Biomedical subjects

A Schinzel

Publications and source records attributed to A Schinzel.

At least 73 records · Page 4Linked to original sources

PubMed1999

Ectopic NORs on human chromosomes 4qter and 8q11: rare chromosomal variants detected in two families.

Two different NOR bearing non-acrocentric chromosomes were detected during prenatal diagnosis performed on two probands because of advanced maternal age. In the first case, a chromosome 4 carried a NOR in the telomeric region of the long arm (4qs), while in the second case a NOR was inserted into chromosome 8q11. Family analysis showed the variant chromosomes to be transmitted through at least three generations in each family. There were no reports of reproductive problems or phenotypic effects in the carriers of these chromosomes, indicating the benign character of the aberrant chromosomes. In order to characterise the chromosomal variants more precisely, various differential banding techniques were applied.

Chromosomes, Human, Pair 4↗

PubMed1999

Duplication of segment 1p21 following paternal insertional translocation, ins(6;1)(q25;p13.3p22.1).

A moderately mentally retarded 3 year old boy showed minor anomalies including a prominent forehead and flat occiput, exophthalmos, large and prominent ears, high arched palate, umbilical hernia, sacral dimple, and irregular position of the toes. Cardiac sonography disclosed a chorda running through the left ventricle. Cytogenetic investigation of the family showed a balanced insertional translocation of segment 1p13-->p22 into distal 6q in the father which had led, through unbalanced segregation, to duplication of 1p13.3-->p22.1 in the proband. Familial duplication of such a small interstitial segment of 1p has not been reported previously, and the paucity of abnormal physical findings in the proband compared to previous patients with a similar aberration is remarkable.

Abnormalities, Multiple↗

PubMed1998

Seven cases of Wiedmann-Beckwith syndrome, including the first reported case of mosaic paternal isodisomy along the whole chromosome 11.

Genomic imprinting of chromosome arm 11p is involved in the Wiedemann-Beckwith syndrome (WBS). About 20% of patients with sporadic WBS have paternal uniparental disomy (UPD) of 11p. Mitotic recombination at the 11p region has been suggested to be responsible for the somatic mosaicism in these patients. Our current study concerning sporadic WBS patients demonstrated six patients with mosaic isodisomy restricted to part of 11p and one patient with mosaic paternal uniparental disomy for the whole chromosome 11. Apparently the clinical findings for this patient did not differ from data reported for other WBS patients. This case makes it unlikely that the proximal short arm and the long arm of chromosome 11 contain imprinted genes with a phenotype recognizable prenatally or in infancy, and gives some support to the hypothesis that non-mosaic UPD-11 is prenatally lethal.

Beckwith-Wiedemann Syndrome↗

PubMed1998

A 5-year-old girl with interstitial deletion of 3p14: clinical, psychologic, cytogenetic, and molecular studies.

An interstitial deletion of segment 3p14 (breakpoints 3p21.1 and 3p13) was found in a 5-year-old short, microcephalic, and mentally retarded girl with a pattern of anomalies comprising a wide forehead, short up-slanting palpebral fissures, small nose and ears, hypoplasia of larynx, trachea, and bronchi, clino- and camptodactyly of little fingers, and sacral vertebral fusion. Determination of microsatellites mapping to the deleted segment demonstrated that the deletion had occurred in the paternal germ line. This is the seventh patient with a deletion of 3p14, and comparison with the six previously reported cases does not yet allow definition of a specific pattern of minor and major anomalies.

Abnormalities, Multiple↗

PubMed1998

22q11.2 deletions in a series of patients with non-selective congenital heart defects: incidence, type of defects and parental origin.

