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.     

Epigenetic modification and uniparental inheritance of H19 in Beckwith-Wiedemann syndrome.

Beckwith-Wiedemann syndrome (BWS) is a congenital overgrowth syndrome associated with a characteristic pattern of visceromegaly and predisposition to childhood tumours. BWS is a genetically heterogeneous disorder; most cases are sporadic but approximately 15% are familial and a small number of BWS patients have cytogenetic abnormalities involving chromosome 11p15. Genomic imprinting effects have been implicated in familial and non-familial BWS. We have investigated the molecular pathology of 106 sporadic BWS cases; 17% (14/83) of informative cases had uniparental disomy (UPD) for chromosome 11p15.5. In each case UPD appeared to result from a postzygotic event resulting in mosaicism for segmental paternal isodisomy. The critical region for isodisomy was refined to a 25 cM interval between D11S861 and D11S2071 which contained the IGF2, H19, and p57(KIP2) genes. In three cases isodisomy for 11q markers was detected but this did not extend further than 11q13-q21 suggesting that complete chromosome 11 disomy may not produce a BWS phenotype. The allele specific methylation status of the H19 gene was investigated in 80 sporadic BWS cases. All 13 cases with UPD tested displayed hypermethylation consistent with an excess of paternal H19 alleles. In addition, five of 63 (8%) cases with normal biparental inheritance had H19 hypermethylation consistent with an "imprinting centre" mutation (ICM) or "imprinting error" (IE) lesion. The phenotype of patients with putative ICM/IE mutations was variable and overlapped with that of non-UPD sporadic BWS cases with normal H19 methylation. However, exomphalos was significantly (p < 0.05) more common in the latter group. These findings may indicate differential effects on the expression of imprinted genes in chromosome 11p15 according to the precise molecular pathology. Analysis of H19 methylation is useful for the diagnosis of both UPD or altered imprinting in BWS and shows that a variety of molecular mechanisms may cause relaxation of IGF2 imprinting in BWS.     

Paternal uniparental disomy for chromosome 14: A case report and review

Uniparental disomy (UPD) for several chromosomes has been associated with disease phenotypes. Maternal UPD for chromosome 14 has been described and has a characteristic abnormal phenotype. Paternal UPD14 is rare and only three previous cases have been reported. We describe a new case of paternal UPD for chromosome 14 in an infant with a 45,XX,der(13q;14q) karyotype, which was confirmed by molecular analysis. The proposita had findings similar to those of the previous cases of patUPD14 and we conclude that there is a characteristic patUPD14 syndrome most likely due to imprinting effects. Couples with Robertsonian translocations involving chromosome 14 should be counseled as to the possibility of UPD14 and the option of prenatal diagnosis when indicated. Am. J. Med. Genet. 70:74–79, 1997. © 1997 Wiley-Liss, Inc.     

Uniparental isodisomy of chromosome 14 in two cases: An abnormal child and a normal adult

Uniparental disomy (UPD) of a number of different chromosomes has been found in association with abnormal phenotypes. A growing body of evidence for an imprinting effect involving chromosome 14 has been accumulating. We report on a case of paternal UPD of chromosome 14 studied in late gestation due to polyhydramnios and a ventral wall hernia. A prenatal karyotype documented a balanced Robertsonian 14:14 translocation. The baby was born prematurely with hairy forehead, retrognathia, mild puckering of the lips and finger contractures. Hypotonia has persisted since birth and at age one year, a tracheostomy for laryngomalacia and gastrostomy for feeding remain necessary. Absence of maternal VNTR polymorphisms and homozygosity of paternal polymorphisms using chromosome 14 specific probes at D14S22 and D14S13 loci indicated paternal uniparental isodisomy (pUPID). Parental chromosomes were normal. We also report on a case of maternal UPD in a normal patient with a balanced Robertsonian 14:14 translocation and a history of multiple miscarriages. Five previous reports of chromosome 14 UPD suggest that an adverse developmental effect may be more severe whenever the UPD is paternal in origin. This is the second reported patient with paternal UPD and the fifth reported with maternal UPD, and only few phenotypic similarities are apparent. Examination of these chromosome 14 UPD cases of maternal and paternal origin suggests that there are syndromic imprinting effects. © 1995 Wiley-Liss, Inc.     

