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PubMed2002

Automated fluorescent genotyping detects 10% of cryptic subtelomeric rearrangements in idiopathic syndromic mental retardation.

Recent studies have shown that cryptic unbalanced subtelomeric rearrangements contribute to a significant proportion of idiopathic syndromic mental retardation cases. Using a fluorescent genotyping based strategy, we found a 10% rate of cryptic subtelomeric rearrangements in a large series of 150 probands with severe idiopathic syndromic mental retardation and normal RHG-GTG banded karyotype. Fourteen children were found to carry deletions or duplications of one or more chromosome telomeres and two children had uniparental disomy. This study clearly shows that fluorescent genotyping is a sensitive and cost effective method that not only detects cryptic subtelomeric rearrangements but also provides a unique opportunity to detect uniparental disomies. We suggest giving consideration to systematic examination of subtelomeric regions in the diagnostic work up of patients with unexplained syndromic mental retardation.

Child↗
PubMed2005

Trisomy 7 mosaicism, maternal uniparental heterodisomy 7 and Hirschsprung's disease in a child with Silver-Russell syndrome.

Prenatal trisomy 7 is usually a cell culture artifact in amniocytes with normal diploid karyotype at birth and normal fetal outcome. In the same way, true prenatal trisomy 7 mosaicism usually results in a normal child except when trisomic cells persist after birth or when trisomy rescue leads to maternal uniparental disomy, which is responsible for 5.5-7% of patients with Silver-Russell syndrome (SRS). We report here on the unusual association of SRS and Hirschsprung's disease (HSCR) in a patient with maternal uniparental heterodisomy 7 and trisomy 7 mosaicism in intestine and skin fibroblasts. HSCR may be fortuitous given its frequency, multifactorial inheritance and genetic heterogeneity. However, the presence of the trisomy 7 mosaicism in intestine as well as in skin fibroblasts suggests that SRS and HSCR might possibly be related. Such an association might result from either an increased dosage of a nonimprinted gene due to trisomy 7 mosaicism in skin fibroblasts (leading to SRS) and in intestine (leading to HSCR), or from an overexpression, through genomic imprinting, of maternally expressed imprinted allele(s) in skin fibroblasts and intestine or from a combination of trisomy 7 mosaicism and genomic imprinting. This report suggests that the SRS phenotype observed in maternal uniparental disomy 7 (mUPD(7)) patients might also result from an undetected low level of trisomy 7 mosaicism. In order to validate this hypothesis, we propose to perform a conventional and molecular cytogenetic analysis in different tissues every time mUPD7 is displayed.

Adult↗
PubMed2005

Clinical outcome and follow-up of the first reported case of Russell-Silver syndrome with the unique combination of maternal uniparental heterodisomy 7 and mosaic trisomy 7.

BACKGROUND: Russell-Silver syndrome (RSS) has been associated with maternal uniparental disomy (UPD) for chromosome 7 although the etiology of the syndrome is still unknown. Cases of RSS associated with maternal UPD7 have involved isodisomies, heterodisomies, and mixed isodisomy with heterodisomy simultaneously. This publication is a follow-up report of the postnatal clinical outcome of the first prenatally suspected case of combined mosaic trisomy 7 with maternal uniparental disomy of chromosome 7 (UPD7). CASE: The diagnosis of RSS in the proband was suspected prenatally because trisomy 7 mosaicism (47,XX,+7[13]/46,XX[19]) and maternal uniparental heterodisomy 7 were both found in amniotic fluid cells. Cord blood karyotype analysis showed only disomic cells (46,XX[50]), whereas postpartum chorionic villus analysis was completely trisomic for chromosome 7 (47,XX,+7[19]). Postnatally, the diagnosis of RSS was confirmed by physical findings, her trisomy 7 mosaicism was confirmed by cytogenetic analysis of her skin biopsy (47,XX,+7[9]/46,XX[20]) and her UPD7 was confirmed on both peripheral blood and skin biopsy using microsatellite markers. During infancy, the proband experienced growth deficiency, persistent hypoglycemia, and psychomotor developmental delay. CONCLUSIONS: Trisomic rescue as a life-saving mechanism, with subsequent chromosomal mosaicism in combination with UPD may occur more frequently in RSS than has been reported. Systematic testing of cases suspected prenatally or postnatally would be informative regarding the individual contribution of each factor. Imprinting, loss of heterozygosity for recessive genes, and mosaicism may explain the short stature, asymmetry, and the variable expression of the phenotype. The contribution of these mechanisms to the syndrome should be evaluated in these cases.

