The contribution of uniparental disomy to congenital development defects in children born to mothers at advanced childbearing age

Most instances of maternal uniparental disomy (UPD) start as trisomies and, similar to the latter, show a significant increase of mean maternal age at delivery. To investigate the incidence of UPD in offspring of older mothers, we investigated two groups of patients: 1) 50 patients with unclassified developmental defects born to mothers 35 years or older at delivery were tested for UPD for all autosomes by means of microsatellite marker analysis; 2) The incidence of UPD versus other etiologies in correlation, with maternal age below versus 35 years and above at delivery was studied in patients investigated in our laboratory for maternal UPD 15 (Prader-Willi syndrome, PWS), paternal UPD 15 (Angelman syndrome, AS), and maternal UPD 7 (Silver-Russell syndrome, SRS). In group 1, four patients of 50 showed UPD for an autosome that clarified the etiology of their developmental problems: a 27-year-old woman with growth retardation and early puberty disclosed maternal heterodisomy 14; a 15-year-old girl revealed paternal isodisomy 15; a 6-year-old boy with suspected Smith-Lemli-Opitz syndrome was shown to have maternal heterodisomy 16 with additional mosaic partial trisomy 16(pter-p13); a 16-month-old girl with intrauterine growth retardation and a dysmorphic pattern revealed maternal heterodisomy 7. In group 2 the offspring of older mothers showed a clear increase of UPD compared with the mothers below 35 years at delivery. The binomial distribution gave P-values of 1.9 x 10(-10), 2.6 x 10(-4), and 0.01 for PWS, AS, and SRS, respectively. The correlation between increase of paternal UPD 15 with advanced maternal age might be explained by maternal non-disjunction leading to hypohaploid gamete (nullisomy) for chromosome 15 with subsequent or concomitant duplication of the paternal homologue (paternal isodisomy). The three UPD 15 AS cases with mothers older than 35 years at delivery revealed isodisomy, whereas the three cases from younger mothers showed heterodisomy. This study confirms the hypothesis that uniparental disomy is a not negligible cause of congenital developmental anomalies in children of older mothers.     

Uniparental disomy of multiple chromosomes in two cases with a complex phenotype

Uniparental disomy (UPD) is the inheritance of both chromosomal homologs from one parent. Depending on the chromosome involved and the parental origin, UPD may result in phenotypic abnormalities due to aberrant methylation patterns or unmasking recessive conditions in isodisomic regions. UPD primarily originates from somatic rescue of a single meiotically-derived aneuploidy, most commonly a trisomy. Double UPD is exceedingly rare and triple UPD has not been previously described. Here, we report two unrelated clinical cases with UPD of multiple chromosomes; an 8-month-old male with maternal isodisomy of chromosome 7 and paternal isodisomy of chromosome 9, and a 4-week-old female with mixed paternal UPD for chromosomes 4, 10, and 14. These cases also demonstrate that although extremely rare, the detection of AOH on two or more chromosomes may warrant additional clinical and laboratory investigation such as methylation and STR marker analysis, especially when involving chromosomes known to be associated with imprinting disorders.     

Origin of uniparental disomy 15 in patients with Prader-Willi or Angelman syndrome

Maternal uniparental disomy (UPD) accounts for approximately 25% of Prader-Willi patients (PWS) and paternal UPD for about 2-5% of Angelman syndrome (AS) patients. These findings and the parental origin of deletions are evidence of genomic imprinting in the cause of PWS and AS. The natural occurrence of UPD individuals allows the study of meiotic mechanisms resulting in chromosomal nondisjunction (ND). We selected patients with UPD15 from our sample of 30 PWS and 40 AS patients to study the origin of ND and the recombination along chromosome 15. These patients were analyzed with 10 microsatellites throughout the entire chromosome 15 (D15S541, D15S542, D15S11, D15S113, GABRB3, CYP19, D15S117, D15S131, D15S984, D15S115). The analysis disclosed seven heterodisomic PWS cases originating by meiosis I (MI) ND (four showed recombination and three no recombination), and one isodisomic PWS UPD15 originating by postzygotic duplication. Among the five paternal UPD15, we detected four isodisomies, three of which showed homozigosity for all markers, corresponding to a mitotic error, and one case originating from a paternal MII ND. Our results indicate that besides maternal MI and MII ND, paternal ND occurs when a PWS UPD15 patient originates from mitotic duplication of the maternal chromosome 15. ND events in AS are mainly due to mitotic errors, but paternal MII ND can occur and give origin to an AS UPD15 individual by two different mechanisms: rescue of a trisomic fetus or fertilization of a nullisomic egg with the disomic sperm, and in this case paternal and maternal ND are necessary.     

