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Title: Molecular and clinical study of 61 Angelman syndrome patients

Abstract

We analyzed 61 Angelman syndrome (AS) patients by cytogenetic and molecular techniques. On the basis of molecular findings, the patients were classified into the following 4 groups: familial cases without deletion, familial cases with submicroscopic deletion, sporadic cases with deletion, and sporadic cases without deletion. Among 53 sporadic cases, 37 (70%) had molecular deletion, which commonly extended from D15S9 to D15S12, although not all deletions were identical. Of 8 familial cases, 3 sibs from one family had a molecular deletion involving only 2 loci, D15S10 and GABRB3, which define the critical region for AS phenotypes. The parental origin of deletion, both in sporadic and familial cases, was exclusively maternal and consistent with a genomic imprinting hypothesis. Among sporadic and familial cases without deletion, no uniparental disomy was found and most of them were shown to inherit chromosomes 15 from both parents (biparental inheritance). A discrepancy between cytogenetic and molecular deletion was observed in 14 (26%) of 53 patients in whom cytogenetic analysis could be performed. Ten (43%) of 23 patients with a normal karyotype showed a molecular deletion, and 4 (13%) of 30 patients with cytogenetic deletion, del(15) (q11q13), showed no molecular deletion. Most clinical manifestations, including neurological signs andmore » facial characteristics, were not distinct in each group except for hypopigmentation of skin or hair. Familial cases with submicroscopic deletion were not associated with hypopigmentation. These findings suggested that a gene for hypopigmentation is located outside the critical region of AS and is not imprinted. 37 refs., 2 figs., 4 tabs.« less

Authors:
; ; ;  [1]; ; ; ; ; ;
  1. Nagasaki Univ. School of Medicine (Japan)
Publication Date:
Sponsoring Org.:
USDOE
OSTI Identifier:
62008
Resource Type:
Journal Article
Resource Relation:
Journal Name: American Journal of Medical Genetics; Journal Volume: 52; Journal Issue: 2; Other Information: PBD: 15 Aug 1994
Country of Publication:
United States
Language:
English
Subject:
55 BIOLOGY AND MEDICINE, BASIC STUDIES; HUMAN CHROMOSOME 15; CHROMOSOMAL ABERRATIONS; GENETIC MAPPING; PATIENTS; MENTAL DISORDERS; EPILEPSY; HEREDITARY DISEASES; GENES; POLYMERASE CHAIN REACTION; GENETICS; KARYOTYPE; PIGMENTS; BANDING TECHNIQUES; RFLPS

