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ABSTRACT: The presence of deletions at the CMT-1a locus containing the gene encoding the myelin protein, PMP-22 on chromosome 17p11.2 was assessed in patients with hereditary neuropathy with liability to pressure palsies (HNPP), with hereditary neuralgic amyotrophy and with hereditary carpal tunnel syndrome. Affected members in all families with HNPP, except in one, had a deletion, in one of them a partial one. None of the non-affected relatives, none of the members of the other three groups and none of the controls showed a deletion. These data confirm that the majority of patients with HNPP have a deletion at the PMP-22 gene locus. They do not suggest, however, that such a deletion accounts for a predisposition to the development of hereditary neuralgic amyotrophy or of carpal tunnel syndrome.
European Journal of Neurology 01/2011; 3(6):588 - 593. · 3.69 Impact Factor
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ABSTRACT: We present clinical and cytogenetic data of a one year old boy with partial monosomy for both 21q and 18p, resulting from a de novo unbalanced translocation. The initial diagnosis of a seemingly full monosomy 21 was revised after fluorescence in situ hybridisation (FISH) with whole chromosome painting probes and a locus-specific chromosome 21 probe. The karyotype was reinterpreted as 45,XY,der(18)t(18;21)(p11.2;q22.1),-21. This karyotype, to our knowledge, has not been previously described. The boy presented with a spectrum of clinical features previously described for (partial) monosomy 18p only, for monosomy 21q only, or for both of these aneusomies. The radiological finding of a neuronal migration disorder with localised polymicrogyria (cortical dysplasia) has not been described for either monosomy before.
Genetic counseling (Geneva, Switzerland) 02/2002; 13(2):151-6. · 0.50 Impact Factor
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ABSTRACT: A male carrying an interstitial deletion of chromosome 14, presumably del(14)(q11.2q13), and presenting with abnormal myelination on magnetic resonance imaging is described. The abnormal myelination was evidenced as a high-signal intensity on T(2)-weighted magnetic resonance imaging. The patient had severe neurologic signs, various dysmorphic features, and a marked microcephaly. To our knowledge, this case is the first patient reported with abnormal myelination and a deletion of chromosome 14.
Pediatric Neurology 09/2000; 23(2):170-2. · 1.52 Impact Factor
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M Hergersberg,
J Balakrishnan,
T Bettecken,
F Chevalier-Porst,
C Brägger,
R Burger,
I Einschenk,
S Liechti-Gallati,
M Morris,
D Schorderet,
F Thonney, H Moser,
N Malik
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ABSTRACT: We have analysed 1173 cystic fibrosis (CF) chromosomes from Switzerland for eight mutations in the CF transmembrane conductance regulator (CFTR) gene. This permitted the identification of 88.5% of all mutations present. A novel insertion mutation in exon 20 of the CFTR gene, 3905insT, was discovered. This mutation accounted for 4.8% of CFTR gene mutations in Switzerland and has since been identified in other populations of probable Swiss descent. It is associated with a highly variable clinical phenotype but always with pancreatic insufficiency. Haplotype analysis with three intragenic microsatellites in the CFTR gene showed that the mutation is associated with a haplotype rarely identified on other CFTR alleles and, therefore, that the frequency of the mutation in Switzerland is explained by a founder effect of a relatively recent mutation event.