Origin of uniparental disomy 15 in patients with Prader‐Willi or Angelman syndrome

Maternal uniparental disomy (UPD) accounts for ∼25% of Prader‐Willi patients (PWS) and paternal UPD for about 2–5% of Angelman syndrome (AS) patients. These findings and the parental origin of deletions are evidence of genomic imprinting in the cause of PWS and AS. The natural occurrence of UPD individuals allows the study of meiotic mechanisms resulting in chromosomal nondisjunction (ND). We selected patients with UPD15 from our sample of 30 PWS and 40 AS patients to study the origin of ND and the recombination along chromosome 15. These patients were analyzed with 10 microsatellites throughout the entire chromosome 15 (D15S541, D15S542, D15S11, D15S113, GABRB3, CYP19, D15S117, D15S131, D15S984, D15S115). The analysis disclosed seven heterodisomic PWS cases originating by meiosis I (MI) ND (four showed recombination and three no recombination), and one isodisomic PWS UPD15 originating by postzygotic duplication. Among the five paternal UPD15, we detected four isodisomies, three of which showed homozigosity for all markers, corresponding to a mitotic error, and one case originating from a paternal MII ND. Our results indicate that besides maternal MI and MII ND, paternal ND occurs when a PWS UPD15 patient originates from mitotic duplication of the maternal chromosome 15. ND events in AS are mainly due to mitotic errors, but paternal MII ND can occur and give origin to an AS UPD15 individual by two different mechanisms: rescue of a trisomic fetus or fertilization of a nullisomic egg with the disomic sperm, and in this case paternal and maternal ND are necessary. Am. J. Med. Genet. 94:249–253, 2000. © 2000 Wiley‐Liss, Inc.     

Paternal nondisjunction in trisomy 21: excess of male patients

Paternal nondisjunction accounts for approximately 5% of casesof 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 thelong arm of chromosome 21. Fifteen of the paternal cases wereconsistent with melosis II errors, 8 with mitotic errors andonly 7 with melosis I nondisjunction. This contrasts markedlywith maternally derived trisomy 21, in which meiosis I errorspredominate. An excess of males was observed in the meloticcases (21 maies:6 females), highly significantly different froma 1.06 ratio. A significant difference in mean maternal agewas found between cases of paternal origin (28.1 years) andthose of maternal origin (31.8 years, n=429). This indicatesthat the maternal age effect is confined to maternal nondisjunction.     

Segmental maternal heterodisomy of the proximal part of chromosome 15 in an infant with Prader-Willi syndrome

Uniparental disomy (UPD) 15, detected in patients with Prader-Willi (PWS) and Angelman syndromes, has to date always involved the entire chromosome 15. We report the first case of segmental maternal uniparental heterodisomy confined to a proximal part of chromosome 15 in a child with clinical features of PWS. This unusual finding can be explained by the rare combination of three consecutive events: a trisomy 15 zygote caused by a maternal meiosis I error, early postzygotic mitotic recombination between maternal and paternal chromatids, and, finally, trisomy rescue by the loss of the rearranged chromosome 15 containing the paternal 15q11-q13 segment.     