Previous studies have indicated a wide spectrum of incidences of 22q11.2 deletions in isolated and syndromic (sporadic or familial) cases of conotruncal heart defects, whereby the detection rate of the deletion varied from 65% in one study to 0 in another. We analysed 110 patients with non-selective syndromic or isolated non-familial congenital heart malformations by fluorescence in situ hybridization (FISH) using the D22S75 DiGeorge chromosome (DGS) region probe. A 22q11.2 microdeletion has been detected in 9/51 (17.6%) syndromic patients. Five were of maternal origin and four of paternal origin. None of the 59 patients with isolated congenital cardiac defect had a 22q11.2 deletion. We compared the cardiac anomalies of our patients with a 22q11.2 deletion with those of previously published series and we describe types of congenital heart defects which appear to be often associated with a 22q11.2 deletion. The ability to detect such types of heart defects and to provide an early diagnosis of 22q11.2 deletion is particularly relevant in very young infants, who often show only very mild expression of the otherwise well-characterized phenotypes of the DiGeorge/velo-cardio-facial syndrome (DG/VCFS).

Adolescent↗

PubMed1998

A chromosomal deletion map of human malformations.

Malformations are common causes of pediatric morbidity and mortality, and genetic factors are a significant component of their etiology. Autosomal deletions, in almost all cases, cause a nonspecific embryopathy that presents after birth as growth failure, mental retardation, and multiple malformations. We have constructed a chromosome map of autosomal deletions associated with 47 different congenital malformations, using detailed clinical and cytogenetic information on 1,753 patients with nonmosaic single contiguous autosomal deletions. The 1,753 deletions involved 258 (89%) of 289 possible autosomal bands (by the use of ISCN 400-band nomenclature), giving a total of 4,190 deleted autosomal bands for analysis. We compared the band distributions of deletions associated with common major malformations with the distribution of all 1,753 deletions. We noted 283 positive associations between deleted bands and specific malformations, of which 199 were significant (P<.05, P>.001) and 84 were highly significant (P<.001). These "malformation-associated bands" (MABs) were distributed among 137 malformation-associated chromosome regions (MACRs). An average of 6 MABs in 2.9 MACRs were detected per malformation studied; 18 (6%) of 283 MABs contain a locus known to be associated with the particular malformation. A further 18 (6%) of 283 are in seven recognized specific malformation-associated aneuploid regions. Therefore, 36 (26%) of 137 of the MACRs contain an MAB coinciding with a previously recognized locus or malformation-associated aneuploid region. This map should facilitate identification of genes important in human development.

Chromosome Aberrations↗

PubMed1998

Histopathologic and ultrastructural study of lupus-like skin lesions in a patient with Bloom syndrome.

The histopathology of the lupus-like skin lesions associated with Bloom syndrome has been sporadically described. Skin biopsies from a 2-year-old boy with the classical features of Bloom syndrome, including lupus-like skin lesions, demonstrated marked interface changes with basal liquefaction degeneration, a moderate superficial mononuclear infiltrate, pigmentary incontinence, and capillary dilation in the papillary dermis. Immunophenotyping of the dermal infiltrate revealed predominance of T-cells. Basement membrane thickening on periodic acid-Schiff examination was not seen. Direct immunofluorescence failed to demonstrate deposits of immunoglobulin other than nonspecific IgM deposition along the basement membrane zone of lesional skin. Ultrastructurally, the most striking findings were disintegration of basal cell cytoplasm and tubuloreticular inclusions in vascular endothelia. Taken together, the histologic and ultrastructural features of lupus-like lesions associated with Bloom syndrome mimic those of cutaneous lupus erythematosus, with the exception of paucity of immune deposits at the dermoepidermal junction.

Basement Membrane↗

PubMed1998

Rapid immunoblot and kinase assay tests for a syndromal form of X linked mental retardation: Coffin-Lowry syndrome.

