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PubMed2000

Paternal UPD15: further genetic and clinical studies in four Angelman syndrome patients.

Among 25 patients diagnosed with Angelman syndrome, we detected 21 with deletion and 4 with paternal uniparental disomy (UPD), 2 isodisomies originating by postzygotic error, and 1 MII nondisjunction event. The diagnosis was obtained by molecular techniques, including methylation pattern analysis of exon 1 of SNRPN and microsatellite analysis of loci within and outside the 15q11-q13 region. Most manifestations present in deletion patients are those previously reported. Comparing the clinical data from our and published UPD patients with those with deletions we observed the following: the age of diagnosis is higher in UPD group (average 7 3/12 years), microcephaly is more frequent among deletion patients, UPD children start walking earlier (average age 2 9/12 years), whereas in deletion patients the average is 4 (1/2) years, epilepsy started later in UPD patients (average 5 10/12 years) than in deletion patients (average 1 11/12 years), weight above the 75th centile is reported mainly in UPD patients, complete absence of speech is more common in the deleted (88.9%) than in the UPD patients because half of the children are able to say few words. Thus, besides the abnormalities already described, the UPD patients have somewhat better verbal development, a weight above the 75th centile, and OFC in the upper normal range.

Angelman Syndrome↗
PubMed2000

Complete maternal isodisomy of chromosome 8 in an individual with an early-onset ileal carcinoid tumor.

Uniparental disomy (UPD) is a condition in which diploid individuals possess a chromosome pair from a single parent. In some instances, UPD causes an abnormal phenotype due to imprinting effects, reduction to homozygosity at recessive disease loci, or trisomy mosaicism. Here we report the first account of an individual with apparently nonmosaic complete maternal isodisomy of chromosome 8. This individual was identified during routine genotyping in a genomewide search for type 2 diabetes susceptibility genes, although he does not have diabetes. He is of normal appearance, stature, and intelligence, but there is an unusual history of early onset ileal carcinoid. The discovery of other maternal UPD 8 cases will be necessary to define whether this condition causes a distinct phenotype.

Adult↗
PubMed2000

Search for imprinted regions on chromosome 14: comparison of maternal and paternal UPD cases with cases of chromosome 14 deletion.

Over the past few years, regions of genomic imprinting have been identified on a small number of chromosomes through a search for the etiology of various disorders. Distinct phenotypes have been associated with both maternal and paternal uniparental disomy (UPD) for chromosome 14. This observation indicates that there are imprinted genes present on chromosome 14, although none have been identified to date. In order to focus the search for imprinted genes on chromosome 14, we analyzed cases of maternal and paternal UPD 14 and compared them with cases of chromosome 14 deletions. Cases of paternal UPD were compared with maternal deletions and maternal UPD compared with paternal deletions. The paternal UPD anomalies seen in maternal deletion cases allowed us to associate the following features and chromosomal regions: Hirsute forehead: del(14)(q12q13. 3) and del(14)(q32); blepharophimosis: del(14)(q32); small thorax: del(14)(q11.2q13); and joint contractures: del(14)(q11.2q13) and del(14)(q31). Comparison of maternal UPD and paternal deletion cases revealed fleshy nasal tip to be most often associated with del(14)(q32), scoliosis with del(14) (q23q24.2), and del(14)(q32. 11qter) and small size at birth to be associated with del(14)(q11q13) and del(14)(q32). Our study, in conjunction with a prior study of UPD 14 and partial trisomy 14 cases, and what is known of imprinting in regions of mouse chromosomes homologous to human chromosome 14, leads us to conclude that 14q23-q32 is likely an area where imprinted genes may reside.

Abnormalities, Multiple↗
PubMed2000

Trisomy 12 mosaicism confirmed in multiple organs from a liveborn child.

This patient, in whom trisomy 12 mosaicism was confirmed in multiple organs, is the fifth case diagnosed postnatally and the first reported for whom a meiotic origin of the trisomy, maternal meiosis I, was determined. Mosaic aneuploidy was suspected because of pigmentary dysplasia, a frequent but non-specific finding in chromosomal mosaicism. The severe phenotype of this child, who died in infancy with a complex heart malformation, was probably a result of the high percentage of trisomic cells. Cytogenetic and interphase fluorescent in situ hybridization analyses showed a highly variable distribution of aneuploid cells in the nine tissues studied, from none in blood and ovary to 100% in spleen and liver. The trisomy arose meiotically with apparent post-zygotic loss of one of the chromosomes 12; uniparental disomy for this chromosome in the diploid cell line was excluded. The phenotype of the cases reported in living or liveborn individuals has been extremely variable, ranging from the present case, in which the child died in infancy with multiple malformations and pigmentary dysplasia, to a fortuitous finding in an adult studied for infertility. The variation in severity is probably determined by the proportion and distribution of the trisomic cells, which is linked to the timing of the non-disjunctional error.