Investigation of two cases of paternal disomy 13 suggests timing of isochromosome formation and mechanisms leading to uniparental disomy

Uniparental disomy (UPD) is the abnormal inheritance of two copies of a chromosome from the same parent. Possible mechanisms for UPD include trisomy rescue, monosomy rescue, gametic complementation, and somatic recombination. Most of these mechanisms can involve rearranged chromosomes, particularly isochromosomes and Robertsonian translocations. Both maternal and paternal UPD have been reported for most of the acrocentric chromosomes. However, only UPD for chromosomes 14 and 15 show an apparent imprinting effect. Herein, we present two cases of paternal UPD 13 involving isochromosomes. Both cases were referred for UPD studies due to the formation of a de novo rea(13q13q). Case 2 was complicated by the segregation of a familial rob(13q14q) of maternal origin. Both propositi were phenotypically normal at the time of examination. Polymorphic marker analysis in Case 1 showed the distribution of alleles of markers along chromosome 13 to be complete isodisomy, consistent with an isochromosome. This rearrangement could have occurred either meiotically, without recombination, or mitotically. A likely mechanism for UPD in this case is monosomy rescue, through postzygotic formation of the isochromosome. In Case 2 the distribution of proximal alleles indicated an isochromosome, but recombination was evident. Thus, this isochromosome must have formed prior to or during meiosis I. A likely mechanism for UPD in this case is gametic complementation, since the mother carries a rob(13q14q) and is at risk of producing aneuploid gametes. However, trisomy rescue of a trisomy 13 conceptus cannot be completely excluded. Given that both cases were phenotypically normal, these data further support that paternal UPD 13 does not have an adverse phenotypic outcome and, thus, does not show an apparent imprinting effect.     

Multiplex PCR of three dinucleotide repeats in the Prader-Willi/Angelman critical region (15q11-q13): molecular diagnosis and mechanism of uniparental disomy

Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are distinctmental retardation disorders caused by a deficiency of paternal(PWS) or maternal (AS) contributions for chromosome 15 by eitherdeletion or uniparental disomy (UPD). To further study the molecularmechanisms involved in these disorders and to improve moleculardiagnostic methods, we have isolated three dinucleotide repeatmarkers in the PWS/AS critical region. An Alu-CA PCR methodwas used to isolate CA-repeat markers directly from yeast artificialchromosome (YAC) clones identified by probes IR4–3R (D15S11),LS6–1 (D15S113), and GABA_A receptor B3 (GABRB3). Threemarkers with 6–11 alleles and 73–83% heterozygositieswere identified and analyzed by multiplex PCR. Gene-centromeremapping was performed on a panel of ovarian teratomas of knownmeiotic origin, and showed the most proximal marker, IR4–3R,to be 13 cM (95% confidence limits: 7–19 cM) from thecentromere of chromosome 15. Molecular diagnostic studies wereperformed on 20 PWS and 9 AS patients. In 17 patients with deletions,the parental origin of deletion was determined. Ten PWS patientswere shown to have maternal heterodisomy. Since these markersare only 13 cM from the centromere, heterodisomy indicates thatmaternal meiosis I nondisjunction is involved in the originof UPD. In contrast, two paternal disomy cases of AS showedisodisomy for all markers tested along the length of chromosome15. This suggests a paternal meiosis II nondisjunction event(without crossing over) or, more likely, monosomic conception(due to maternal nondisjunction) followed by chromosome duplication.This latter mechanism would indicate that UPD in PWS and ASmay initiate as reciprocal products of maternal nondisjunctionevents.     

Third Prader-Willi syndrome phenotype due to maternal uniparental disomy 15 with mosaic trisomy 15

We report on a boy with mosaicism for trisomy 15 and Prader-Willi syndrome (PWS) due to maternal isodisomy for chromosome 15. His phenotype is consistent with PWS and trisomy 15 mosaicism. Although our patient is unusual in having maternal isodisomy rather than the more common maternal heterodisomy, we think that his more severe PWS phenotype is due to his trisomy 15 mosaicism rather than to homozygosity for deleterious chromosome 15 genes. We propose that individuals with PWS have one of three similar but distinctive phenotypes depending on the cause of their condition. Patients with paternal deletions have the typical PWS phenotype, patients with maternal UPD have a slightly milder phenotype with better cognitive function, and those with maternal UPD and mosaic trisomy 15 have the most severe phenotype with a high incidence of congenital heart disease. These phenotype-genotype differences are useful to guide the work-up of patients with suspected PWS and to provide prognostic counseling for families.     