Human Genetics 09/1997; 100(2):220-3. · 5.07 Impact Factor
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ABSTRACT: Autosomal recessive spinal muscular atrophy (SMA) is, after cystic fibrosis, the second most common fatal monogenic disorder. The disease is characterized by degeneration of anterior horn cells leading to progressive paralysis with muscular atrophy. Depending on the clinical type (Werdnig-Hoffmann = type I, intermediate form = type II, Kugelberg-Welander = type III), SMA causes early death or increasing disability in childhood. The SMA-critical region on the long arm of chromosome 5q13.1 contains many duplicated genes and polymorphisms. Recently, two presumptive SMA genes (survival motoneuron gene = SMN, and neuronal apoptosis inhibitory protein = NAIP) have been identified. Deletions involving critical regions of these genes are very often associated with SMA, and the extent of the deletions seems to correlate in part with disease severity. We have evaluated the diagnostic and prognostic value of molecular analysis in a large number of SMA patients. 57 patients and 78 healthy relatives were molecularly screened for deletions in the SMA critical region. We demonstrated homozygous deletions removing the SMN genes in over 90% of patients, whereas nearly 45% of patients exhibited NAIP gene deletions. Large deletions involving both genes on each chromosome are generally found in patients with severe SMA (Werdnig-Hoffman cases), while mildly affected Kugelberg-Welander cases frequently show only deleted SMN genes. Molecular classification based on combined deletion sizes, however, seems not to be exact, especially for the group with chronic SMA (type II and III). Direct DNA testing of patients in whom SMA is suspected is a highly reliable, fast, and noninvasive method. The ability to detect homozygous gene deletions in a high percentage of typical SMA patients will much improve genetic counselling and prenatal diagnosis in affected families.
Schweizerische medizinische Wochenschrift 06/1996; 126(21):907-14. · 1.68 Impact Factor
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ABSTRACT: Van der Woude syndrome (VWS) is an autosomal dominant disorder associated with one or more of the following features: clefting of the primary or secondary palate, hypodontia or lower lip pits. It has been estimated to account for 2% of all cases of cleft lip and palate. VWS is one of the rare disorders in which clefting of the primary and secondary palate may be seen to segregate as components associated with the same gene. Because of its autosomal dominant inheritance, VWS is readily accessable to linkage analysis as a preliminary step in the identification of the molecular abnormality underlying the clefting effect in the primary and secondary palate. A reported linkage between REN and VWS has promoted us to use pHRnX3.6 (REN) and several markers surrounding REN for a linkage analysis in a large Swiss family. In a second step, linkage analysis was performed to study restriction fragment length polymorphisms for the candidate gene TGFB2 and other loci recently mapped to the candidate region 1q32-1q41. Evidence for linkage (theta = 0.00, lod score = 3.01) between REN and VWS could be confirmed in this pedigree. TGFB2 demonstrated recombination with the disease locus and is unlikely to be causative in VWS. The results of a multipoint linkage analysis showed that VWS was flanked by D1S65 and TGFB2 at a maximum location score of 20.3.
Human Genetics 04/1993; 91(1):55-62. · 5.07 Impact Factor
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ABSTRACT: A striking clinical phenomenon of cystic fibrosis is the heterogeneous disease expression. It must therefore be assumed that the nature of the mutations associated with cystic fibrosis might partly determine the phenotypic manifestations. The relation between the cystic fibrosis mutations delta F508, R553X, and 3905insT and clinical parameters such as sweat test electrolytes, age at chronic Pseudomonas aeruginosa colonization, Chrispin-Norman x-ray scores, and relative underweight have been investigated in 45 patients homozygous for delta F508 (delta F2), in 12 compound heterozygotes for delta F508/R553X (delta F1/RX1), in three R553X homozygotes (RX2), and in 13 patients compound heterozygous for delta F508/3905insT (delta F16). We have found significant differences between the genetically defined subgroups concerning the mean age at onset and the cumulative incidence of chronic P. aeruginosa colonization and Chrispin-Norman x-ray scores. The significant results as well as some trends regarding the relative underweight demonstrate a milder clinical course in R553X heterozygotes and more severe disease in the delta F16 group compared to delta F508 homozygotes. The three patients homozygous for R553X presented with a two-stage course showing mild progression before P. aeruginosa infection and as severe a course as the delta F16 patients after P. aeruginosa colonization at the age of 12 y. The findings presented here indicate that specific mutations can influence the severity and progression of the disease, implicating the importance of mutation and haplotype analyses. However, wide variations within the genetically homogeneous subgroups illustrate that other determinants of the clinical status do exist.