Short-limb dwarfism and hypertrophic cardiomyopathy in a patient with paternal isodisomy 14: 45,XY,idic(14)(p11)

Uniparental disomy (UPD) has been shown to result in specific disorders either due to imprinting and/or homozygosity of mutant alleles. Here we present the findings in a child with paternal UPD14. Ultrasound evaluation was performed at 30 weeks of gestation because of abnormally large uterine size. Pertinent ultrasound findings included polyhydramnios, short limbs, abnormal position of hands, small thorax, and non-visualization of the fetal stomach. Postnatally the infant was found to have a low birth weight, short birth length, contractures, short limbs, and a small thorax with upslanting ribs. Assisted ventilation and gastrostomy were required. At age 6 months, the infant required hospitalization for hypertrophic cardiomyopathy which responded to Atenolol®. Initial cytogenetic studies demonstrated an apparently balanced de novo Robertsonian translocation involving chromosomes 14 and a karyotype designation of 45,XY,t(14q14q). No indication of mosaicism for trisomy 14 was observed in metaphase spreads prepared from peripheral blood lymphocytes or skin-derived fibroblasts. C-band and fluorescence in situ hybridization results demonstrated that the chromosome was dicentric. DNA analyses showed paternal uniparental isodisomy for chromosome 14. Based on the cytogenetic and DNA results a final karyotype designation of 45,XY,idic(14)(p11) was assigned to this infant with paternal isodisomy of chromosome 14. © 1996 Wiley-Liss, Inc.     

Mosaic uniparental disomy in Beckwith-Wiedemann syndrome.

Beckwith-Wiedemann syndrome (BWS) is a congenital overgrowth syndrome with variable expression. The major features are anterior abdominal wall defects, macroglossia, and gigantism and less commonly neonatal hypoglycaemia, organomegaly, congenital renal anomalies, hemihypertrophy and embryonal tumours occur. BWS is a genetically heterogeneous disorder; most cases are sporadic but approximately 15% are familial and a small number of BWS patients have cytogenetic abnormalities involving chromosome 11p15. Genomic imprinting effects have been implicated in familial and non-familial BWS, and uniparental disomy (UPD) for chromosome 11 has been reported in sporadic cases. We investigated the incidence, pathogenesis, and clinical associations of UPD in 49 patients with non-familial BWS and a normal karyotype. UPD for chromosome 11p15 was detected in nine of 32 (28%) informative patients. A further two patients appeared to be disomic at the WT1 locus in chromosome 11p13, but were uninformative at chromosome 11p15.5 loci tested. In all cases with UPD the affected person was mosaic for a paternal isodisomy and a normal cell line indicating that UPD had arisen as a postzygotic event. Compared to cases in which paternal isodisomy for chromosomes 11p15.5 had been excluded (n = 23), BWS patients with UPD was more likely to have hemihypertrophy (6/9 versus 1/23, p < 0.001) and less likely to have exomphalos (0/9 versus 13/23, p < 0.01), but there were no significant differences between disomic and non-disomic cases in the incidence of hypoglycaemia, nephromegaly, neoplasia, and developmental delay. The detection of UPD in BWS patients allows accurate genetic counselling to be provided and provides an insight into the molecular pathogenesis of BWS.     

Genome-wide paternal uniparental disomy mosaicism in a woman with Beckwith–Wiedemann syndrome and ovarian steroid cell tumour

Uniparental disomy (UPD) of single chromosomes is a well-known molecular aberration in a group of congenital diseases commonly known as imprinting disorders (IDs). Whereas maternal and/or paternal UPD of chromosomes 6, 7, 11, 14 and 15 are associated with specific IDs (Transient neonatal diabetes mellitus, Silver–Russell syndrome, Beckwith–Wiedemann syndrome (BWS), upd(14)-syndromes, Prader–Willi syndrome, Angelman Syndrome), the other autosomes are not. UPD of the whole genome is not consistent with life, in case of non-mosaic genome-wide paternal UPD (patUPD) it leads to hydatidiform mole. In contrast, mosaic genome-wide patUPD might be compatible with life. Here we present a 19-year-old woman with BWS features and initially diagnosed to be carrier of a mosaic patUPD of chromosome 11p15. However, the patient presented further clinical findings not typically associated with BWS, including nesidioblastosis, fibroadenoma, hamartoma of the liver, hypoglycaemia and ovarian steroid cell tumour. Additional molecular investigations revealed a mosaic genome-wide patUPD. So far, only nine cases with mosaic genome-wide patUPD and similar clinical findings have been reported, but these patients were nearly almost diagnosed in early childhood. Summarising the data from the literature and those from our patient, it can be concluded that the mosaic genome-wide patUPD (also known as androgenic/biparental mosaicism) might explain unusual BWS phenotypes. Thus, these findings emphasise the need for multilocus testing in IDs to efficiently detect cases with disturbances affecting more than one chromosome.     