Fumarase deficiency caused by homozygous P131R mutation and paternal partial isodisomy of chromosome 1

We report on the first case of fumarase deficiency (FD) caused by uniparental isodisomy. An affected patient was found to be homozygous for the P131R mutation in the FH gene. In this nonconsanguineous family, the unaffected father was found to be heterozygous for the same mutation, and the mother was found to be homozygous wild-type. Analysis of chromosome 1 markers showed that the patient inherited both paternal alleles with complete absence of the maternal homolog. The two copies of the paternal chromosome 1 are heterodisomic for most of the chromosome except the distal 1q region which is isodisomic for the mutant alleles of the FH gene. The genotypes of other chromosome markers are consistent with the patient inheriting alleles from both parents. Although FD is an autosomal recessive disorder, the effects of uniparental disomy (UPD) should be considered in genetic counseling since the recurrence risk of an affected child is significantly reduced when the disorder is due to UPD.     

Third Prader‐Willi syndrome phenotype due to maternal uniparental disomy 15 with mosaic trisomy 15

We report on a boy with mosaicism for trisomy 15 and Prader‐Willi syndrome (PWS) due to maternal isodisomy for chromosome 15. His phenotype is consistent with PWS and trisomy 15 mosaicism. Although our patient is unusual in having maternal isodisomy rather than the more common maternal heterodisomy, we think that his more severe PWS phenotype is due to his trisomy 15 mosaicism rather than to homozygosity for deleterious chromosome 15 genes. We propose that individuals with PWS have one of three similar but distinctive phenotypes depending on the cause of their condition. Patients with paternal deletions have the typical PWS phenotype, patients with maternal UPD have a slightly milder phenotype with better cognitive function, and those with maternal UPD and mosaic trisomy 15 have the most severe phenotype with a high incidence of congenital heart disease. These phenotype–genotype differences are useful to guide the work‐up of patients with suspected PWS and to provide prognostic counseling for families. Am. J. Med. Genet. 93:215–218, 2000. © 2000 Wiley‐Liss, Inc.     

A clinical, cytogenetic, and molecular study of 40 adults with the Prader-Willi syndrome.

A clinical, cytogenetic, and molecular study has been carried out on 40 adults with a firm diagnosis of Prader-Willi syndrome. A cytogenetically detectable deletion was observed in 58% while further subjects had a deletion which was detectable by molecular methods only, giving a total of 76%. Four cases of maternal uniparental disomy (UPD) were all female. Three of them were heterodisomic while the fourth was isodisomic. Two male probands were heterozygous at all loci tested yet did not have UPD. Although methylation studies showed that one of them had a single band using probe PW71, the other one had two bands. Psychiatric studies suggest that females with maternal UPD are indistinguishable psychologically from those with a paternal deletion in 15q11q13.     

Somatic segregation errors predominantly contribute to the gain or loss of a paternal chromosome leading to uniparental disomy for chromosome 15

Paternal uniparental disomy (UPD) for chromosome 15 (UPD15), which is found in approximately 2% of Angelman syndrome (AS) patients, is much less frequent than maternal UPD15, which is found in 25% of Prader-Willi syndrome patients. Such a difference cannot be easily accounted for if 'gamete complementation' is the main mechanism leading to UPD. If we assume that non-disjunction of chromosome 15 in male meiosis is relatively rare, then the gain or loss of the paternal chromosome involved in paternal and maternal UPD15, respectively, may be more likely to result from a post-zygotic rather than a meiotic event. To test this hypothesis, the origin of the extra chromosome 15 was determined in 21 AS patients with paternal UPD15 with a paternal origin of the trisomy. Only 4 of 21 paternal UPD15 cases could be clearly attributed to a meiotic error. Furthermore, significant non-random X-chromosome inactivation (XCI) observed in maternal UPD15 patients (p < 0.001) provides indirect evidence that a post-zygotic error is also typically involved in loss of the paternal chromosome. The mean maternal and paternal ages of 33.4 and 39.4 years, respectively, for paternal UPD15 cases are increased as compared with normal controls. This may be simply the consequence of an age association with maternal non-disjunction leading to nullisomy for chromosome 15 in the oocyte, although the higher paternal age in paternal UPD15 as compared with maternal UPD15 cases is suggestive that paternal age may also play a role in the origin of paternal UPD15.     

