 (mUPD7). Genomic DNA samples from five SRS patients with mUPD7 have been analysed for common regions of isodisomy using 40 polymorphic markers distributed along the length of chromosome 7. No regions of common isodisomy were found among the five patients. It is most likely that imprinted gene(s) rather than recessive mutations cause the common phenotype. Heterodisomy of markers around the centromere indicated that the underlying cause of the mUPD7 is a maternal meiosis I non-disjunction error in these five subjects.Journal of Medical Genetics 07/1999; 36(6):457-60. · 6.36 Impact Factor -
Article: Genetics of Silver-Russell syndrome.
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ABSTRACT: The Silver-Russell syndrome (SRS) is generally sporadic, but with sufficient reported cases of dominant and recessive patterns of inheritance to suggest a genetic cause in some cases, at least. No consistent cytogenetic abnormalities have been found although some features of the syndrome have been reported to be associated with structural abnormalities of distal 15q. More recently it has been shown that about 10% of SRS patients have maternal uniparental disomy of chromosome 7 which suggests the presence of a maternally imprinted gene on chromosome 7 that is associated with SRS. In the majority of patients with normal biparental inheritance of chromosome 7 the same gene could be involved if the paternal copy were deleted or mutated so that it is disabled and the maternal copy is silent because of the imprinting.Hormone Research 02/1998; 49 Suppl 2:32-6. · 2.48 Impact Factor -
Article: Human EGFR, a candidate gene for the Silver-Russell syndrome, is biallelically expressed in a wide range of fetal tissues.
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ABSTRACT: Maternal uniparental disomy of chromosome 7 (mUPD7) has been reported in around 10% of cases of Silver-Russell syndrome (SRS). This suggests that at least one gene on chromosome 7 is imprinted and involved in the pathogenesis of this condition. One candidate is epidermal growth factor receptor (EGFR) which maps to chromosome 7p12, a region homologous to an imprinted region on mouse chromosome 11. Using a restriction fragment length polymorphism, biallelic expression of EGFR was found in a range of normal human fetal tissues. Expression was also demonstrated in fibroblasts and lymphoblasts from SRS patients with mUPD7. Thus no evidence that EGFR is imprinted was found, making its involvement in SRS unlikely. However, EGFR was shown to be widely expressed in the human fetus, evidence that this gene plays an important role in early development.European Journal of HumanGenetics 6(2):158-64. · 4.40 Impact Factor -
Article: Epigenotype-phenotype correlations in Silver-Russell syndrome
Top co-authors
Top Journals
Institutions
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2010
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North West London Hospitals NHS
Harrow, ENG, United Kingdom
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2007
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St. Mark's Hospital
Salt Lake City, UT, USA
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1999–2000
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Imperial College London
London, ENG, United Kingdom
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