Abnormalities, Multiple↗
PubMed2000

Prader-Willi and Angelman syndromes: sister imprinted disorders.

Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are clinically distinct complex disorders mapped to chromosome 15q11-q13. They both have characteristic neurologic, developmental, and behavioral phenotypes plus other structural and functional abnormalities. However, the cognitive and neurologic impairment is more severe in AS, including seizures and ataxia. The behavioral and endocrine disorders are more severe in PWS, including obsessive-compulsive symptoms and hypothalamic insufficiency. Both disorders can result from microdeletion, uniparental disomy, or an imprinting center defect in 15q11-q13, although the abnormality is on the paternally derived chromosome 15 for PWS and the maternally derived 15 for AS because of genomic imprinting. Although the same gene may control imprinting for both disorders, the gene(s) causing their phenotypes differ. AS results from underexpression of a single gene, UBE3A, which codes for E6-AP, a protein that functions to transfer small ubiquitin molecules to certain target proteins, to enable their degradation. The genes responsible for PWS are not determined, although several maternally imprinted genes in 15q11-q13 are known. The most likely candidate is SNRPN, which codes for a small nuclear ribonucleoprotein, a ribosome-associated protein that controls gene splicing and thus synthesis of critical proteins in the brain. Animal models exist for both disorders. The genetic relationship between PWS and AS makes them unique and potentially highly instructive disorders that contribute substantially to the population burden of cognitive impairment.

Angelman Syndrome↗
PubMed2001

Recurrent trisomy 15 in a female carrier of der(15)t(Y;15)(q12;p13).

We report on a female carrier of der(15) t(Y;15)(q12;p13) who had two pregnancy losses with trisomy 15 and one with tetraploidy. Molecular analysis showed that both non-disjunction events resulting in the trisomy 15 pregnancies occurred in maternal meiosis I. This finding raises the possibility that there may be an increased risk for trisomy 15 in some carriers of unbalanced t(Y;15) which, if followed by trisomic zygote rescue, may lead to uniparental disomy (UPD).

Abortion, Habitual↗
PubMed2000

Retrospective diagnosis of trisomy 15 in formalin-fixed, paraffin-embedded placental tissue in a newborn girl with Prader-Willi syndrome.

Paternal deletion of 15q11-q13 and maternal uniparental disomy (UPD) of chromosome 15 are the main causes of Prader-Willi syndrome (PWS). The finding of an UPD(15) is associated with increased maternal age. We present a retrospective diagnosis of a trisomy 15 mosaicism confined to the placenta (CPM) after birth of a girl with clinical features of PWS born to a 43-year-old mother. Chromosome analysis after amniocentesis, performed because of advanced maternal age, had shown a normal female karyotype. In peripheral blood cells molecular studies showed the absence of the paternal allele at the SNRPN locus and fluorescence in situ hybridization (FISH) analysis excluded a deletion of the SNRPN locus on both chromosomes 15. Trisomic cells were detected by FISH on nuclei isolated from formalin-fixed, paraffin-embedded placental tissue using a DNA-probe specific for the centromeric region of chromosome 15.

Adult↗
PubMed2000

Current awareness in prenatal diagnosis.

In order to keep subscribers up-to-date with the latest developments in their field, John Wiley & Sons are providing a current awareness service in each issue of the journal. The bibliography contains newly published material in the field of prenatal diagnosis. Each bibliography is divided into 17 sections: 1 Books, Reviews & Symposia; 2 General Interest; 3 Normal Fetal Development; 4 Gametogenesis and Pre-implantation Diagnosis; 5 First Trimester Diagnosis; 6 Second Trimester Diagnosis; 7 Fetal Diagnosis by Ultrasound and Other Imaging; 8 Maternal Screening; 9 Screening for Carriers of Genetic Abnormality; 10 Technological Developments; 11 Confined Placental Mosaicism and Uniparental Disomy; 12 Molecular Cytogenetics; 13 Fetal Cells in Maternal Circulation; 14 Fetal Therapy; 15 Psychosocial Aspects; 16 Epidemiology and Environmental Factors; 17 Developmental Pathology. Within each section, articles are listed in alphabetical order with respect to author. If, in the preceding period, no publications are located relevant to any one of these headings, that section will be omitted.

Humans↗
PubMed1998

Imprinted genes in the Prader-Willi deletion.

