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Biomedical subjects

A Schinzel

Publications and source records attributed to A Schinzel.

At least 109 records · Page 6Linked to original sources
PubMed1994

Angelman syndrome due to paternal uniparental disomy of chromosome 15: a milder phenotype?

The Angelman syndrome (AS) is a neurological disorder characterized by severe mental retardation, absent speech, seizures, gait disturbances, and a typical age-dependent facial phenotype. Most cases are due to an interstitial deletion on the maternally inherited chromosome 15, in the critical region q11-q13. Rare cases also result from paternal uniparental disomy of chromosome 15. In a group of 14 patients with sporadic AS diagnosed in Switzerland, we found 2 unrelated females with paternal isodisomy for the entire chromosome 15. Their phenotypes were milder than usually seen in this syndrome: one girl did not show the typical AS facial changes; both patients had late-onset mild seizures; as they grew older, they had largely undisturbed gross motor functions, in particular no severe ataxia. Both girls were born to older fathers (45 and 43 years old, respectively). The apparent association of a relatively milder phenotype in AS with paternal uniparental disomy will have to be confirmed by detailed clinical descriptions of further patients.

Adult↗
PubMed1994

A gene for Holt-Oram syndrome maps to the distal long arm of chromosome 12.

Holt-Oram syndrome (HOS) is an autosomal dominant condition of unknown origin characterized by congenital septal heart defects with associated malformations of the upper limbs (radial ray). Here, we report on the mapping of a gene causing HOS to the distal long arm of chromosome 12 (12q21-qter) by linkage analysis in nine informative families (Zmax = 6.81 at theta = 0 at the D12S354 locus). Also, multipoint linkage analysis places the HOS gene within the genetic interval between D12S84 and D12S79 (multipoint lod-score in log base 10 = 8.10). The mapping of a gene for HOS is, to our knowledge, the first chromosomal localization of a gene responsible for congenital septal heart defect in human. The characterization of the HOS gene will hopefully shed light on the molecular mechanisms that govern heart septation in the early stages of embryogenesis.

Abnormalities, Multiple↗
PubMed1994

A common mutation in the fibroblast growth factor receptor 1 gene in Pfeiffer syndrome.

Pfeiffer syndrome (PS) is one of the classic autosomal dominant craniosynostosis syndromes with craniofacial anomalies and characteristic broad thumbs and big toes. We have previously mapped one of the genes for PS to the centromeric region of chromosome 8 by linkage analysis. Here we present evidence that mutations in the fibroblast growth factor receptor-1 (FGFR1) gene, which maps to 8p, cause one form of familial Pfeiffer syndrome. A C to G transversion in exon 5, predicting a proline to arginine substitution in the putative extracellular domain, was identified in all affected members of five unrelated PS families but not in any unaffected individuals. FGFR1 therefore becomes the third fibroblast growth factor receptor to be associated with an autosomal dominant skeletal disorder.

Abnormalities, Multiple↗
PubMed1994

A gene for hereditary multiple exostoses maps to chromosome 19p.

Hereditary multiple exostoses (EXT) is an autosomal dominant bony disorder characterized by the formation of cartilage-capped juxta-epiphyseal prominences on the long bones. Recently, a disease gene (EXT 1) has been mapped to chromosome 8q23-q24 by linkage analysis in informative families. Here, we report on the genetic mapping of a second locus (EXT 2) to the short arm of chromosome 19 by linkage to a microsatellite DNA marker at the D19S221 locus, which gives additional support to the view that EXT is a genetically heterogeneous condition.

Chromosome Mapping↗
PubMed1994

Molecular genetic analysis of the 3p- syndrome.

Molecular genetic analysis of five cases of 3p- syndrome (del(3)(qter-->p25:)) was performed to investigate the relationship between the molecular pathology and clinical phenotype. Fluorescence in situ hybridization studies and analysis of polymorphic DNA markers from chromosome 3p25-p26 demonstrated that all four informative cases had distal deletions. However, the extent of the deletion was variable: in two patients with the most extensive deletions the deletion breakpoint mapped between RAF1 and D3S1250, in one patient the deletion breakpoint was between D3S1250 and D3S601, and in two patients the deletion commenced telomeric to D3S601 (and telomeric to D3S1317 in one of these). All five patients displayed the classical features of 3p- syndrome (mental retardation, growth retardation, microcephaly, ptosis and micrognathia) demonstrating that loss of sequences centromeric to D3S1317 is not required for expression of the characteristic 3p- syndrome phenotype. The three patients with the most extensive deletions had cardiac septal defects suggesting that a gene involved in normal cardiac development is contained in the interval D3S1250 and D3S18. The PMCA2 gene is contained within this region and deletion of this gene may cause congenital heart defects. At least three patients were deleted for the von Hippel-Lindau (VHL) disease gene although none had yet developed evidence of VHL disease. We conclude that molecular analysis of 3p- syndrome patients enhances the management of affected patients by identifying those at risk for VHL disease, and can be used to elucidate the critical regions for the 3p- syndrome phenotype.