Coffin-Lowry syndrome (CLS) is a syndromal form of X linked mental retardation, in which some associated facial, hand, and skeletal abnormalities are diagnostic features. Accurate diagnosis, critical for genetic counselling, is often difficult, especially in early childhood. We have recently shown that Coffin-Lowry syndrome is caused by mutations in the gene encoding RSK2, a growth factor regulated protein kinase. RSK2 mutations are very heterogeneous and most of them lead to premature termination of translation or to loss of phosphotransferase activity or both. In the present study, we have evaluated immunoblot and RSK2 kinase assays as a rapid and simple diagnostic test for CLS, using cultured lymphoblastoid or fibroblast cell lines. Western blot analysis failed to detect RSK2 in six patients, suggesting the presence of truncated proteins in these patients. This conclusion was confirmed in four patients, in whom the causative mutations, all leading to premature termination of translation, were identified. Of four patients showing a normal amount of RSK2 protein on western blot and tested for RSK2 phosphotransferase activity, one had a dramatically impaired activity. Analysis of the RSK2 cDNA sequence in this patient showed a mutation of a putative phosphorylation site that would be critical for RSK2 activity. Preliminary results show that, at least, the western blot protocol can be successfully applied to lymphocyte protein extracts prepared directly from blood samples. These assays promise to become important diagnostic tools for CLS, particularly with regard to very young patients with no family history of the condition.

Abnormalities, Multiple↗

PubMed1997

Laryngeal atresia type III (glottic web) with 22q11.2 microdeletion: report of three patients.

The clinical manifestations of patients with a 22q11.2 deletion are highly variable and mainly include developmental defects of structures derived from the third and fourth pharyngeal pouches. Laryngeal atresia has occasionally been reported in DiGeorge syndrome as well as in velo-cardio-facial syndrome. We observed three patients with type III laryngeal atresia (glottic web) and 22q11.2 microdeletion. One patient showed a "classical" 22q11.2 deletion phenotype with clinical overlap with DiGeorge and velo-cardio-facial syndromes. However, the pattern of congenital anomalies of the two others was less specific, heart defects and minor anomalies being the only outstanding clinical manifestations suspicious for monosomy 22q11.2. Our findings suggest that laryngeal atresia represents an additional malformation which should prompt investigation of 22q11.2 deletion, especially in combination with congenital heart defects.

Child↗

PubMed1997

Linkage mapping in 29 Bardet-Biedl syndrome families confirms loci in chromosomal regions 11q13, 15q22.3-q23, and 16q21.

Bardet-Biedl syndrome (BBS) is a clinically and genetically heterogeneous autosomal recessive disorder characterized by retinitis pigmentosa, polydactyly, obesity, hypogenitalism, mental retardation, and renal anomalies. To detect linkage to BBS loci, 29 BBS families, of mixed but predominantly European ethnic origin, were typed with 37 microsatellite markers on chromosomes 2, 3, 11, 15, 16, and 17. The results show that an estimated 36-56% of the families are linked to the 11q13 chromosomal site (BBS1) previously described by M. Leppert et al. (1994, Nature Genet. 7, 108-112), with the gene order cen-D11S480-5 cM-BBS1-3 cM-D11S913/D11S987-qter. A further 32-35% of the families are linked to the BBS4 locus, reported by R. Carmi et al. (1995, Hum. Mol. Genet. 4, 9-13) in chromosomal region 15q22.3-q23, with the gene order cen-D15S125-5 cM-BBS4-2 cM-D15S131/D15S204-qter. Three consanguineous BBS families are homozygous for three adjacent chromosome 15 markers, consistent with identity by descent for this region. In one of these families haplotype analysis supports a localization for BBS4 between D15S131 and D15S114, a distance of about 2 cM. Weak evidence of linkage to the 16q21 (BBS2) region reported by A. E. Kwitek-Black et al. (1993, Nature Genet. 5, 392-396) was observed in 24-27% of families with the gene order cen-D16S408-2 cM-BBS2-5 cM-D16S400. A fourth group of families, estimated at 8%, are unlinked to all three of the above loci, showing that at least one other BBS locus remains to be found. No evidence of linkage was found to markers on chromosome 3, corresponding to the BBS3 locus, reported by V. C. Sheffield et al. (1994, Hum. Mol. Genet. 3, 1331-1335), or on chromosome 2 or 17, arguing against the involvement of a BBS locus in a patient with a t(2;17) translocation.