Parent-of-origin-specific deletions of proximal chromosome 15q cause either the Prader-Willi syndrome (paternal deletion) or the Angelman syndrome (maternal deletion), two distinct neurodevelopmental disorders. In contrast to the Angelman syndrome, which can also be caused by mutations in a single gene (UBE3A, encoding a ubiquitin ligase), the Prader-Willi syndrome is caused by deletions in about two-thirds of cases and by maternal uniparental disomy in the remaining third. The consequence of both mechanisms, in addition to rare microdeletions or so-called 'imprinting mutations', is lack of the products of multiple genes in the region that are normally expressed only from the paternal chromosome. One gene that is consistently silent in the Prader-Willi syndrome is SNRPN, which encodes the small nuclear ribonucleoprotein particle-associated polypeptide N that forms part of the spliceosomes in the brain. A systematic search for other imprinted genes in the Prader-Willi syndrome region revealed a paternally expressed transcript (IPW, for imprinted in the Prader-Willi region) and a similarly imprinted mouse homologue (Ipw) in the conserved syntenic region on mouse chromosome 7. Ipw is highly expressed in the brain and alternatively spliced to generate different transcripts. Since there is no open reading frame that is conserved in the human and mouse IPW genes, they are postulated to function as untranslated RNAs, possibly regulating transcription in cis in the region.

Animals↗
PubMed1991

Biochemical and genetic analysis of a child with cystic fibrosis and cystinosis.

We have studied a child with cystic fibrosis (CF), nephropathic cystinosis, and manifestations of Bartter syndrome, a finding reported previously in both of these diseases (CF and cystinosis). The chance of an individual inheriting a mutant allele for both CF and cystinosis from each of his parents by independent segregation is very small. Therefore, other mechanisms of inheritance were investigated, including whether his diseases were caused by a chromosome deletion or rearrangement that caused defects in both genes, whether his phenotype was caused by a new mutation or variant of either disease, or whether both diseases were inherited together due to inheritance of 2 copies of the same chromosome from one of the parents (uniparental disomy). An investigation was made of whether having mutations for both CF and cystinosis resulted in a different phenotype for either disease and whether the child was a heterozygote rather than a homozygote for one of the mutations. The results suggest that neither disease influenced the expression of the defect in the other and that this child inherited a mutant allele for both diseases independently from each parent.

Cysteine↗
PubMed1993

Age-associated chromosome 21 loss in Down syndrome: possible relevance to mosaicism and Alzheimer disease.

We previously observed low level mosaicism (2-4% normal cells) in phytohemagglutinin-stimulated peripheral blood lymphocytes (PBL) in 29% of a small group of elderly persons with Down syndrome (DS). An analysis of cytogenetic data on 154 trisomy 21 cases (age 1 day to 68 years) showed that the proportion of diploid cells in such cultures significantly increased (P < 0.005) with advancing age. Thus, the "occult" mosaicism in PBL of the elderly persons with DS is likely due to the accumulation of cells that have lost a chromosome 21. A consequence of chromosome 21 loss could be uniparental disomy of the 2n cells, a factor that might have significant biological consequences if some chromosome 21 genes are imprinted. Loss of a chromosome 21 from trisomic cells might result in tissue-specific mosaicism and "classical" mosaicism in different age groups. Chromosome 21 loss might also be relevant to the development of Alzheimer-type dementia in DS and in the general population.

Adolescent↗
PubMed1993

Cytogenetic and molecular analysis in Angelman syndrome.

We report on cytogenetic and molecular analyses of 29 Angelman syndrome (AS) individuals ascertained in 1990 through the first National Angelman Syndrome Conference. High resolution GTG- and GBG-banded chromosomes were studied. Standard molecular analysis with six 15q11q13 DNA sequences was used to analyze copy number and parental origin of 15q11q13. Concordance between molecular and cytogenetic data was excellent. The combined data showed that 23 of the 27 probands (85%) on whom we had definitive results have deletions of the chromosome 15q11q13 region. Two classes of deletion were detected molecularly: most patients were deleted for the 5 more proximal probes, but in 2 cases the deletion extended distally to include in sixth probe. In the 13 cases where the parental origin of the deleted chromosome 15 could be established, it was maternal. There were no cases of uniparental disomy. Cytological observations of the relative sizes of the heterochromatic regions of the short arm of chromosome 15 suggested that chromosomes with large heterochromatic blocks may be more prone to de novo deletion.

Angelman Syndrome↗
PubMed1994

Isochromosome 15q of maternal origin in two Prader-Willi syndrome patients previously diagnosed erroneously as cytogenetic deletions.

Since our previous report on two Prader-Willi syndrome (PWS) patients with t(15q;15q) (Niikawa and Ishikiriyama; Hum Genet 69:22-27, 1985) was erroneous, we report here new data and a corrected interpretation. Reexamination of the parental origin of their t(15q;15q) using polymorphic DNA markers that are mapped to various regions of 15q documented no molecular deletions at the 15q11-q13 region in either patient. Both patients were homozygous at all loci examined and their haplotypes on 15q coincided with one of those in their respective mothers. These results indicate that the presumed t(15q;15q) in each patient was actually an isochromosome 15q producing maternal uniparental disomy, consistent with genomic imprinting at the PWS locus.