Citation Formats

Saitoh, Shinji, Harada, Naoki, Jinno, Yoshihiro, Niikawa, Norio, Imaizumi, Kiyoshi, Kuroki, Yoshikazu, Fukushima, Yoshimitsu, Sugimoto, Tateo, and Renedo, Monica. Molecular and clinical study of 61 Angelman syndrome patients. United States: N. p., 1994. Web. doi:10.1002/ajmg.1320520207.
Saitoh, Shinji, Harada, Naoki, Jinno, Yoshihiro, Niikawa, Norio, Imaizumi, Kiyoshi, Kuroki, Yoshikazu, Fukushima, Yoshimitsu, Sugimoto, Tateo, & Renedo, Monica. Molecular and clinical study of 61 Angelman syndrome patients. United States. doi:10.1002/ajmg.1320520207.
Saitoh, Shinji, Harada, Naoki, Jinno, Yoshihiro, Niikawa, Norio, Imaizumi, Kiyoshi, Kuroki, Yoshikazu, Fukushima, Yoshimitsu, Sugimoto, Tateo, and Renedo, Monica. 1994. "Molecular and clinical study of 61 Angelman syndrome patients". United States. doi:10.1002/ajmg.1320520207.
@article{osti_62008,
title = {Molecular and clinical study of 61 Angelman syndrome patients},
author = {Saitoh, Shinji and Harada, Naoki and Jinno, Yoshihiro and Niikawa, Norio and Imaizumi, Kiyoshi and Kuroki, Yoshikazu and Fukushima and Yoshimitsu and Sugimoto, Tateo and Renedo, Monica},
abstractNote = {We analyzed 61 Angelman syndrome (AS) patients by cytogenetic and molecular techniques. On the basis of molecular findings, the patients were classified into the following 4 groups: familial cases without deletion, familial cases with submicroscopic deletion, sporadic cases with deletion, and sporadic cases without deletion. Among 53 sporadic cases, 37 (70%) had molecular deletion, which commonly extended from D15S9 to D15S12, although not all deletions were identical. Of 8 familial cases, 3 sibs from one family had a molecular deletion involving only 2 loci, D15S10 and GABRB3, which define the critical region for AS phenotypes. The parental origin of deletion, both in sporadic and familial cases, was exclusively maternal and consistent with a genomic imprinting hypothesis. Among sporadic and familial cases without deletion, no uniparental disomy was found and most of them were shown to inherit chromosomes 15 from both parents (biparental inheritance). A discrepancy between cytogenetic and molecular deletion was observed in 14 (26%) of 53 patients in whom cytogenetic analysis could be performed. Ten (43%) of 23 patients with a normal karyotype showed a molecular deletion, and 4 (13%) of 30 patients with cytogenetic deletion, del(15) (q11q13), showed no molecular deletion. Most clinical manifestations, including neurological signs and facial characteristics, were not distinct in each group except for hypopigmentation of skin or hair. Familial cases with submicroscopic deletion were not associated with hypopigmentation. These findings suggested that a gene for hypopigmentation is located outside the critical region of AS and is not imprinted. 37 refs., 2 figs., 4 tabs.},
doi = {10.1002/ajmg.1320520207},
journal = {American Journal of Medical Genetics},
number = 2,
volume = 52,
place = {United States},
year = 1994,
month = 8
}
  • Recent studies have identified a new class of Prader-Willi syndrome (PWS) and Angelman syndrome (AS) patients who have biparental inheritance, but neither the typical deletion nor uniparental disomy (UPD) or translocation. However, these patients have uniparental DNA methylation throughout 15q11-q13, and thus appear to have a mutation in the imprinting process for this region. Here we describe detailed clinical findings of five AS imprinting mutation patients (three families) and two PWS imprinting mutation patients (one new family). All these patients have essentially the classical clinical phenotype for the respective syndrome, except that the incidence of microcephaly is lower in imprintingmore » mutation AS patients than in deletion AS patients. Furthermore, imprinting mutation AS and PWS patients do not typically have hypopigmentation, which is commonly found in patients with the usual large deletion. Molecular diagnosis of these cases is initially achieved by DNA methylation analyses of the DN34/ZNF127, PW71 (D15S63), and SNRPN loci. The latter two probes have clear advantages in the simple molecular diagnostic analysis of PWS and AS patients with an imprinting mutation, as has been found for typical deletion or UPD PWS and AS cases. With the recent finding of inherited microdeletions in PWS and AS imprinting mutation families, our studies define a new class of these two syndromes. The clinical and molecular identification of these PWS and AS patients has important genetic counseling consequences. 49 refs., 4 figs., 3 tabs.« less
  • Twenty-seven cases of inverted duplications of chromosome 15 (inv dup[15]) were investigated by FISH with two DNA probes specific for the Prader-Willi syndrome/Angelman syndrome (PWS/AS) region on proximal 15q. Sixteen of the marker chromosomes displayed two copies of each probe, while in the remaining 11 markers no hybridization was observed. A significant association was found between the presence of this region and an abnormal phenotype (P<.01). This is the largest study to date of inv dup(15) chromosomes, that uses molecular cytogenetic methods and is the first to report a significant association between the presence of a specific chromosomal region inmore » such markers and an abnormal phenotype. 30 refs., 1 fig., 4 tabs.« less
  • Angelman syndrome (AS) was initially considered a rather rare abnormality, but in later years, with the possibilities for cytogenetic and molecular diagnosis an increasing number of patients have been reported. The incidence is quoted to be around 1:20,000. The etiology of AS is associated with the lack of maternal allele(s) of one or more loci at 15q11-q13, and is considered an effect of parental imprinting of that region, since a similar deficiency of paternal alleles leads to Prader-Willi syndrome. 9 refs., 1 tab.
  • Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are distinct mental retardation syndromes caused by paternal and maternal deficiencies, respectively, in chromosome 15q11{minus}q13. Approximately 70% of these patients have a large deletion of {approximately}4 Mb extending from D15S9 (ML34) through D15S12 (IR10A). To further characterize the deletion breakpoints proximal to D15S9, three new polymorphic microsatellite markers were developed that showed observed heterozygosities of 60%-87%. D15S541 and D15S542 were isolated for YAC A124A3 containing the D15S18 (IR39) locus. D15S543 was isolated from a cosmid cloned from the proximal right end of YAC 254B5 containing the D15S9 (ML34) locus. Gene-centromere mapping of thesemore » markers, using a panel of ovarian teratomas of known meiotic origin, extended the genetic map of chromosome 15 by 2-3 cM toward the centromere. Analysis of the more proximal S541/S542 markers on 53 Prader-Willi and 33 Angelman deletion patients indicated two classes of patients: 44% (35/80) of the informative patients were deleted for these markers (class I), while 56% (45/80) were not deleted (class II), with no difference between PWS and AS. In contrast, D15S543 was deleted in all informative patients (13/48) or showed the presence of a single allele (in 35/48 patients), suggesting that this marker is deleted in the majority of PWS and AS cases. These results confirm the presence of two common proximal deletion breakpoint regions in both Prader-Willi and Angelman syndromes and are consistent with the same deletion mechanism being responsible for paternal and maternal deletions. One breakpoint region lies between D15S541/S542 and D15S543, with an additional breakpoint region being proximal to D15S541/S542. 46 refs., 2 figs., 3 tabs.« less
  • The [gamma]-aminobutyric acid (GABA[sub A]) receptors are a family of ligand-gated chloride channels constituting the major inhibitory neurotransmitter receptors in the nervous system. In order to determine the genomic organization of the GABA[sub A] receptor [beta]3 subunit gene (GABRB3) and [alpha]5 subunit gene (GABRA5) in chromosome 15q11-q13, the authors have constructed a high-resolution physical map using the combined techniques of field-inversion gel electrophoresis and phage genomic library screening. This map, which covers nearly 1.0 Mb, shows that GABRB3 and GABRA5 are separated by less than 100 kb and are arranged in a head-to-head configuration. GABRB3 encompasses approximately 250 kb, whilemore » GABRA5 is contained within 70 kb. This difference in size is due in large part to an intron of 150 kb within GABRB3. The authors have also identified seven putative CpG islands within a 600-kb interval. Chromosomal rearrangement breakpoints -- in one Angelman syndrome (AS) patient with an unbalanced translocation and in another patient with a submicroscopic deletion -- are located within the large GABRB3 intron. These findings will facilitate chromosomal walking strategies for cloning the regions disrupted by the DNA rearrangements in these AS patients and will be valuable for mapping new genes to the AS chromosomal region. 64 refs., 6 figs., 2 tabs.« less