Chromosomes, Human, Pair 7↗
PubMed2002

Imprinting of a small nucleolar RNA gene on mouse chromosome 12.

We have identified a novel, maternally expressed imprinted gene encoding a C/D-box small nucleolar RNA (snoRNA) called MBII-343, which may regulate RNA editing or alternative splicing of an as yet unknown target gene. This gene is closely linked to an imprinted gene, Meg3, on mouse distal chromosome 12, which is syntenic to human chromosome 14. The paternal duplication of mouse distal chromosome 12 leads to late embryonal/neonatal lethality, growth promotion, and cardiomyopathy, whereas maternal duplication leads to late embryonal lethality and growth retardation. Human paternal uniparental disomy for chromosome 14 leads to musculoskeletal problems and mental retardation, whereas maternal uniparental disomy leads to intrauterine growth retardation, motor developmental delay, premature puberty, hypotonia, joint laxity, macrocephaly, short statue, neonatal poor sucking, skill with jigsaw puzzles, skin picking, obesity, and maturity onset diabetes of the young.

Animals↗
PubMed1998

Maternal disomy and Prader-Willi syndrome consistent with gamete complementation in a case of familial translocation (3;15) (p25;q11.2).

Maternal uniparental disomy (UPD) for chromosome 15 is responsible for an estimated 30% of cases of Prader-Willi syndrome (PWS). We report on an unusual case of maternal disomy 15 in PWS that is most consistent with adjacent-1 segregation of a paternal t(3;15)(p25;q11.2) with simultaneous maternal meiotic nondisjunction for chromosome 15. The patient (J.B.), a 17-year-old white male with PWS, was found to have 47 chromosomes with a supernumerary, paternal der(15) consisting of the short arm and the proximal long arm of chromosome 15, and distal chromosome arm 3p. The t(3;15) was present in the balanced state in the patient's father and a sister. Fluorescent in situ hybridization analysis demonstrated that the PWS critical region resided on the derivative chromosome 3 and that there was no deletion of the PWS region on the normal pair of 15s present in J.B. Methylation analysis at exon alpha of the small nuclear ribonucleoprotein-associated polypeptide N (SNRPN) gene showed a pattern characteristic of only the maternal chromosome 15 in J.B. Maternal disomy was confirmed by polymerase chain reaction analysis of microsatellite repeats at the gamma-aminobutyric acid receptor beta3 subunit (GABRB3) locus. A niece (B.B.) with 45 chromosomes and the derivative 3 but without the der(15) demonstrated a phenotype consistent with that reported for haploinsufficiency of distal 3 p. Uniparental disomy associated with unbalanced segregation of non-Robertsonian translocations has been reported previously but has not, to our knowledge, been observed in a case of PWS. Furthermore, our findings are best interpreted as true gamete complementation resulting in maternal UPD 15 and PWS.

Adolescent↗
PubMed2002

Paternal UPD14 is responsible for a distinctive malformation complex.

We present a boy and two girls with paternal uniparental disomy of chromosome 14q (patUPD14). One girl had a Robertsonian translocation, whereas two a normal karyotype. Based on the manifestations of these patients and four previously reported patients who all had translocated chromosome 14, The patUPD14 was thought to constitute a distinctive syndrome. The hallmarks included abdominal muscular defects, skeletal anomalies, and characteristic facies. The phenotype of patUPD14 was consistent with that of a previously reported mouse model, i.e., mouse embryos with paternal uniparental disomy of chromosome 12 that has a region orthologous to that of human chromosome 14. Dose effects of newly recognized imprinted genes on human chromosome 14q32, DLK1 and GTL2, could play an important role in the pathogenic mechanism of the distinctive malformation complex.