Parental age and the origin of extra chromosome 21 in Down syndrome

We present a report of the parental ages (n = 865) and parental origin of meiotic nondisjunction (n = 236) that are likely to show a predisposition in the etiology of Down syndrome (DS). Chromosomal analysis, performed over a 20-year period, on 1001 Down syndrome subjects, revealed pure trisomy 21 karyotype in 880 subjects (87.92%), mosaic trisomy karyotype in 77 (7.69%), and translocation karyotype in 44 (4.39%). The mean maternal age was found to be 30.34 years, and mean paternal age was 31.04 years. Nondisjunctional error was 79.24% maternal and 20.76% paternal. The findings of the study revealed the significant contribution of advanced parental age and increased maternal meiotic nondisjunctional error to the origin of trisomy 21 Down syndrome. Received: December 21, 2000 / Accepted: March 5, 2001     

Low incidence of UPD in spontaneous abortions beyond the 5th gestational week

Approximately 15-20% of all clinically recognised pregnancies abort, most commonly between 8-12 gestational weeks. While the majority of early pregnancy losses is attributed to cytogenetic abnormalities, the aetiology of approximately 40% of early abortions remains unclear. To determine additional factors causing spontaneous abortions we retrospectively searched for uniparental disomies (UPD) in 77 cytogenetically normal diploid spontaneous abortions. In all cases an unbalanced chromosome anomaly was ruled out by cytogenetic investigation of chorionic/amniotic membranes and/or chorionic villi. For UPD screening microsatellite analyses were performed on DNA of abortion specimens and parental blood using highly polymorphic markers showing UPD in two cases. The distribution of markers analysed indicated maternal heterodisomy for chromosome 9 (UPhD(9)mat) in case 1 and paternal isodisomy for chromosome 21 (UPiD(21)pat) in case 2. The originating mechanism suggested was monosomy complementation in UPiD(21)pat and trisomy rescue in UPhD(9)mat. In the case of UPhD(9)mat purulent chorioamnionitis was noted and a distinctly growth retarded embryo of 3 cm crown-rump length showing no gross external malformations. Histological analysis in the case of UPiD(21)pat suggested a primary anlage defect. Our results indicate that less than 3% of genetically unexplained pregnancy wastage is associated with total chromosome UPD. UPD may contribute to anlage defects of human conception. Chromosome aneuploidy correction can occur in very early cleavage stages. More research, however, ought to be performed into placental mosaicism to further clarify timing and mechanisms involved in foetal UPD.     

Uniparental disomy (UPD) other than 15: phenotypes and bibliography updated

Uniparental disomy (UPD) describes the inheritance of a pair of chromosomes from only one parent. The concept was introduced in Medical Genetics by Engel (1980); Am J Med Genet 6:137-143. Aside UPD 15, which is the most frequent one, up to now (February 2005) 197 cases with whole chromosome maternal UPD other than 15 (124 X heterodisomy, 59 X isodisomy, and 14 cases without information of the mode of UPD) and 68 cases with whole chromosome paternal UPD other than 15 (13 X heterdisomy, 53 X isodisomy, and 2 cases without information of the mode of UPD) have been reported. In this review we discuss briefly the problems associated with UPD and provide a comprehensive clinical summary with a bibliography for each UPD other than 15 as a guide for genetic counseling.     

Prenatal and postnatal growth failure associated with maternal heterodisomy for chromosome 7.

The association of maternal uniparental disomy for chromosome 7 and postnatal growth failure has been reported in four cases and suggests the presence of genomic imprinting of one or more growth related genes on chromosome 7. However, in the reported cases, the possibility of homozygosity for a recessive mutation could not be excluded as the cause of the growth failure as in all cases isodisomy rather than heterodisomy for chromosome 7 was present. We report a case of prenatal and postnatal growth retardation associated with a prenatal diagnosis of mosaicism for trisomy 7 confined to the placenta. DNA typing of polymorphic markers on chromosome 7 has established that the zygote originated as a trisomy 7 with two maternal and one paternal chromosomes 7 with subsequent loss of the paternal chromosome resulting in a disomic child with maternal heterodisomy for chromosome 7. The growth failure seen in this child with heterodisomy 7 lends strong support to the hypothesis of imprinted gene(s) on chromosome 7.     

