Showing papers by "Stylianos E. Antonarakis published in 1993"
TL;DR: Evidence is presented to support a model based on the possibility of recombination between homologous sequences located in intron 22 and upstream of the factor VIII gene that leads to an inversion of all intervening DNA and a disruption of the gene.
Abstract: Mutations in the factor VIII gene have been discovered for barely more than half of the examined cases of severe haemophilia A. To account for the unidentified mutations, we propose a model based on the possibility of recombination between homologous sequences located in intron 22 and upstream of the factor VIII gene. Such a recombination would lead to an inversion of all intervening DNA and a disruption of the gene. We present evidence to support this model and describe a Southern blot assay that detects the inversion. These findings should be valuable for genetic prediction of haemophilia A in approximately 45% of families with severe disease.
782 citations
TL;DR: It is suggested that these novel human genes with triplet repeats are candidates for causing neuropsychiatric diseases, such as Huntington's disease, bipolar affective disorder, and possibly others, show features of anticipation.
186 citations
TL;DR: The study of DNA polymorphisms has permitted the determination of the parental and meiotic origin of the supernumerary chromosome 21 in families with free trisomy 21 and there was no preference in the parentalorigin of the duplicated chromosome 21.
Abstract: The study of DNA polymorphisms has permitted the determination of the parental and meiotic origin of the supernumerary chromosome 21 in families with free trisomy 21. Chromosomal segregation errors in somatic cells during mitosis were recognized after analysis of DNA markers in the pericentromeric region and (in order to identify recombination events) along the long arm of chromosome 21. Mitotic errors accounted for about 4.5% (11 of 238) of free trisomy 21 cases examined. The mean maternal age of mitotic errors was 28.5 years and there was no association with advanced maternal age. There was no preference in the parental origin of the duplicated chromosome 21. The 43 maternal meiosis II errors in this study had a mean maternal age of 34.1 years-the highest mean maternal age of all categories of chromosomal segregation errors.
139 citations
Journal Article•
TL;DR: The study of de novo Robertsonian translocations of the type reported here should reveal both the extent of UPD in these events and the contribution of particular chromosomes involved in certain phenotypes.
Abstract: Uniparental disomy (UPD) for particular chromosomes is increasingly recognized as a cause of abnormal phenotypes in humans. We recently studied a 9-year-old female with a de novo Robertsonian translocation t(13;14), short stature, mild developmental delay, scoliosis, hyperextensible joints, hydrocephalus that resolved spontaneously during the first year of life, and hypercholesterolemia. To determine the parental origin of chromosomes 13 and 14 in the proband, we have studied the genotypes of DNA polymorphic markers due to (GT)n repeats in the patient and her parents' blood DNA. The genotypes of markers D14S43, D14S45, D14S49, and D14S54 indicated maternal UPD for chromosome 14. There was isodisomy for proximal markers and heterodisomy for distal markers, suggesting a recombination event on maternal chromosomes 14. In addition, DNA analysis first revealed--and subsequent cytogenetic analysis confirmed--that there was mosaic trisomy 14 in 5% of blood lymphocytes. There was normal (biparental) inheritance for chromosome 13, and there was no evidence of false paternity in genotypes of 11 highly polymorphic markers on human chromosome 21. Two cases of maternal UPD for chromosome 14 have previously been reported, one with a familial rob t(13;14) and the other with a t(14;14). There are several similarities among these patients, and a "maternal UPD chromosome 14 syndrome" is emerging; however, the contribution of the mosaic trisomy 14 to the phenotype cannot be evaluated. The study of de novo Robertsonian translocations of the type reported here should reveal both the extent of UPD in these events and the contribution of particular chromosomes involved in certain phenotypes.
99 citations
TL;DR: Paternal nondisjunction accounts for approximately 5% of cases of trisomy 21, and a significant difference in mean maternal age was found between cases of paternal origin and those of maternal origin, indicating that the maternal age effect is confined to maternal nondisJunction.
Abstract: Paternal nondisjunction accounts for approximately 5% of cases of trisomy 21. We have studied 36 cases of free trisomy 21, in which the supernumerary chromosome was of paternal origin, with DNA markers in the pericentromeric region and along the long arm of chromosome 21. Fifteen of the paternal cases were consistent with meiosis II errors, 8 with mitotic errors and only 7 with meiosis I nondisjunction. This contrasts markedly with maternally derived trisomy 21, in which meiosis I errors predominate. An excess of males was observed in the meiotic cases (21 males:6 females), highly significantly different from a 1.06 ratio. A significant difference in mean maternal age was found between cases of paternal origin (28.1 years) and those of maternal origin (31.8 years, n = 429). This indicates that the maternal age effect is confined to maternal nondisjunction.
75 citations
TL;DR: A comprehensive physical map of overlapping YACs, a dense linkage map and an almost complete long-range restriction map have been produced much earlier than expected, helping to characterize both genes and their impact in health and disease.
66 citations
TL;DR: This map of HC 21 represents a highly informative and dense meiotic linkage map and will be useful in linking disease phenotypes to loci on this chromosome.