Abnormalities, Multiple↗
PubMed2005

Prader-Willi syndrome with a karyotype 47,XY,+min(15)(pter->q11.1:) and maternal UPD 15--case report plus review of similar cases.

Prader-Willi (PWS) and Angelman (AS) are syndromes of developmental impairment that can result either from a 15q11-q13 deletion, paternal uniparental disomy (UPD), imprinting, or UBE3A mutations. A small cytogenetic subset of PWS and AS patients are carriers of a so-called small supernumerary marker chromosome (sSMC). Here, we report on an previously unreported PWS case with a karyotype 47,XY,+min(15)(pter->q11.1:) plus maternal heterodisomic UPD 15. A review of the literature revealed, that for both, PWS and AS patients, cases with (1) a sSMC plus microdeletion of the PWS/AS critical region, (2) inv dup(15) plus uniparental disomy (UPD) 15 and (3) cases without exclusion of a microdeletion an UBE3A mutation or UPD are described. The present case as well as the review of similar cases provides further evidence for the necessity to test UPD in prenatal cases with a de novo sSMC and in postnatal cases with otherwise unexplainable clinical phenotype.

Angelman Syndrome↗
PubMed2005

Trisomy 20 mosaicism caused by a maternal meiosis II error is associated with normal intellect but multiple congenital anomalies.

Mosaicism for trisomy 20 is generally ascertained following prenatal sampling and rarely is associated with significant phenotypic abnormalities. Uniparental disomy for chromosome 20 in the euploid lines has been found in several cases, which showed relatively mild clinical features, primarily growth delay. Here we report on a case of mosaic trisomy 20 in a child with normal neurologic development who was ascertained because of multiple physical anomalies including spinal segmentation anomalies and altered skin pigmentation. Trisomic cells were found in buccal epithelial cells and in cultured skin fibroblasts but not in peripheral blood. Molecular analysis of blood cells, fibroblasts, and parental cells gave evidence of a maternal meiosis II error as the cause of the trisomy. Disomic cells presumably arose through trisomy rescue, and no evidence was found for uniparental disomy in these cells.

Abnormalities, Multiple↗
PubMed2006

Body composition and fatness patterns in Prader-Willi syndrome: comparison with simple obesity.

OBJECTIVE: To characterize the body composition of Prader-Willi syndrome (PWS) subjects and compare with simple obesity. RESEARCH METHODS AND PROCEDURES: Seventy-two individuals (27 PWS deletion, 21 PWS uniparental disomy, and 24 obese controls) 10 to 49 years old were studied with the use of DXA. Body composition measures were obtained, and regional fat and lean mass patterns were characterized. Significant differences were assessed with Student's t test and ANOVA adjusting for age, gender, and BMI. RESULTS: Significant differences between the PWS and obese groups were found for lean measures of the arms, legs, and trunk. Total lean mass was significantly lower in PWS than in obese subjects for arms, trunk, and especially legs. Furthermore, two body regions (legs and trunk) showed significant differences for fat and lean measures between PWS and obese males. However, significant differences between PWS and obese females for these measures were found only for the legs. No significant differences were identified between PWS deletion and uniparental disomy subjects. DISCUSSION: Our results demonstrate that PWS individuals do, in fact, have an unusual body composition and fatness patterns, characterized by reduced lean tissue and increased adiposity, with PWS males contributing most with fat patterns more similar to females.

Absorptiometry, Photon↗
PubMed1997

UBE3A/E6-AP mutations cause Angelman syndrome.