Third case of paternal isodisomy for chromosome 7 with cystic fibrosis: a new patient presenting with normal growth

Many patients with maternal uniparental disomy of chromosome 7 (UPD7) have been described, mainly with intrauterine and postnatal growth retardation or with Silver-Russell syndrome. In contrast, only three cases of paternal UPD7 have been reported, all associated with recessive disorders. Here, we report on the clinical and molecular data of the third patient with paternal UPD7 and cystic fibrosis. Pre- and postnatal growth were normal. These findings support the hypothesis that paternal isodisomy for human chromosome 7 may have no phenotypic effect on growth.     

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 origin effects in human trisomy for chromosome 14q: implications for genomic imprinting.

Parental origin specific congenital anomalies have been noted in patients with uniparental disomy of the long arm of human chromosome 14 (UPD14). This suggests the presence of imprinted genes, consistent with observations of imprinting in the region of syntenic homology in the mouse. It is not known whether the distinct defects reported for paternal and maternal UPD14 are the result of biallelic expression or absence of expression of imprinted genes. Furthermore, identification of the genes responsible would be facilitated by a higher resolution map of the imprinted region(s) involved. Subjects with partial trisomy for chromosome 14 (Ts14) have been reported and hence also have an alteration in the dosage of their parental chromosomes. In this study, we have carried out genotype-phenotype correlations considering the parental origin of the extra chromosome in previously reported cases of maternal and paternal partial Ts14. The analysis has provided evidence of a correlation between distal maternal Ts14 and anomalies including low birth weight, short philtrum, and small hands. The clinical features found in the maternal and paternal trisomies are compared with those associated with maternal and paternal UPD14 and their significance is discussed in relation to genomic imprinting on chromosome 14.     

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.     

Paternal uniparental isodisomy for chromosome 14 in a patient with a normal 46,XY karyotype

Chromosome 14 demonstrates imprinting with differing phenotypes for both maternal and paternal uniparental disomy (UPD). Although only 11 cases of paternal uniparental disomy 14 (patUPD14) have been reported, a distinct clinically recognizable syndrome has emerged. The major features are polyhydramnios, small thorax, mildly short limbs, abdominal wall defects, and characteristic face with short palpebral fissures, broad flat nasal bridge, prominent philtrum, and small ears. Radiographically, the chest is bell-shaped and the ribs are distinctive with caudal bowing anteriorly and cranial bowing posteriorly. Several affected infants have died from respiratory failure. The survivors have short stature and mental retardation. The initial cases were all recognized because of translocations involving chromosome 14. Subsequently, several patients with a similar phenotype and normal chromosomes have been reported, including two with mixed iso- and hetero-disomy as well as one with segmental UPD14. Our patient is the first with pure paternal isodisomy 14 in the absence of a translocation. We present additional clinical information, review the literature, and discuss mechanisms that may explain paternal isodisomy 14 in our chromosomally normal patient. Paternal UPD14 with normal karyotype may be more common than previously suspected and may be overlooked unless recognition of the clinical phenotype prompts investigation for UPD.     

Paternal uniparental isodisomy for chromosome 14 with mosaicism for a supernumerary marker chromosome 14

Uniparental disomy (UPD) describes the inheritance of two homologous chromosomes from a single parent. Disease phenotypes associated with UPD and chromosomal imprinting, rather than with mutations, include Beckwith-Wiedemann syndrome (paternal UPD11p), Angelman syndrome (paternal UPD15), Prader-Willi syndrome (maternal UPD15), and transient neonatal diabetes (paternal UPD6). Here we report on the first case of paternal uniparental isodisomy of chromosome 14 with a mosaicism for a supernumerary marker chromosome 14. The patient demonstrated a small thorax with a 'coat hanger' shape of the ribs, kyphoscoliosis, hypoplasia of the maxilla and mandible, a broad nasal bridge with anteverted nares, contractures of the wrists with ulnar deviation bilaterally, diastasis recti, and marked muscle hypotonia. Vertical skin creases under the chin and stippled epiphyses of the humeri were features not previously described in patients with paternal UPD14. This case illustrates that as with the finding of an isochromosome, a supernumerary marker chromosome can be an important clue to the presence of UPD14.     

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.     

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.     

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.     

