Molecular studies of translocations and trisomy involving chromosome 13

Twenty-four cases of trisomy 13 and one case with disomy 13, but a de novo dic(13,13) (p12p12) chromosome, were examined with molecular markers to determine the origin of the extra (or rearranged) chromosome. Twenty-one of 23 informative patients were consistent with a maternal origin of the extra chromosome. Lack of a third allele at any locus in both paternal origin cases indicate a somatic duplication of the paternal chromosome occurred. Five cases had translocation trisomy: one de novo rob(13q14q), one paternally derived rob(13q14q), two de novo t(13q13q), and one mosaic de novo t(13q13q)/r(13). The patient with a paternal rob(13q14q) had a maternal meiotic origin of the trisomy; thus, the paternal inheritance of the translocation chromosome was purely coincidental. Since there is not a significantly increased risk for unbalanced offspring of a t(13q14q) carrier and most trisomies are maternal in origin, this result should not be surprising; however, it illustrates that one cannot infer the origin of translocation trisomy based on parental origin of the translocation. Lack of a third allele at any locus in one of the three t(13q13q) cases indicates that it was most likely an isochromosome of postmeiotic origin, whereas the other two cases showed evidence of recombination. One balanced (nontrisomic) case with a nonmosaic 45,−13,−13,t(13;13) karyotype was also investigated and was determined to be a somatic Robertsonian translocation between the maternal and paternal homologues, as has been found for all balanced homologous Robertsonian translocations so far investigated. Thus, it is also incorrect to assume in de novo translocation cases that the two involved chromosomes are even from the same parent. Despite a maternal origin of the trisomy, we cannot therefore infer anything about the parental origin of the chromosomes 13 and 14 involved in the translocation in the de novo t(13q14q) case nor for the two t(13;13) chromosomes showing a meiotic origin of the trisomy. © 1996 Wiley-Liss, Inc.     

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.     

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.     

Maternal uniparental heterodisomy of chromosome 14: chromosomal mechanism and clinical follow up

To our knowledge, 22 cases of chromosome 14 maternal uniparental disomy (UPD(14)mat) have been reported so far. The majority of cases were ascertained because of an abnormal phenotype associated with a Robertsonian translocation involving chromosome 14. We report here on a child with UPD(14)mat detected prenatally and resulting from trisomy rescue in a maternal meiosis I non-disjunction trisomic zygote. After four years of clinical follow up, in addition to intrauterine growth retardation (IUGR), only short stature and small hands and feet were observed. These clinical data as well as the ascertainment and mechanism of origin of UPD(14)mat were compared with those observed in previously reported cases. It appears that the clinical spectrum of UPD(14)mat is milder in our patient than in patients with UPD(14)mat resulting from other chromosomal mechanisms. In addition, a hypothesis based on abnormal imprinting is proposed to explain the variability of the UPD(14)mat.


Keywords: maternal UPD; chromosome 14; MCP; imprinting     

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.     

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.     

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.     

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.     

Maternal uniparental disomy for chromosome 14.

We report the first case of maternal uniparental disomy of chromosome 14 in humans. The male proband inherited a balanced 13;14 Robertsonian translocation from his mother. Molecular studies showed that neither chromosome 14 was of paternal origin. The proband is of above average intelligence, but he has hydrocephalus, a bifid uvula, premature puberty, short stature, and small testes. It is not known if the clinical findings are related or coincidental to the uniparental disomy.     

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.     

Identification of uniparental disomy in phenotypically abnormal carriers of isochromosomes or Robertsonian translocations

Carriers of either homologous or non-homologous acrocentric rearrangements are at an increased risk for aneuploidy, and, thus, for uniparental disomy (UPD). Abnormal phenotypes due to genomic imprinting are associated with UPD for the acrocentric chromosomes 14 and 15. The purpose of this study was to determine the prevalence of UPD in a population with acrocentric rearrangements (either an isochromosome or a Robertsonian translocation) and abnormal phenotypes. Fifty individuals were studied. Of the 50 rearrangements, two were homologous rearrangements and both showed UPD. Forty-eight were non-homologous Robertsonian translocations, of which two showed UPD. This study demonstrates that UPD explains the abnormal phenotypes in some balanced carriers of acrocentric rearrangements. Our results and the large number of case reports in the literature suggest that patients with abnormal phenotypes and acrocentric rearrangements of chromosomes 14 or 15 should be tested for UPD.     

Unstable translocations: a new case?

A female patient with Down syndrome due to unbalanced Robertsonian translocation (14;21) is reported. A different Robertsonian translocation involving a chromosome no. 14 was observed in her father, who was a carrier of a balanced Robertsonian t(13;14), while the maternal karyotype was normal. Hypotheses about the origin of the translocation in the daughter are discussed.     

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.     

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.     

