Down syndrome due to de novo Robertsonian translocation t(14q;21q): DNA polymorphism analysis suggests that the origin of the extra 21q is maternal.

Down syndrome is rarely due to a de novo Robertsonian translocation t(14q;21q). DNA polymorphisms in eight families with Down syndrome due to de novo t(14q;21q) demonstrated maternal origin of the extra chromosome 21q in all cases. In seven nonmosaic cases the DNA markers showed crossing-over between two maternal chromosomes 21, and in one mosaic case no crossing-over was observed (this case was probably due to an early postzygotic nondisjunction). In the majority of cases (five of six informative families) the proximal marker D21S120 was reduced to homozygosity in the offspring with trisomy 21. The data can be best explained by chromatid translocation in meiosis I and by normal crossover and segregation in meiosis I and meiosis II.     

A patient with Down syndrome with a de novo derivative chromosome 21

Pure partial trisomy of chromosome 21 is a rare event. The patients with this aberration are very important for setting up precise karyotype-phenotype correlations particularly in Down syndrome phenotype. We present here a patient with Down syndrome with a de novo derivative chromosome 21. Karyotype of the patient was designated as 46,XY,der(21)(p13)dup(21)(q11.2q21.3)dup(21)(q22.2q22.3) with regard to cytogenetic, FISH and array-CGH analyses. Non-continuous monosomic, disomic and trisomic chromosomal segments through the derivative chromosome 21 were detected by array-CGH analysis. STR analyses revealed maternal origin of the de novo derivative chromosome 21. The dual-specificity tyrosine (Y)-phosphorylation regulated kinase 1A (DYRK1A) and Down Syndrome Critical Region 1 (DSCR1) genes that are located in Down syndrome critical region, are supposed to be responsible for most of the clinical findings of Down syndrome. However, our patient is the first patient with Down syndrome whose clinical findings were provided in detail, with a de novo derivative chromosome 21 resulting from multiple chromosome breaks excluding DYRK1A and DSCR1 gene regions.     

A Somatic Origin of Homologous Robertsonian Translocations and Isochromosomes

One t(14q14q), three t(15q15q), two t(21q21q), and two t(22q22q) nonmosaic, apparently balanced, de novo Robertsonian translocation cases were investigated with polymorphic markers to establish the origin of the translocated chromosomes. Four cases had results indicative of an isochromosome: one t(14q14q) case with mild mental retardation and maternal uniparental disomy (UPD) for chromosome 14, one t(15q15q) case with the Prader-Willi syndrome and UPD(15), a phenotypically normal carrier of t(22q22q) with maternal UPD(22), and a phenotypically normal t(21q21q) case of paternal UPD(21). All UPD cases showed complete homozygosity throughout the involved chromosome, which is supportive of a postmeiotic origin. In the remaining four cases, maternal and paternal inheritance of the involved chromosome was found, which unambiguously implies a somatic origin. One t(15q15q) female had a child with a ring chromosome 15, which was also of probable postmeiotic origin as recombination between grandparental haplotypes had occurred prior to ring formation. UPD might be expected to result from de novo Robertsonian translocations of meiotic origin; however, all de novo homologous translocation cases, so far reported, with UPD of chromosomes 14, 15, 21, or 22 have been isochromosomes. These data provide the first direct evidence that nonmosaic Robertsonian translocations, as well as isochromosomes, are commonly the result of a mitotic exchange.     

De novo 21/21 translocation Down syndrome

Summary Among ten families with de novo 21/21 translocation Down syndrome (tDS), four were informative, according to the studies of structural variants of chromosome 21, about the origin of the aberrant chromosome. In three of these, the translocation originated in the paternal and in one in the maternal gametogenesis. The parents with meiotic failure were compared with 20 control individuals (10 males and 10 females). There were no significant differences between them in the association coefficient of chromosome 21 and in the frequency of 21–21 associations. Similar results were obtained previously with the entire sample of tDS parents. The results obtained, unless they reflect too small a sample, suggest that the origin of the aberrant chromosome is not related to an increased chromosome 21 association tendency. It could be supposed that in the case of an apparent 21/21 translocation, the 21q isochromosome, morphologically indistinguishable from the Robertsonian translocation, is in question. The Ag-NoR negative acrocentrics in the tDS parents reappeared in the probands confirming the heritability of that nucleolus organizer regions (NOR) trait.     

Translocation Down syndrome in Ohio 1970-1981: epidemiologic and cytogenetic factors and mutation rate estimates.