Abnormalities, Multiple↗

PubMed1997

Acrocallosal syndrome in an Algerian boy born to consanguineous parents: review of the literature and further delineation of the syndrome.

We present a 17-month-old boy with the acrocallosal syndrome. He was born to consanguineous parents. Abnormal findings included agenesis of the corpus callosum, a ventricular septal defect (VSD), postaxial polydactyly of fingers, cleft soft palate, intestinal malrotation, large anterior fontanelle, prominent forehead, hypertelorism, epicanthic folds, short nose and mandible and preauricular skin tags, mixed hearing loss, laryngomalacia, and growth and severe motor and mental retardation. A review of previous reports on the acrocallosal syndrome shows considerable clinical variability; minimal diagnostic criteria are proposed. A developmental field defect with disturbance of midline development is suggested.

Abnormalities, Multiple↗

PubMed1997

Human neuroserpin (PI12): cDNA cloning and chromosomal localization to 3q26.

Neuroserpin is a novel serine protease inhibitor of the serpin family. It has been reported as a 55-kDa glycoprotein that is secreted from the axons of cultured central and peripheral nervous system neurons. In situ hybridization and Northern blot analyses at different developmental stages of the chicken revealed that neuroserpin is predominantly expressed in the nervous system and that most cells expressing neuroserpin can be qualified as bona fide neurons. We have isolated the full-length cDNA for human neuroserpin from a fetal retina cDNA library. The open reading frame of the cDNA of human neuroserpin, like that of its chicken counterpart, encodes a protein of 410 amino acids. The human and the chicken neuroserpin exhibit an amino acid sequence identity of 80%. Northern blot analysis of human organs demonstrated predominant expression of neuroserpin in the brain. By fluorescence in situ hybridization the human neuroserpin gene (HGMW-approved symbol PI12) was mapped to region q26 of chromosome 3.

Amino Acid Sequence↗

PubMed1997

Ataxic gait and mental retardation with absence of the paternal chromosome 8 and an idic(8)(p23.3): imprinting effect or nullisomy for distal 8p genes?

A female child with mild dysmorphisms, motor and mental retardation had a 45,XX,-8,-8,+psu dic(8)(p23.3) karyotype in blood lymphocytes, skin fibroblasts and in a lymphoblastoid cell line. DNA analysis showed that the proposita was nullisomic for the 8pter region distal to D8S264, at less than 1 cM from the telomere. Analysis of DNA polymorphisms of 38 loci spread along the entire chromosome 8 revealed that only maternal alleles were present, distributed in four heterozygous and four homozygous regions. This finding indicated that the rearrangement occurred during maternal meiosis in a chromosome recombinant with a minimum of seven crossovers. To our knowledge this is the first case of uniparental maternal disomy for chromosome 8 and of nullisomy for the distal 1-cM portion of the short arm. The available data are in favour of the assumption that no imprinted genes are present on chromosome 8. Thus, dysmorphisms, motor and mental retardation of the proposita are likely to be caused by the nullisomy for the region distal to D8S264, a region in which a recessive gene for epilepsy with progressive mental retardation is known to be located.

Adult↗

PubMed1997

Clinical and genetic heterogeneity in Meckel syndrome.

Meckel syndrome (MKS) is a lethal malformation syndrome characterised by posterior meningoencephalocele, polycystic kidneys, fibrotic changes of the liver, and polydactyly. We have previously shown a linkage to chromosome 17q in 17 Finnish Meckel families. In this study we have analysed one Italian, one Austrian (of Turkish origin) and three British MKS families (Caucasian, Pakistani, and Bangladeshi families) for linkage to the MKS locus on chromosome 17q22-q24. We did not observe co-segregation of the disease and marker haplotypes in the Austrian family or in the three British families, of which two represented classical MKS and one a slightly atypical MKS phenotype with longer survival of the patient. In the Italian family the affected and non-affected children did not share the same maternal chromosome and thus this family could represent the same allelic disease as the Finnish MKS families. These results suggest locus heterogeneity in Meckel syndrome--a feature previously suspected based on the highly variable clinical phenotype.