Pediatric Research 09/1992; 32(2):175-8. · 2.70 Impact Factor
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Human Molecular Genetics 08/1992; 1(4):288. · 7.64 Impact Factor
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ABSTRACT: The parental origin of the additional sex chromosomes in 8 cases with high-order sex chromosome polysomies was determined using DNA polymorphisms. The additional sex chromosomes were paternally derived in 3 48,XXYY cases, and maternal in origin in 1 48,XXXY case and 4 49,XXXXY cases. Thus, all extra chromosomes, within a particular patient, were always derived from only one parent. Their most likely origin was successive nondisjunction at the first and second meiotic division in one germ cell. The mechanism involved remains unclear, but appears to be independent of parental ages.
Human Heredity 02/1992; 42(3):193-7. · 1.79 Impact Factor
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ABSTRACT: Cystic fibrosis (CF) is the most common severe autosomal recessive genetic disorder in Caucasian populations, with an incidence of about 1 in 2000 live births, implying a carrier frequency of about 1 in 22. In 1989, the CF gene was isolated and characterized and the major mutation (delta F508), a 3-bp deletion that results in the loss of a phenylalanine residue at position 508, was detected. To determine the frequency of the delta F508 mutation and the predicted number of additional mutations in our population, we have undertaken a collaborative study of 215 CF patients and 175 CF parents in Switzerland. The delta F508 mutation in exon 10 has been found in 70% of the CF chromosomes, and the exon-11 mutation R553X seems to be the second most common CF mutation in our population, with a frequency of 5.3%, whereas the G551D mutation (also in exon 11) has not been detected at all. Haplotype determination of 430 CF and 175 normal chromosomes using XV-2c, KM19, MP6d-9, and J3.11 has been proven to be very helpful in providing additional carrier risk calculations: Haplotypes 1 (1221), 2 (1222), 6 (2111), and 7 (2221) increase the risk of being a carrier from 1 in 55 (haplotype 6) to 1 in 17 (haplotype 1), whereas haplotypes 3 (1122), 4 (1112), 8 (2222) and 10 (1111) lower the risk from 1 in 144 (haplotype 3) to 1 in 1678 (haplotype 10). Moreover, the mutation R553X shows strong correlation with haplotype 3, leading to the suggestion that haplotypes 1, 2, 5, and 6 may account for four additional mutations in Switzerland.(ABSTRACT TRUNCATED AT 250 WORDS)
Pediatric Research 11/1991; 30(4):304-8. · 2.70 Impact Factor
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Advances in experimental medicine and biology 02/1991; 290:367-8. · 1.09 Impact Factor
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ABSTRACT: The X-linked recessive centronuclear/myotubular myopathy (XLR-CNM/MTM1), a severe neonatal disorder characterized by generalized hypotonia, muscle weakness and primary asphyxia, has recently been mapped to Xq28. This report presents linkage analysis data of eight families with X-linked centronuclear myopathy. Four probes from the region Xq26-27 and five Xq28 probes were used to get more precise gene localization and marker order. St14 (DXS52), fully informative in all families, shows significant linkage to the CNM gene (z = 3.60; theta = 0.05), followed by DX13 (DXS15) (z = 2.03; theta = 0.06) and F8 (z = 1.86; theta = 0.00). Combination of the physical map derived by Kenwrick and Gitschier (1989) and our linkage data lead to the most probable order R/GCP-G6PD-(XLR-CNM-F8)-p767-St14-cpX67-++ +DX13 placing the CNM gene close to F8. The results of this study confirm strong linkage of the CNM gene to the region Xq28 and will permit carrier testing and prenatal diagnosis in CNM families. We conclude that the precise localization of this devastating disorder may be of great importance for genetic counselling in families at risk. The lack of information about gene frequency and mutation rate as well as the severity and burden of the disease point to the inevitable need for accurate clinical diagnosis.