Angelman syndrome (AS), characterized by mental retardation, seizures, frequent smiling and laughter, and abnormal gait, is one of the best examples of human disease in which genetic imprinting plays a role. In about 70% of cases, AS is caused by de novo maternal deletions at 15q11-q13 (ref. 2). Approximately 2% of AS cases are caused by paternal uniparental disomy (UPD) of chromosome 15 (ref. 3) and 2-3% are caused by "imprinting mutations'. In the remaining 25% of AS cases, no deletion, uniparental disomy (UPD), or methylation abnormality is detectable, and these cases, unlike deletions or UPD, can be familial. These cases are likely to result from mutations in a gene that is expressed either exclusively or preferentially from the maternal chromosome 15. We have found that a 15q inversion inherited by an AS child from her normal mother disrupts the 5' end of the UBE3A (E6-AP) gene, the product of which functions in protein ubiquitination. We have looked for novel UBE3A mutations in nondeletion/non-UPD/non-imprinting mutation (NDUI) AS patients and have found one patient who is heterozygous for a 5-bp de novo tandem duplication. We have also found in two brothers a heterozygous mutation, an A to G transition that creates a new 3' splice junction 7 bp upstream from the normal splice junction. Both mutations are predicted to cause a frameshift and premature termination of translation. Our results demonstrate that UBE3A mutations are one cause of AS and indicate a possible abnormality in ubiquitin-mediated protein degradation during brain development in this disease.

Amino Acid Sequence↗
PubMed1999

The search for the gene for Silver-Russell syndrome.

Patients with Silver-Russell syndrome display intrauterine growth restriction and other dysmorphic features. No single genetic cause for this syndrome has been found, although there are a small number of familial cases and some patients with chromosomal rearrangements. Maternal uniparental disomy of chromosome 7 has been found in approximately 7% of patients with Silver-Russell syndrome. In five of these patients exhibiting maternal uniparental disomy, no common regions of isodisomy were found, thereby ruling out the expression of a recessive allele. It is most likely that one or more imprinted genes are responsible for the phenotype of Silver-Russell syndrome. Human chromosome 7 demonstrates homology with two imprinted regions on mouse chromosomes 6 and 11, which are equivalent to human chromosome regions 7q32 and 7p11-p13, respectively. We directly analysed the imprinting status of candidate genes from chromosome 7 that mapped to homologous imprinted regions in the mouse and also had a potential role in growth. The candidates were the genes that encode the epidermal growth factor receptor and the insulin-like growth factor binding proteins-1 and -3. All three of these candidate genes are localized to chromosome region 7p11-p13. Using intragenic polymorphisms as markers, we found that all three genes showed biallelic expression in different fetal tissues. Therefore, it is unlikely that these candidate genes are directly involved in producing the phenotype of Silver-Russell syndrome. Other candidates are under analysis, including two newly identified genes that are known to be imprinted.

Abnormalities, Multiple↗
PubMed2005

[Clinical, genetic and molecular features in 45 patients with Prader-Willi syndrome].

BACKGROUND: Prader-Willi syndrome (PWS) is a neurogenetic disease characterized by neonatal hypotonia, retarded mental and motor development, hypogonadism, hyperphagia, morbid obesity and dysmorphic facial features. It has an incidence of 1:12.000-15.000 newborns and is caused by abnormalities in genes located in 15q11q13. PWS is one of the most frequent genetic disorders and microdeletion syndromes. It is also the most common cause of obesity from genetic origin and it was the first disease in which imprinting and uniparental disomy were recognized as cause of genetic disorders. Seventy to seventy five percent of PWS cases are due to 15q11q13 deletions, 20-25% to uniparental disomy and 1% to mutations in the imprinting center. AIM: To analyze the clinical, genetic and molecular features of patients with PWS, seen at one institution. PATIENTS AND METHODS: Retrospective review of 45 patients (27 males) with PWS seen at the Genetics Outpatient Clinic at INTA. RESULTS: Twenty three (51.1%) patients had a deletion, 13 (28.9%) patients did not have a deletion. In nine patients, fluorescence in situ hybridization (FISH) study was not performed, therefore the presence of deletion was unknown. The clinical score was 8 points for patients younger than 3 years (n=11) and 11.5 points for patients older than 3 years (n=34); for patients aged 12 months or less, the clinical score was 7 points. Mean clinical score was 11 points for patients with deletion and 10 points for patients without deletion. CONCLUSIONS: Most patients with PWS have a deletion; the phenotype depends on age and the clinical score is useful for Chilean patients with PWS.

Adolescent↗
PubMed1996

Comprehensive 4-year follow-up on a case of maternal heterodisomy for chromosome 16.