Aneuploidy↗
PubMed1994

Molecular diagnosis of Prader-Willi syndrome: parent-of-origin dependent methylation sites and non-isotopic detection of (CA)n dinucleotide repeat polymorphisms.

We describe our experience in the molecular diagnosis of 22 patients suspected of Prader-Willi syndrome (PWS) using a DNA probe PW71 (D15S63) which detects a parent-of-origin specific methylated site in the PWS critical region. The cause of the syndrome was determined as deletion or uniparental disomy according to the segregation of (CA)n dinucleotide repeat polymorphisms of the PWS/AS region and more distal markers of chromosome 15. In 10 patients the clinical diagnosis was confirmed by this approach, 6 with paternal deletion and 4 with maternal disomy. In one patient, the aberrant methylation pattern that was detected by PW71 could not be confirmed by the segregation of (CA)n, probably due to paternal microdeletion in the PWS critical region which did not include the loci D15S97, D15S113, GABRB3, and GABRA5. This case demonstrates the advantage of the DNA probe PW71 in the diagnosis of PWS.

Adolescent↗
PubMed1994

Molecular and clinical study of 61 Angelman syndrome patients.

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.

Adolescent↗
PubMed1994

Familial Angelman syndrome with a crossover in the critical deletion region.

More than two thirds of the patients with Angelman syndrome (AS) carry a deletion or other chromosomal abnormality in the 15q11-13 region. A much less frequent cause (4%) is paternal uniparental disomy of the entire chromosome. In general no abnormalities are detectable in familial cases and an inherited submicroscopic deletion was described only once. Here a familial case of 2 sibs with AS is reported. No major cytogenetic or molecular abnormality was identified, but a recombination event had occurred in the AS critical region. The AS locus, D15S113, D15S10, D15S11, and D15S18 mapped proximal and the GABRB3 gene, D15S97, the GABRA5 gene, and D15S12 distal to the crossover site. This recombination within the AS critical region confirmed the exclusion of GABRB3 as a candidate gene for AS. Other markers and candidate genes can be tested genetically as well for a possible role in AS.

Adolescent↗
PubMed1994

A variety of genetic mechanisms are associated with the Prader-Willi syndrome.

An extensive set of chromosome 15 DNA polymorphisms and densitometric analysis with four markers mapping to the Prader-Willi chromosome region (PWCR) of chromosome 15 have been used to characterize a cohort of 30 subjects with classical Prader-Willi syndrome (PWS). Molecular analysis enabled the classification of the PWS subjects into four groups: (A) 18 subjects (60%) had deletions of paternal 15q11-13 involving a common set of DNA markers. Two subjects had differently sized deletions, one larger and one smaller than the other cases. (B) Eight (27%) had maternal uniparental disomy for chromosome 15. (C) One (3%) had a marker chromosome carrying an extra copy of the PWCR. The marker chromosome was demonstrated to be of paternal origin and the two intact chromosomes were maternally derived. This case represents an apparent exception to the generally held view that PWS is associated with an absence of paternally inherited gene(s) located in the PWCR. (D) The remaining three cases (10%) had none of the above abnormalities. This last subgroup of patients has not previously been well characterized but could represent limited deletions not detectable with the markers used or abnormalities in the imprinting process. These cases represent potentially valuable resources to elucidate more precisely the fundamental disorders responsible for PWS.

Adolescent↗
PubMed1995

Replication banding and molecular studies of a mosaic, unbalanced dic(X;15)(Xpter-->Xq26.1::15p11-->15qter).

We present a patient with a chromosomal mosaicism involving the X chromosome. One cell line is 45,X and the other has a de novo paternally derived dicentric X;15 translocation. Her karyotype is therefore 45,X/45,X,dic(X;15)(Xpter-->Xq26.1::15p11-->15 qter) based on G-banding. The presence of 2 centromeres on the derivative X was confirmed by fluorescence in situ hybridization (FISH) and a deletion of Xq26.1-->qter was confirmed by polymerase chain reaction (PCR) using DXS52 and DXYS154. Replication banding studies indicate that the derivative X is late replicating. Based on these studies, it is unclear whether inactivation has spread to proximal 15q. The patient has a unique phenotype distinct from Ullrich-Turner or Prader-Willi syndromes, but includes ataxia and language delay which are commonly seen in Angelman syndrome. These findings are contrary to those anticipated since deficiency of paternal genes at 15q12 typically leads to Prader-Willi syndrome. Molecular analysis of PCR-based polymorphisms of chromosome 15 and X indicates that uniparental disomy is not present for the X chromosome or chromosome 15 in either cell line. It is hypothesized that her phenotype results from the interaction of the 2 abnormal genotypes. Each abnormality may be diluted by the mosaicism and, in the derivative X line, by the possible variation among cells of inactivation spreading to chromosome 15.

Abnormalities, Multiple↗