Comparative analysis of isodisomic and heterodisomic segments in cases with maternal uniparental disomy 14 suggests more than one imprinted region

The results of molecular investigations of 21 cases with complete or segmental maternal uniparental disomy (UPD) 14 published in the literature were compared with respect to isodisomic and heterodisomic segments. The aim of the study was to find hints toward imprinted regions other than the recently defined imprinted segment 14q32. Three regions with no isodisomic molecular marker were found. The most distal of these regions located on 14q32.12 and 14q32.13 supports the hypothesis of genomic imprinting as the cause of the maternal UPD 14 phenotype by synteny to the maternally imprinted region on mouse distal chromosome 12 and correlation with the recently defined imprinting cluster on human chromosome 14q32. The other two heterodisomic areas located on 14q11.2-->14q12 and 14q21.1-->14q31.2 are hints toward one or more additional regions of genomic imprinting on human chromosome 14.     

Genome-wide UPD screening in patients with intellectual disability

Uniparental disomy (UPD) describes the inheritance of a pair of chromosomes from only one parent. It may occur as isodisomy, heterodisomy or a combination of both and may involve only chromosome segments. UPD can affect each chromosome. The incidence is estimated to be around 1:3500 in live births. Some parts of chromosomes are subject to ‘parent-of-origin imprinting'' and the phenotypic effect in UPD syndromes is mainly due to functional imbalance of imprinted genes. Isodisomy can result in mutation homozygosity in autosomal-recessive inherited diseases. UPD causes several well-defined imprinting syndromes associated with intellectual disability (ID). Although knowledge on frequency and size of UPDs in patients with unexplained ID remains largely unknown as no efficient genome-wide screening technique was available for detection of both isodisomic and heterodisomic UPDs. SNP microarrays have been proven to be capable to detect UPDs through Mendelian errors. The correct subclassification of UPD requires child–parent trio experiments. To further elucidate the role of UPD in patients with unexplained ID, we analyzed a total of 322 child–parent trios. We were not able to detect UPDs (isodisomies and heterodisomies) within our cohort spanning whole chromosomes or chromosomal segments. We conclude that UPD is rare in patients with unexplained ID.     

X-chromosome inactivation patterns in females with Prader-Willi syndrome

Prader-Willi syndrome (PWS) is a complex neurodevelopmental disorder caused by loss of paternally expressed genes from the 15q11-q13 region generally due to a paternally-derived deletion of the 15q11-q13 region or maternal disomy 15 (UPD). Maternal disomy 15 is usually caused by maternal meiosis I non-disjunction associated with advanced maternal age and after fertilization with a normal sperm leading to trisomy 15, a lethal condition unless trisomy rescue occurs with loss of the paternal chromosome 15. To further characterize the pathogenesis of maternal disomy 15 process in PWS, the status of X-chromosome inactivation was calculated to determine whether non-random skewing of X-inactivation is present indicating a small pool of early embryonic cells. We studied X-chromosome inactivation in 25 females with PWS-UPD, 35 with PWS-deletion, and 50 controls (with similar means, medians, and age ranges) using the polymorphic androgen receptor (AR) gene assay. A significant positive correlation (r = 0.5, P = 0.01) was seen between X-chromosome inactivation and age for only the UPD group. Furthermore, a significantly increased level (P = 0.02) of extreme X-inactivation skewness (>90%) was detected in our PWS-UPD group (24%) compared to controls (4%). This observation could indicate that trisomy 15 occurred at conceptus with trisomy rescue in early pregnancy leading to extreme skewness in several PWS-UPD subjects. Extreme X-inactivation skewness may also lead to additional risks for X-linked recessive disorders in PWS females with UPD and extreme X-chromosome skewness.