Uniparental disomy for chromosome 16 has been previously identified in fetal deaths and newborn infants with limited follow-up. Thus there is a lack of information about the long-term effects of maternal uniparental disomy 16 on growth and development. We present a case of maternal heterodisomy for chromosome 16 and a comprehensive 4-year physical and cognitive evaluation. Cytogenetic analysis of chorionic villus obtained at 10 weeks gestation for advanced maternal age showed trisomy 16. At 15 weeks, amniocentesis demonstrated low level mosaicism 47,XY,+16[1]/46,XY[25]. Decreased fetal growth was noted in the last 2 months of pregnancy and the infant was small for gestational age at birth. Molecular studies revealed only maternal alleles for chromosome 16 in a peripheral blood sample from the child, consistent with maternal uniparental heterodisomy 16. Although short stature remains a concern, there appears to be no major cognitive effects of maternal disomy 16. Clinical evaluation and follow-up on additional cases should further clarify the role of placental mosaicism and maternal disomy 16 in intrauterine growth retardation and its effects on long-term growth in childhood.

Abnormalities, Multiple↗
PubMedDate not supplied

Linkage analysis between manic-depressive illness and the region on chromosome 15q involved in Prader-Willi syndrome, including two GABAA receptor subtype genes.

Cooccurrence of Prader-Willi syndrome and psychosis has been reported in a few cases. Prader-Willi syndrome is most often associated with interstitial deletion or uniparental disomy of chromosome 15q11-q13. The cooccurrence of Prader-Willi syndrome and psychosis may thus be due to deletion of, or in the case of uniparental disomy, duplication of a gene involved in the etiology of psychosis, possibly manic-depressive illness localized in this region. The region contains two assumed candidate genes for manic-depressive illness, the alpha 5 and beta 3 subunits of the gamma-aminobutyric acid (GABA)A receptor. This study investigates linkage between manic-depressive illness and this region. Furthermore, an additional case with Prader-Willi syndrome and psychosis is briefly described. No evidence of linkage was found assuming dominant or recessive modes of inheritance. Linkage to the GABAA receptor subunits was excluded assuming a dominant mode of transmission for all models, and to the proximal part of the chromosome 15q11-q13 region for broader phenotypic models. Negative though largely inconclusive lod scores were obtained assuming a recessive mode of transmission; however close linkage to the beta 3 subtype of the GABAA receptor was excluded.

Adult↗
PubMed1997

Mosaic trisomy 22: a case presentation and literature review of trisomy 22 phenotypes.

In a case of mosaic trisomy 22 the trisomic cells were detected primarily in fibroblasts. Results of initial lymphocyte chromosome analysis were normal. However, mosaicism was suspected because the patient had hypomelanosis of Ito, hemiatrophy, failure to thrive, and mental retardation. Mosaicism was confirmed in cultured fibroblasts. Repeat cytogenetic analysis of peripheral blood demonstrated a low level of trisomic metaphase cells, which was confirmed by interphase fluorescent in situ hybridization (FISH) analysis. Molecular studies supported maternal disomy in the child's disomic cells. The phenotype of this condition overlaps that of non-mosaic trisomy 22 chromosome mosaicism in general and to some extent the Ullrich-Turner syndrome phenotype. Improved cytogenetic and molecular techniques now allow better delineation of aneuploidy syndromes. Molecular and FISH studies added information about this case (mosaicism and uniparental disomy) not appreciated by routine cytogenetic analysis of lymphocytes. The detection of low-level mosaicism and/or uniparental disomy in such cases may change the clinical classification and our understanding of pathogenesis and recurrence risk of these disorders.

Adult↗
PubMed2000

[Detection of Prader-Willi syndrome by methylation-specific PCR].