Neuromuscular Disorders 02/1991; 1(4):239-45. · 2.80 Impact Factor
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ABSTRACT: Severe neonatal centronuclear myopathy is inherited as an X-linked condition characterized by primary asphyxia, extreme muscular hypotonia and absent spontaneous movements. We report seven cases from three families to point out the importance of diagnosis with regard to prognosis, outcome and genetic counselling. In hypotonic diseases, analysis of cerebrospinal fluid, electromyography, nerve conduction velocity creatine kinase and a skin biopsy for fibroblast cultures for metabolic investigations are usually carried out. Needle muscle biopsy is an additional valuable investigation to establish diagnosis. In all our patients we found an increased number of centrally located nuclei with perinuclear halos confirming the diagnosis of centronuclear myopathy. The diagnosis of this disorder will become of greater importance as soon as carrier detection and prenatal diagnosis by DNA-technology are routinely available.
European Journal of Pediatrics 01/1991; 150(2):132-5. · 1.88 Impact Factor
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ABSTRACT: Pediatric Research (1990) 28, 302–302; doi:10.1203/00006450-199009000-00175
151 X-linked centronuclear myopathy: gene localization and prenatal diagnosis
S Liechti-Gallati1, B Müller1, T Grimm1, W Kress1, E Boltshauser1, H Moser1 and S Braga11Departments of Pediatrics, University of Beme and Zurich, and Department of Human Genetics, University of Würzburg.
Pediatric Research 08/1990; 28(3):302-302. · 2.70 Impact Factor
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ABSTRACT: A total of 295 patients, parents and unaffected sibs from 106 CF-families in central and northeastern Switzerland were investigated with probes 7C22(D7S16), metH, metD, pKM19, pXV-2c and pJ3.11(D7S8) for eight DNA polymorphisms (RFLP's). Linkage disequilibrium to the CF locus and haplotype frequencies were compared to those in other populations. They are comparable to other Caucasian populations and, for pKM 19 and pXV-2c, very close to the findings in Italy. The prevalence of certain haplotypes among the CF and the normal allele-bearing chromosomes indicate that the majority of the CF cases are probably the result of one ancient mutation in a common ancestor, but that there may be allelic heterogeneity accounting for an important proportion of patients, that may differ between countries or regions. Informative family constellations for the different polymorphisms in Switzerland and strategies for carrier detection and prenatal diagnosis are discussed. Haplotype analyses for each country and its ethnic subgroups are recommended.
Clinical Genetics 07/1990; 37(6):442-9. · 3.13 Impact Factor
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ABSTRACT: The complete 14-kb cDNA for the gene causing the X-linked recessive muscular dystrophy (MD) type Duchenne (DMD) and Becker (BMD) has recently been cloned and made available for deletion/duplication screening in patients. It detects 65 exon-containing nonpolymorphic HindIII fragments spread over a gene locus of about 2,000 kb. When the entire DMD cDNA is used, deletions/duplications can be found in about 65%-70% of affected patients, permitting direct carrier detection by densitometric scanning. But in cases where no deletion/duplication is detectable, RFLP analysis, specially favored within the gene, will be the method for carrier-status determination. Clones 9 and 10-1.2-kb and 0.7-kb fragments, respectively, of the 14-kb DMD cDNA--have been hybridized with human genomic DNA digested by nine different restriction enzymes. Five RFLPs, involving Asp700, PvuII, XbaI, and EcoRV sites, were detected, and Mendelian inheritance could be demonstrated. Since clones 9 and 10 are localized telomeric to the mutation-hot-spot region, their polymorphisms are thought to be very helpful as flanking markers for indirect carrier detection in families with a family history of DMD/BMD. Moreover, these RFLPs can be used for direct carrier detection or exclusion in families with patients showing a deletion/duplication in the region of p9 or p10.
The American Journal of Human Genetics 07/1990; 46(6):1090-4. · 10.60 Impact Factor
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ABSTRACT: We have studied the inheritance of several polymorphic Xq27/28 DNA marker loci in two three generation families with the X linked neonatal lethal form of centronuclear/myotubular myopathy (XL MTM). We found complete linkage of XLMTM to all four informative Xq28 markers analysed, with GCP/RCP (Z = 3.876, theta = 0.00), with DXS15 (Z = 3.737, theta = 0.00), with DXS52 (Z = 2.709, theta = 0.00), and with F8C (Z = 1.020, theta = 0.00). In the absence of any observable recombination, we are unable to sublocalise the XLMTM locus further within the Xq28 region. This evidence for an Xq28 localisation may allow us to carry out useful genetic counselling within such families.