Abnormalities, Multiple↗

PubMed1997

Mutations in human TBX3 alter limb, apocrine and genital development in ulnar-mammary syndrome.

Ulnar-mammary syndrome is a rare pleiotropic disorder affecting limb, apocrine gland, tooth and genital development. We demonstrate that mutations in human TBX3, a member of the T-box gene family, cause ulnar-mammary syndrome in two families. Each mutation (a single nucleotide deletion and a splice-site mutation) is predicted to cause haploinsufficiency of TBX3, implying that critical levels of this transcription factor are required for morphogenesis of several organs. Limb abnormalities of ulnar-mammary syndrome involve posterior elements. Mutations in TBX5, a related and linked gene, cause anterior limb abnormalities in Holt-Oram syndrome. We suggest that during the evolution of TBX3 and TBX5 from a common ancestral gene, each has acquired specific yet complementary roles in patterning the mammalian upper limb.

Abnormalities, Multiple↗

PubMed1997

Mutational analysis of the SOX9 gene in campomelic dysplasia and autosomal sex reversal: lack of genotype/phenotype correlations.

It has previously been shown that, in the heterozygous state, mutations in the SOX9 gene cause campomelic dysplasia (CD) and the often associated autosomal XY sex reversal. In 12 CD patients, 10 novel mutations and one recurrent mutation were characterized in one SOX9 allele each, and in one case, no mutation was found. Four missense mutations are all located within the high mobility group (HMG) domain. They either reduce or abolish the DNA-binding ability of the mutant SOX9 proteins. Among the five nonsense and three frameshift mutations identified, two leave the C-terminal transactivation (TA) domain encompassing residues 402-509 of SOX9 partly or almost completely intact. When tested in cell transfection experiments, the recurrent nonsense mutation Y440X, found in two patients who survived for four and more than 9 years, respectively, exhibits some residual transactivation ability. In contrast, a frameshift mutation extending the protein by 70 residues at codon 507, found in a patient who died shortly after birth, showed no transactivation. This is apparently due to instability of the mutant SOX9 protein as demonstrated by Western blotting. Amino acid substitutions and nonsense mutations are found in patients with and without XY sex reversal, indicating that sex reversal in CD is subject to variable penetrance. Finally, none of 18 female patients with XY gonadal dysgenesis (Swyer syndrome) showed an altered SOX9 banding pattern in SSCP assays, providing evidence that SOX9 mutations do not usually result in XY sex reversal without skeletal malformations.

Child↗

PubMed1997

Escher-Hirt syndrome.

A mother and her two daughters are reported with bilateral conductive deafness due to incudo-stapedial abnormalities, and microtia with thickened ear lobes. This pattern of abnormal findings, transmitted with an autosomal dominant mode of inheritance, is characteristic of the Escher-Hirt syndrome. One of the daughters died from an additional cardiac malformation (VSD). Anomalies of the middle ear were demonstrated in the surviving patients by computed tomography. Differential diagnosis with other genetic syndromes associated with deafness, and possible therapeutic approaches are discussed.

Adult↗

PubMed1997

Multiple congenital anomalies including the Rieger eye malformation in a boy with interstitial deletion of (4) (q25-->q27) secondary to a balanced insertion in his normal father: evidence for haplotype insufficiency causing the Rieger malformation.

A 7 year old boy with minor facial anomalies, the Rieger eye malformation, reduced vision, genital anomalies, and severe mental retardation had deletion of the segment 4q24-->q26. His phenotypically normal father had a balanced insertion of that segment into the distal long arm of chromosome 6: 46,XY,ins(6;4)(q26;q24q26). Microsatellite loci flanking the RIEG gene on 4q25 were deleted giving indirect evidence of deletion of this locus. This finding and the normal ocular findings in the insertion carrier father show that haplotype insufficiency can cause the Rieger eye malformation.

Adult↗