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. Am. J. Med. Genet. 78:134–139, 1998. © 1998 Wiley-Liss, Inc.     

Allelic methylation of H19 and IGF2 in the Beckwith -- Wiedemann syndrome

Beckwith-Wiedemann syndrome (BWS) Is a congenital overgrowthsyndrome with associated embryonal tumours. Most BWS cases aresporadic but familial cases occur In 15% of patients and inthese there is linkage to chromosome 11p15. In addition, a smallnumber of patients have cytogenetic abnormalities involvingchromosome 11 p15. Approximately 20% of sporadic BWS patientshave uniparental paternal dlsomy (UPD) of chromosome 11 p15.This finding together with the observation that penetrance infamilial cases depends on parental transmission, suggests thatthe gene(s) for BWS are imprinted. The recent demonstrationof blallellc expression of the otherwise maternally imprintedIGF2 gene In some BWS patients implicates excess IGF2 expressionin the disease. Here we have analysed the allele-specific methylationpatterns In the IGF2 gene and in the neighbouring and reciprocallyImprinted H19 gene in a group of 42 BWS patients, 10 of whichwere mosaic UPD cases. We found that allelic methylation ofboth genes was normal in all non-UPD cases, with the paternalallele being methylated, and was Increased In UPD cases in proportionwith the disomlc lineage. These findings suggest that sporadicBWS is not associated with a general alteration of methylationimprinting of the IGF2 and H19 genes. The methylation assayused in this study thus also offers a simple and reliable diagnostictest of UPD for 11p15.5. An unexpected finding was a distortionof the frequency of AvaU alleles at the IGF2 locus exclusivelyin UPD BWS cases (P < 0.001). This further Implicates theIGF2 gene in aspects of the BWS phenotype.     

Prenatal diagnosis of trisomy 6 rescue resulting in paternal UPD6 with novel placental findings

Uniparental disomy (UPD) is defined by the inheritance of both copies of a chromosome pair from one single parent. Although 23 cases of paternal UPD6 have been reported earlier, the occurrence of trisomy 6 rescue with paternal UPD6 has not been previously reported. The phenotype of paternal UPD6 results from biallelic expression of the maternally imprinted, paternally expressed ZAC and HYMAI genes, and includes transient neonatal diabetes mellitus (TNDM), intra-uterine growth restriction (IUGR), macroglossia, and minor anomalies. Trisomy rescue has been proposed as a pathogenic mechanism leading to UPD of other chromosomes. We report on the first case of a prenatally diagnosed infant with UPD6 and describe the clinical, cytogenetic, molecular, and novel placental findings in a female infant with paternal UPD6. Low-level trisomy 6 and paternal UPD6 were prenatally diagnosed through amniocentesis. After birth trisomy 6 was documented in the placenta but was not found in three different cell lines from the infant. The placenta was small with a peculiar pattern of vascular proliferation. Our results of trisomy 6 cells predominantly present in the placenta and only in low levels in the amniotic fluid suggest that the distribution and proportion of trisomic and diploid UPD cells contribute to the variability of fetal and placental phenotypes.     

Molecular cytogenetic characterization of 18;21 whole arm translocation associated with monosomy 18p

Monosomy of the entire short arm of chromosome 18 as a result of an 18;acrocentric whole arm translocation has been reported in over 20 patients, 3 of which were familial. The centromeric origin in de novo cases has not been characterized. We report molecular cytogenetic studies of two prenatally-detected de novo cases. Amniocenteses were performed because of sonographic findings of fetal holoprosencephaly. Cytogenetic studies and dual color fluorescence in situ hybridization using Oncor α-satellite probes for D18Z1 and D13Z1/D21Z1 showed monosomy 18p with presence of a dicentric 18;21 chromosome in both cases [45,XY,dic(18;21)(p11.1;p11.1)]. In one case, a second cell line was found, which contained 46 chromosomes with a del(18)(p11.1) and an apparently telocentric 21 not present in either parent [46,XY,del(18)(p11.1),del(21)(p11.1)]. The del(18)(p11.1) contained only the 18 alphoid sequence and the telocentric 21 contained only the 21 alphoid sequence. No centromeric break was detected. We propose that the second cell line arose from dissociation of the dic(18;21) with no centromeric DNA break. In addition to our case, there have been three previous reports of dissociation of dicentric 18;acrocentric chromosomes indicating that the translocation site can be unstable and dissociate. Am. J. Med. Genet. 71:463–466, 1997. © 1997 Wiley-Liss, Inc.