Sixteen hundred eighty-eight Down syndrome live births, including 65 (5.2%) translocations, were ascertained in Ohio between 1970 and 1981. Translocations of known origin were 24.4% maternal, 2.2% paternal, and 73.3% de novo. Translocation subtypes were 14/21 (45.7%), 15/21 (2.9%), 21/21 (40.0%), 21/22 (2.9%), and other (8.5%). Among 14/21 translocations, 33.3% were maternal in origin and 66.7% were de novo, while 100% of 21/21 translocations were de novo. No differences were found when the maternal- and paternal-age distributions of all translocations or various translocation subsets were compared with the live-birth control distributions. However, mean maternal and paternal ages of de novo translocations were significantly lower than that of the live-birth controls. Ohio data showed the average maternal age of de novo D/21 cases to be significantly lower than the control. Ages of both parents of de novo G/21 cases and paternal age of D/21 cases were not different from the control. De novo translocation mutation rate estimates were 0.8 X 10(-5) for 14/21, 1.2 X 10(-5) for 21/21, and 2.2 X 10(-5) overall. Ohio estimates (3.2 X 10(-5) for 1970-1972 and 1.4 X 10(-5) for 1973-1975) did not reflect the increase in mutation rate previously found in New York during 1973-1977.     

Parental origin of the extra chromosome in prenatally diagnosed fetal trisomy 21

Trisomy 21 (Down syndrome) is one of the most common chromosomal abnormalities. Of cases of free trisomy 21 causing Down syndrome, about 95% result from nondisjunction during meiosis, and about 5% are due to mitotic errors in somatic cells. Previous studies using DNA polymorphisms of chromosome 21 showed that paternal origin of trisomy 21 occurred in only 6.7% of cases. However, these studies were conducted in liveborn trisomy 21-affected infants, and the possible impact of fetal death was not taken into account. Using nine distinct DNA polymorphisms, we tested 110 families with a prenatally diagnosed trisomy 21 fetus. Of the 102 informative cases, parental origin was maternal in 91 cases (89.2%) and paternal in 11 (10.8%). This percentage differs significantly from the 7.0% observed in previous studies (P<0.001). In order to test the influence of genomic parental imprinting, we determined the origin of the extra chromosome 21 in relation to different factors: advanced maternal age, maternal serum human chorionic gonadotropin (hormone of placental origin), severity of the disease, gestational age at diagnosis and fetal gender. We found that the increased frequency of paternal origin of nondisjunction in trisomy 21-affected fetuses cannot obviously be explained by factors leading to selective loss of paternal origin fetuses.     

Dup(13)(q14.2-q14.3): yet another new differential diagnostic aspect for short stature-like phenotype.

We report on the case of a pregnant woman with hyposomia who was previously suspected of having Turner syndrome. Prenatal cytogenetic diagnostics showed a fetal karyotype of 46,XX,dup(13)(q14.2q21.1) ish.13q14(RB1 x 3). Parental and grandparental chromosome analyses were performed and the dup(13) was found to be of maternal origin (de novo). The pregnancy was continued and a healthy female child was born with normal development apart from growth retardation. The reported chromosomal aberration is, together with two other cases reported in the literature, the first hint of a short stature-like phenotype due to dup(13)(q14.2q14.3).     

Molecular characterization of de novo secondary trisomy 13.

Unbalanced Robertsonian translocations are a significant cause of mental retardation and fetal wastage. The majority of homologous rearrangements of chromosome 21 in Down syndrome have been shown to be isochromosomes. Aside from chromosome 21, very little is known about other acrocentric homologous rearrangements. In this study, four cases of de novo secondary trisomy 13 are presented. FISH using alpha-satellite sequences, rDNA, and a pTRI-6 satellite I sequence specific to the short arm of chromosome 13 showed all four rearrangements to be dicentric and apparently devoid of ribosomal genes. Three of four rearrangements retained the pTRI-6 satellite I sequence. Case 1 was the exception, showing a deletion of this sequence in the rearrangement, although both parental chromosomes 13 had strong positive hybridization signals. Eleven microsatellite markers from chromosome 13 were also used to characterize the rearrangements. Of the four possible outcomes, one maternal Robertsonian translocation, two paternal isochromosomes, and one maternal isochromosome were observed. A double recombination was observed in the maternally derived rob(13q13q). No recombination events were detected in any isochromosome. The parental origins and molecular chromosomal structure of these cases are compared with previous studies of de novo acrocentric rearrangements.     

Excess of deletions of maternal origin in the DiGeorge/Velo-cardio-facial syndromes. A study of 22 new patients and review of the literature

We have determined the parental origin of the deleted chromosome 22 in 29 cases of DiGeorge syndrome (DGS) using a CA-repeat mapping within the commonly deleted region, and in one other case by using a chromosome 22 short arm heteromorphism. The CA-repeat was informative in 21 out of 29 families studied and the deleted chromosome was of maternal origin in 16 cases (72%). When these data are pooled with recent results from the literature, 24 de novo DGS, velo-cardio-facial syndrome (VCFS) and isolated conotruncal cardiac disease deletions are found to be of maternal origin and 8 of paternal origin, yielding a ² of 8 with a probability level lower than 0.01. These data, and review of the literature on familial DGS/VCFS and isolated conotruncal cardiopathies suggest that there is a strong tendency for the 22q11.2 deletions to be of maternal origin.     

Meiotic crossing-over in nondisjoined chromosomes of children with trisomy 21 and a congenital heart defect.