Abnormalities, Multiple↗
PubMed1993

Physical mapping of the holoprosencephaly critical region on chromosome 7q36.

Holoprosencephaly (HPE) is a developmental field defect involving the brain and face. Cytogenetic deletions in patients with HPE have localized one of the HPE genes to chromosomal region 7q36. We have characterized the 7q deletions in thirteen HPE patients. The result is the construction of a high resolution physical map of 7q32-qter. As a first step towards cloning an HPE gene crucial for normal brain development, we have defined the HPE minimal critical region in 7q36 between D7S292 and D7S392.

Adult↗
PubMed1993

Iduronate-2-sulfatase gene mutations in 16 patients with mucopolysaccharidosis type II (Hunter syndrome).

Mutations of the iduronate-2-sulfatase gene were identified in 16 patients with mucopolysaccharidosis type II (Hunter syndrome). Together with another 10 cases reported by us earlier it emerges that about 20% of the patients have deletions of the whole gene or other major structural alterations. One, two or three base pair deletions are found in about 23% of the cases while the remaining about 57% carry point mutations predicting amino acid replacement, premature termination of translation, or aberrant splicing. Molecular analysis of mRNA in splice site mutants showed that these latter defects frequently resulted in use of cryptic splice sites in exons or introns. 62% of the small deletions and point mutations have occurred in 3 of the 9 iduronate-2-sulfatase gene exons. Knowledge of the primary genetic defect allows fast and reliable carrier detection and prenatal diagnosis as well as insight into the relationship between genotype and phenotype.

Amino Acid Sequence↗
PubMed1993

Modification of 15q11-q13 DNA methylation imprints in unique Angelman and Prader-Willi patients.

The clearest example of genomic imprinting in humans comes from studies of the Angelman (AS) and Prader-Willi (PWS) syndromes. Although these are clinically distinct disorders, both typically result from a loss of the same chromosomal region, 15q11-q13. AS usually results from either a maternal deletion of this region, or paternal uniparental disomy (UPD; both chromosomes 15 inherited from the father). PWS results from paternal deletion of 15q11-q13 or maternal UPD of chromosome 15. We have recently described a parent-specific DNA methylation imprint in a gene at the D15S9 locus (new gene symbol, ZNF127), within the 15q11-q13 region, that identifies AS and PWS patients with either a deletion or UPD. Here we describe an AS sibship and three PWS patients in which chromosome 15 rearrangements alter the methylation state at ZNF127, even though this locus is not directly involved in the rearrangement. Parent-specific DNA methylation imprints are also altered at ZNF127 and D15S63 (another locus with a parent-specific methylation imprint) in an AS sibship which have no detectable deletion or UPD of chromosome 15. These unique patients may provide insight into the imprinting process that occurs in proximal chromosome 15 in humans.

Angelman Syndrome↗
PubMed1993

Clinical and molecular analysis of five inv dup(15) patients.

Five patients with inv dup(15) chromosomes were investigated with molecular probes on proximal 15q to determine the parental origin and extent of the duplicated segment. Cytogenetic investigation showed that four patients carried one and a fifth patient had two extra chromosomes derived from number 15 in all cells. In situ hybridization with a chromosome 15 library and a centromere 15 probe confirmed that the entire inv dup chromosomes were derived from chromosome 15. Molecular analysis using probes mapping in the region deleted in Prader-Willi syndrome (PWS) and Angelman syndrome (AS) patients implied that in at least two patients the extra chromosomes were asymmetric with one copy of the PWS region on the extra marker chromosome but two copies of the region centromeric to the PWS region. Three other cases had an inv dup(15) with two extra copies of the PWS region, but in one of these, heteromorphisms clearly demonstrated that the two centromeres derived from two different chromosomes. The inv dup(15) presumably resulted from an illegitimate recombination event between two different chromosomes 15 in most or all of these cases. All patients showed a maternal origin of the duplicated chromosome. The clinical severity appears to be associated with dosage of the PWS/AS region rather than with differences in the extent of the duplicated segment.

Abnormalities, Multiple↗
PubMed1993

Karyotype-phenotype correlations in autosomal chromosomal aberrations.