Paternal uniparental disomy of chromosome 14: confirmation of a clinically-recognizable phenotype

We report on a girl with a dicentric chromosome 14 [45,XX,inv(9)(p11q13),dic(14;14)(p11.1;p11.1)] with paternal uniparental disomy (UPD) for chromosome 14. Clinical findings include severe hypotonia, thoracic dystrophy, diastasis recti, swallowing difficulties with aspiration, developmental delay, and multiple minor anomalies. UPD for chromosome 14 has been documented with paternal UPD much less commonly than with maternal UPD. There have been ten cases of paternal UPD for chromosome 14 and one case of segmental paternal isodisomy of chromosome 14. Many of the findings are nonspecific, but the radiographic rib findings (referred to as the "coat-hanger" sign) are characteristic for this condition. UPD 14 studies should be performed in children thought to have Jeune asphyxiating thoracic dystrophy or other related osteochondrodysplasias when the diagnosis is in question. Our patient and the previously reported cases support a discrete recognizable phenotype for paternal UPD for chromosome 14.     

A case of Prader – Willi syndrome arising as a result of familial unbalanced translocation t(11;15)(q25;q13)

We report on a case of Prader-Willi syndrome (PWS) with a true reciprocal unbalanced translocation, 45,XX,-15,der(11)t(11;15)pat. The proposita was diagnosed clinically as having severe PWS. Molecular studies revealed loss of the paternal methylation pattern at locus D15S63 and a deletion encompassing the loci from at least D15S10 to D15S97 of paternal chromosome 15. FISH studies confirmed the deletion of 15q11-q13 region and the presence of two telomeres on all chromosomes. The proposita's father, the father's sister and their mother are all carriers of the same balanced translocation t(11;15)(q25;q13). By genomic imprinting we would expect that if the father's sister were to give birth to a child with the same unbalanced translocation as the proband, it would be affected by Angelman syndrome.
To date, a similar familial unbalanced translocation due to loss of the small chromosome 15 derivative has not been described.     

Paternal Robertsonian translocation t(13q;14q) and maternal reciprocal translocation t(7p;13q) in a couple with repeated fetal loss.

Marriages involving partners both of whom have abnormal karyotypes are rare and are usually ascertained because of a history of infertility, repeated abortions, or the birth of a balanced translocation carrier or chromosomally abnormal offspring. Abnormalities which have been noted include sex chromosome aberrations in both parents or a sex chromosome abnormality in one parent and an autosomal abnormality in the other. Four papers have reported balanced reciprocal autosomal translocations in both parents, two couples representing a first cousin marriage. We present a case of a paternal 13;14 Robertsonian translocation and a maternal (7p;13q) reciprocal translocation in a couple with repeated fetal loss.     

Maternal uniparental disomy for chromosome 14 in a boy with a normal karyotype

We report on a boy with a maternal uniparental disomy for chromosome 14 (UPD(14)). At 7 years of age he was referred to us by the paediatrician because of symptoms of Prader-Willi syndrome (PWS). He showed short stature, obesity, mild developmental delay, cryptorchidism, and some mild dysmorphic features. The history further indicated intrauterine growth retardation at the end of the pregnancy. His mother was 44 years of age at the time of his birth. After birth he showed hypotonia with poor sucking, for which gavage feeding was needed. Motor development was delayed. After 1 year he became obese despite a normal appetite. Recurrent middle ear infections, a high pain threshold, and a great skill with jigsaw puzzles were reported. There were no behavioural problems or sleep disturbance. Chromosomal analysis was normal (46,XY). DNA analysis for Prader-Willi syndrome showed no abnormalities. Two years later he was re-examined because we thought his features fitted the PWS-like phenotype associated with maternal UPD(14). At that time precocious puberty was evident. DNA analysis showed maternal heterodisomy for chromosome 14. In all the previously described 11 cases with maternal UPD(14), a Robertsonian translocation involving chromosome 14 was detected cytogenetically before DNA analysis. This is the first report of diagnosis of maternal UPD(14) based on clinical features. This finding underlines the importance of DNA analysis for maternal UPD(14) in patients with a similar PWS-like phenotype even without previous identification of a Robertsonian translocation involving chromosome 14.     

Familial robertsonian translocation 15;21 and rare paracentric inv(21): unexpected re-inversion in a child with translocation trisomy 21

We present a family with a Robertsonian translocation (RT) 15;21 and an inv(21)(q21.1q22.1) which was ascertained after the birth of a child with Down syndrome. Karyotyping revealed a translocation trisomy 21 in the patient. The mother was a carrier of a paternally inherited RT 15;21. Additionally, she and her mother showed a rare paracentric inversion of chromosome 21 which could not be observed in the Down syndrome patient. Thus, we concluded that the two free chromosomes 21 in the patient were of paternal origin. Remarkably, short tandem repeat (STR) typing revealed that the proband showed one paternal allele but two maternal alleles, indicating a maternal origin of the supernumerary chromosome 21. Due to the fact that chromosome analysis showed structurally normal chromosomes 21, a re-inversion of the free maternally inherited chromosome 21 must have occurred. Re-inversion and meiotic segregation error may have been co-incidental but unrelated events. Alternatively, the inversion or RT could have predisposed to maternal non-disjunction.