OBJECTIVE: Using a faster and more efficient method to diagnose Prader-Willi syndrome(PWS). METHODS: Differential DNA methylation at several sites in the PWS critical region where the maternal homologue is unmethylated and transcriptionally active. Methylation-specific PCR(MSPCR) is based on sodium bisulfite treatment of DNA, which converts unmethylated but not methylated cytosine residues to uracil, and PCR primers specific for the maternal and the paternal allele. Methylation analysis by Southern blot is made to validate the MSPCR result. RESULTS: Bisulfite-modified DNA from PWS patients amplified only with methylated allele-specific primer pair showed only maternal 174bp PCR product. MSPCR and PW71B methylation studies showed an abnormal pattern consistent with the clinical diagnosis of PWS. Untreated DNA does not produce a PCR product. CONCLUSION: MSPCR can be used to detect all presently testable causes of PWS (deletion, uniparental disomy, and imprinting mutation) in an efficient first step for stepwise diagnostic testing, compared with either Southern blot analysis which is more timeconsuming, or fluorescence in situ hybridization(FISH) which can not detect uniparental disomy or imprinting mutation.

Adolescent↗
PubMed1992

Differential expression of insulin-like growth factors I and II (IGF I and II), mRNA, peptide and binding protein 1 during mouse palate development: comparison with TGF beta peptide distribution.

Development of the mammalian secondary palate involves a series of epithelial mesenchymal interactions: during one of these, a mesenchymal signal specifies regionally distinct palatal epithelial differentiation. Extracellular matrix molecules and soluble growth factors may be involved in this signalling process. In this study, we have mapped the expression of the genes for insulin-like growth factors (IGF I and II), the peptides they encode, and the IGF binding protein 1 (IGF BP-1) during murine palatogenesis (embryonic days (E) 12-15). IGF-I gene expression was below detectable levels in the craniofacial region at all ages. IGF-I peptide was at the threshold of immunocytochemical detection and widely distributed in the palatal mesenchyme, decreasing in staining intensity from E12 to E14. By contrast, IGF-II mRNA was intensely localised in several tissues. IGF-II gene expression within the forming palate was developmentally regulated. In the vertical palatal shelves (E12 to E13) IGF-II gene expression was absent. On early E14, in the horizontal prefusion palate, significant expression was present in the palatal mesenchyme, but not the epithelium. Once palatal fusion had occurred, mesenchymal expression fell rapidly to undetectable levels. IGF-II mRNA was next detectable in the secondary palate on late E15 at sites of membranous bone formation. By contrast to the mRNA distribution, IGF-II peptide was localised predominantly in the palatal epithelia (particularly the nasal and medial edge epithelia) but also in the mesenchyme of the E14 prefusion palate. Significantly, the IGF binding protein had a similar distribution pattern to the IGF-II peptide. At all ages, the developing tongue myotubes labelled heavily for IGF-II mRNA, protein and binding protein. These data suggest that IGF-II may play a localised paracrine role during murine palatogenesis, perhaps in the mesenchymal signalling of epithelial differentiation. IGF-II may also serve to coordinate the development of the tongue and palate. The distribution of IGF-II peptide was very similar to that of TGF-beta, suggesting a possible interactive role of these growth factors during palate development. Finally, evidence that the IGF-II gene is imprinted (Ferguson-Smith et al. 1991) and may be the target for uniparental disomy in the human Beckwith Wiedemann syndrome (Henry et al. 1991), which is characterised by the overgrowth of tissues (especially the tongue) expressing IGF II in the embryo, indicates the necessity of reanalysing human cleft palate families for disruption (including uniparental disomy) of the genes encoding IGFs, their receptors and binding proteins.

Animals↗
PubMed1993

Detection of cryptic chromosomal abnormalities in unexplained mental retardation: a general strategy using hypervariable subtelomeric DNA polymorphisms.

Given the availability of DNA from both parents, unusual segregation of hypervariable DNA polymorphisms (HVPs) in the offspring may be attributable to deletion, unbalanced chromosomal translocation, or uniparental disomy. The telomeric regions of chromosomes are rich in both genes and hypervariable minisatellite sequences and may also be particularly prone to cryptic breakage events. Here I describe and analyze a general approach to the detection of subtelomeric abnormalities and uniparental disomy in patients with unexplained mental retardation. With 29 available polymorphic systems, approximately 50%-70% of these abnormalities could currently be detected. Development of subtelomeric HVPs physically localized with respect to their telomeres should provide a valuable resource in routine diagnostics.

Chromosome Aberrations↗