Karyotype phenotype correlation studies on the basis of clinical findings released the following consistent results. 1. Monosomy for an autosomal segment causes more and more severe alterations to the phenotype and restricts survival more than does trisomy for the same segment. The clinical pictures of monosomy versus trisomy for the same segment do not go into an opposite direction (the type-contratype approach). 2. For trisomy versus tetrasomy of a given autosomal segment, clinical pictures are principally similar, but tetrasomy leads to more severe alterations of the phenotype and to more restricted survival. Therefore, tetrasomy seems to allow for survival in only few segments, and often only in mosaic state. 3. Mapping of specific traits to the aneuploid segment of a specific chromosome region is partially successful. 3.1. For certain patterns of minor anomalies, the aneuploid segment can be narrowed down to a very short region. Both in trisomy and monosomy, these regions tend to be closer to the telomere. 3.2. Deletion mapping has allowed the mapping of a number of autosomal dominant gene mutations to small segments of a chromosome and hereby often gave the first hint towards the fine localization and cloning of these genes. Both deletion and duplication mapping have also shown associations of some congenital anomalies, mostly rarer malformations, to the aneuploid state of a small chromosome segment. The approach, however, has not been successful for most of the malformations frequent in many autosomal chromosome aberrations. 4. Comparison of congenital anomalies in monozygotic twins with autosomal chromosome aberrations revealed the following. 4.1. Monozygotic twins are highly concordant for patterns or minor anomalies. 4.2. Monozygotic twins tend to be concordant for rare congenital defects and malformations, but they are predominantly discordant for more common major malformations; the more undergrown twin is usually more severely affected. The latter finding might be explained by differences in placental blood supply between the twins during early embryogenesis, either due to different placental nutrition in general or to differences in secondary mutations in the placentas allowing for a better embryonic blood supply during organogenesis. 5. The data are in accordance with a multifactorial model for frequent congenital malformations in which placental function is the modifying environmental influence besides the action of more than one gene in aneuploid state.

Animals↗
PubMed1993

A third patient with median cleft upper lip, mental retardation and pugilistic facies (W syndrome): corroboration of a hitherto private syndrome.

We report a severely mentally retarded young male with the features of the W syndrome. This syndrome, to date described in only two brothers of one family, is characterized by severe mental retardation with seizures and a pattern of facial dysmorphisms including high broad forehead, down-slanting palpebral fissures, hypertelorism, abnormal configuration of the maxilla and mandible, peculiar nose, and incomplete midline oral cleft. The face has been compared to that of a boxer (pugilistic face). Mild skeletal anomalies have also been described. Inheritance is probably X-linked. The present report corroborates the existence of this hitherto private syndrome.

Abnormalities, Multiple↗
PubMed1992

[Molecular genetics diagnosis of Steinert's myotonic dystrophy].

Myotonic dystrophy (DM) is the most common neuromuscular disease with adult onset (incidence 1 in 8000). The biochemical basis of this autosomal dominantly inherited disease is still unknown. The most striking features are myotonia and progressive muscular wasting. There is high variability of disease severity in patients from different families, but also within the same family. For practical reasons three subtypes can be defined: The classical adult onset form of the disease, a mild form with late onset and/or very moderate symptoms, eg. cataracts only, and the most severe congenital form which is transmitted by affected females. Furthermore, the progression of DM in affected families may exhibit an increase in the severity of the disease in successive generations. This observation is called anticipation. Very recently the DM gene has been cloned and an unstable DNA sequence specific for the disease has been characterized. Detection of an enlarged DNA fragment due to the expansion of a trinucleotide (CTG) repeat within the DM gene can be used for direct DNA diagnosis in affected individuals and persons at risk. Furthermore, there is a strong correlation between the length of fragment expansion and the degree of disease severity in gene carriers. We report here our preliminary results of the investigation of over 70 patients and demonstrate the clinical usefulness of this new method by the findings in three families.

Adult↗
PubMed1992

Molecular study of 45,X conceptuses: correlation with clinical findings.

The parental origin of the single X in 45 cases (40 liveborns and 5 fetuses) with a 45,X karyotype was studied using polymorphic DNA probes. The single X was paternal in origin (Xp) in 10 cases (22.2%) and maternal (Xm) in 35 cases (77.8%). Y chromosome material was detected in 1 out of the 35 cases with a 45,Xm constitution. Analysis of parental ages and clinical data of the patients with respect to the origin of the single X revealed no significant differences between the origins.

Fetus↗
PubMed1992

Clinical and ERG data in a family with autosomal dominant RP and Pro-347-Arg mutation in the rhodopsin gene.

In a family with autosomal dominant retinitis pigmentosa, documented over six generations, a previously undescribed point mutation in the rhodopsin gene could be identified. The mutation found in the six affected members examined but in none of the controls, including healthy members of the family, was a point mutation in codon 347 predicting a substitution of the amino acid arginine for proline, designated Pro-347-Arg. Six affected members from two generations were examined clinically and with ganzfeld rod and cone electroretinography. The cone and, more dramatically, the rod electroretinograms were reduced to residual b-wave amplitudes or were non-detectable as early as ages 18 to 22 years. The Pro-347-Arg mutation resulted in a subjectively and clinically homogeneous phenotype: early onset of night blindness before age 11, relatively preserved usable visual fields until about age 30, blindness at ages 40 to 60, and change from an initial apparently sine pigmento to a hyperpigmented and atrophic fundus picture between 30 and 50 years of age.

Adolescent↗