Journal of Medical Genetics 06/1990; 27(5):284-7. · 6.36 Impact Factor
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ABSTRACT: DNA from 80 Duchenne (DMD) and 15 Becker (BMD) index patients was analyzed with 12 genomic probes and the total cDNA. Deletions were detected in 24 DMD (30%) and 10 BMD patients (67%) by genomic probes alone, mostly p20, pXJ, and/or pERT87. All deletions were confirmed by cDNA probes, and an additional 29 DMD deletions were detected, resulting in a total of 63/95 deletions (66%). The majority of the deletions are localized between kb 6.7 and 9.7 of the cDNA; a smaller group, between kb 0.5 and 3.5. Of the deletions, 90% are detected by the three cDNA probes 1-2a, 7, and 8. This can be applied to strategies for carrier detection and prenatal diagnosis. The order of 13 exon-containing HindIII fragments in the region between probes 7 and 9-10, where most of the deletions are found, could be defined. The deletion patterns in DMD and BMD patients are different and well in accordance with the "reading frame theory" of Monaco and coworkers. Thus our findings indicate that a DMD or BMD phenotype may be predicted according to the breakpoint position and the number of deleted exons.
Human Genetics 04/1989; 81(4):343-8. · 5.07 Impact Factor
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ABSTRACT: Deletions giving rise to Duchenne muscular dystrophy (DMD) and the less severe Becker muscular dystrophy (BMD) occur in the same large gene on the short arm of the human X chromosome. We present a molecular mechanism to explain the clinical difference in severity between DMD and BMD patients who bear partial deletions of the same gene locus. The model is based on the breakpoints of intragenic deletions and their effect on the translation of triplet codons into amino acids of the protein product. Deletions identified in three DMD patients are shown to shift the translational open reading frame (ORF) of triplet codons for amino acids, and each deletion is predicted to result in a truncated, abnormal protein product. Deletions identified in three BMD patients are shown to maintain the translational ORF for amino acids and predict a shorter, lower molecular weight protein. The smaller protein product is presumed to be semifunctional and to result in a milder clinical phenotype. The same ORF mechanism is also applicable to potential 5' and 3' intron splice mutations and their effect on protein production and clinical phenotype.
Genomics 02/1988; 2(1):90-5. · 3.02 Impact Factor
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ABSTRACT: Haplotypes for 7 flanking and 16 "intragenic" X-linked DNA polymorphisms were determined in 204 members of 31 families with Duchenne (DMD) and 27 members of 4 families with Becker type muscular dystrophy (BMD) and combined with CK and pedigree data to estimate carrier and fetal risks. All of the 27 younger female relatives of the familial cases (8 DMD, 2 BMD) could either be identified (11) or ruled out (16) as carriers with 95% or higher probability. Out of 49 possible carriers in the 23 DMD and 2 BMD families with isolated cases, 19 were classified as carriers and 18 as homozygote-normal females. In 3 families the mutation could be traced indirectly to a defined ancestor (mother, grand-parent), and in 5 families a molecular deletion was found. In all identified carriers and in medium risk females an informative DNA-constellation for prenatal predictions was present for at least one "intragenic" or two flanking markers. Prenatal DNA-investigations were carried out during pregnancy in 9 possible DMD carriers. There was one termination due to an XYY karyotype. Of the remaining 8 cases, the carrier state could be ruled out in 4 mothers, the fetal sex was female in another 3, and one male fetus was predicted normal. All babies (3 boys, 5 girls) are healthy. The practical significance of these findings with regard to the prevention of DMD/BMD and the present diagnostic strategies are discussed.
Schweizerische medizinische Wochenschrift 01/1988; 117(51):2061-73. · 1.68 Impact Factor