66 citations
Journal Article•
TL;DR: It is concluded that pUPiD21 is not associated with abnormal phenotypes and that there are probably no imprinted genes on chromosome 21.
Abstract: Uniparental disomy (UPD) involving several different chromosomes has been described in several cases of human pathologies. In order to investigate whether UPD for chromosome 21 is associated with abnormal phenotypes, we analyzed DNA polymorphisms in DNA from a family with de novo Robertsonian translocation t(21q;21q). The proband was a healthy male with 45 dup(21q) who was ascertained through his trisomy 21 offspring. No phenotypic abnormalities were noted in the physical exam, and his past medical history was unremarkable. We obtained genotypes for the proband and his parents' leukocyte DNAs from 17 highly informative short sequence repeat polymorphisms that map in the pericentromeric region and along the entire length of 21q. The order of the markers has been previously determined through the linkage and physical maps of this chromosome. For the nine informative markers there was no maternal allele contribution to the genotype of the proband; in addition, there was always reduction to homozygosity of a paternal allele. These data indicated that there was paternal uniparental isodisomy for chromosome 21 (pUPiD21). We conclude that pUPiD21 is not associated with abnormal phenotypes and that there are probably no imprinted genes on chromosome 21.
57 citations
TL;DR: A review of the literature and the assay of FVIII antigen in 5 hemophilia A patients with previously identified missense mutations from this laboratory yielded a total of 20 other unique cross-reacting material (CRM)-reduced and CRM-positive mutations.
53 citations
TL;DR: This report summarizes progress toward completing the mapping of human chromosome 21, as presented and discussed at the Fourth International Workshop on Human Chromosome 21, a special effort was made to integrate all mapping information.
30 citations
TL;DR: The analysis of somatic cell hybrids has elucidated the true nature of the F8C mutation in the proband, revealing a more complex rearrangement than that expected from cytogenetic analysis, chromosome painting, and Southern blots.
TL;DR: A polymorphism due to a T-to-C substitution at nucleotide 549 of the 3′UT region with heterozygosity of 46% has been identified and is placed in the linkage map of human chromosome 21.
Abstract: We used single-strand conformation polymorphism (SSCP) to detect DNA polymorphisms in the 3′ untranslated (3′UT) region of the gene for cystathionine β-synthase (CBS). A polymorphism due to a T-to-C substitution at nucleotide 549 of the 3′UT region with heterozygosity of 46% has been identified. Genotypes for this polymorphism have been obtained in all of the informative CEPH families, and CBS has been placed in the linkage map of human chromosome 21.
TL;DR: It is concluded that the 3'UT region of genes is a relatively rich source of polymorphisms and that SSCA is an effective method of detecting the normal sequence variation in the human genome.
TL;DR: The zinc finger cDNA described here maps in an area where other zinc finger sequences and multiple cosmid clones containing zinc fingers have been previously localized, indicating that pentanucleotide repeat polymorphisms may be a particularly useful class of DNA markers for linkage studies.
TL;DR: A long range restriction map of the pericentromeric 21q region between the centromere, identified by the alphoid DNA sequence D21Z1, and D21S13E showed the order and intermarker distances of five new loci, including two for which highly informative dinucleotide repeat polymorphisms were identified.
TL;DR: A highly polymorphic (GT)n repeat with 14 alleles that is closely linked to the amyloid precursor protein (APP) gene on human chromosome 21 will be useful for studies of linkage of disorders such as Alzheimer disease to the APP gene.
Abstract: We describe a highly polymorphic (GT)n repeat with 14 alleles that is closely linked to the amyloid precursor protein (APP) gene on human chromosome 21. This marker, D21S210, will be useful for studies of linkage of disorders such as Alzheimer disease to the APP gene.
TL;DR: The results demonstrate the power of FISH in conjunction with DNA analysis for examination of chromosome rearrangements that may be misclassified by traditional cytogenetic studies alone.
Abstract: We report on an 8-year-old girl with minor anomalies consistent with 18q- syndrome and mild developmental delay. Initially cytogenetics showed a terminal deletion of chromosome 21 with mosaicism for a small ring chromosome 21 as the only apparent karyotypic abnormality: mos 45,XX,-21/46,XX,+r(21) (48%/52%). Further studies including FISH and DNA analysis demonstrated a de novo unbalanced translocation of chromosomes 18 and 21 with the likely breakpoints in 18q23 and 21q21.1. Most of 21q was translocated to the distal long arm of one chromosome 18, and this derivative 18 appeared to lack 18q23-qter. The small ring chromosome 21 [r(21)], present in only 52% of the patient's blood lymphocytes, did not appear to be associated with the abnormal phenotype since all 13 chromosome 21 markers that were examined in genomic DNA were present in 2 copies, and the phenotype of the patient was consistent with the 18q- syndrome. The karyotype was reinterpreted as mos 45,XX,-18,-21,+der(18) t(18;21) (q23;q21.1)/46,XX,-18,-21,+der(18) t(18;21) (q23;q21.1), +r(21) (p13q21.1) (48%/52%). These results demonstrate the power of FISH in conjunction with DNA analysis for examination of chromosome rearrangements that may be misclassified by traditional cytogenetic studies alone.