We have used DNA polymorphisms to study meiotic crossovers of chromosome 21q in 27 nuclear families. Each family had a child with Down syndrome and a congenital heart defect. Twenty DNA polymorphisms on chromosome 21 were used to determine parental and meiotic origin of nondisjunction and to identify crossovers. Twenty-four cases were of maternal origin, and three were of paternal origin. Twenty-two unequivocal crossover events were identified. Sixteen crossovers were observed in 22 chromosome pairs nondisjoining at the second meiotic division. Fifty percent of crossover events in MI nondisjunction are detectable by molecular genetic means. Thus, the results suggest that, in this sample, each nondisjoined chromosome 21 pair has been involved in at least one crossover event.     

Isolation of chromosome-21-specific DNA probes and their use in the analysis of nondisjunction in Down syndrome

Summary Thirteen single-copy, chromosome-21-specific DNA probes were isolated from a recombinant library made from flow-sorted chromosome 21 DNA and regionally mapped using a panel of somatic cell hybrids. Five probes mapped in the 21q21-q22.1 region, six to the 21q22.1-qter region, and one to each of the regions 21q22.1-q22.2 and 21q22.3. Two of these probes, one of which maps in the critical region for Down syndrome, have recently been shown to be expressed at high levels in Down syndrome brain tissue (Stefani et al. 1988). Following preliminary screening for restriction fragment lenght polymorphisms (RFLPs), five polymorphisms were discovered with four of the chromosome 21 DNA probes. A frequent MspI polymorphism detected by one of the probes was used in conjunction with four previously described polymorphic chromosome 21 probes to analyse the origin of nondisjunction in 33 families with a child or fetus with trisomy 21. The parental origin of the additional chromosome 21 was determined in 12 cases: in 9 (75%) of these it was derived from the mother and in the other 3 cases (25%) it was of paternal origin. Cytogenetic analysis of Q-banding heteromorphisms was informative in three of five families tested, and in each case the RFLP results were confirmed. The meiotic stage of nondisjunction was defined with confidence in five families, the results being obtained with pericentromeric RFLP or cytogenetic markers. Recombination between two nondisjoined chromosomes was demonstrated in one family and is consistent with the view that a lack of recombination between chromosome 21 homologues or failure of their conjunction is not the invariable cause of trisomy 21.     

Enhanced Maternal Origin of the 22q11.2 Deletion in Velocardiofacial and DiGeorge Syndromes

Velocardiofacial and DiGeorge syndromes, also known as 22q11.2 deletion syndrome (22q11DS), are congenital-anomaly disorders caused by a de novo hemizygous 22q11.2 deletion mediated by meiotic nonallelic homologous recombination events between low-copy repeats, also known as segmental duplications. Although previous studies exist, each was of small size, and it remains to be determined whether there are parent-of-origin biases for the de novo 22q11.2 deletion. To address this question, we genotyped a total of 389 DNA samples from 22q11DS-affected families. A total of 219 (56%) individuals with 22q11DS had maternal origin and 170 (44%) had paternal origin of the de novo deletion, which represents a statistically significant bias for maternal origin (p = 0.0151). Combined with many smaller, previous studies, 465 (57%) individuals had maternal origin and 345 (43%) had paternal origin, amounting to a ratio of 1.35 or a 35% increase in maternal compared to paternal origin (p = 0.000028). Among 1,892 probands with the de novo 22q11.2 deletion, the average maternal age at time of conception was 29.5, and this is similar to data for the general population in individual countries. Of interest, the female recombination rate in the 22q11.2 region was about 1.6–1.7 times greater than that for males, suggesting that for this region in the genome, enhanced meiotic recombination rates, as well as other as-of-yet undefined 22q11.2-specific features, could be responsible for the observed excess in maternal origin.     

Normal phenotype with paternal uniparental isodisomy for chromosome 21.

Uniparental disomy (UPD) involving several different chromosomes has been described in several cases of human pathologies. In order to investigate whether UPD for chromosome 21 is associated with abnormal phenotypes, we analyzed DNA polymorphisms in DNA from a family with de novo Robertsonian translocation t(21q;21q). The proband was a healthy male with 45 dup(21q) who was ascertained through his trisomy 21 offspring. No phenotypic abnormalities were noted in the physical exam, and his past medical history was unremarkable. We obtained genotypes for the proband and his parents' leukocyte DNAs from 17 highly informative short sequence repeat polymorphisms that map in the pericentromeric region and along the entire length of 21q. The order of the markers has been previously determined through the linkage and physical maps of this chromosome. For the nine informative markers there was no maternal allele contribution to the genotype of the proband; in addition, there was always reduction to homozygosity of a paternal allele. These data indicated that there was paternal uniparental isodisomy for chromosome 21 (pUPiD21). We conclude that pUPiD21 is not associated with abnormal phenotypes and that there are probably no imprinted genes on chromosome 21.     

Parental origin of the extra chromosome in Down's syndrome

Summary Chromosome 21 fluorescent heteromorphisms were studied in 42 patients with Down's syndrome, their parents and their siblings. Included in this number are two instances of an aunt and niece affected with trisomy 21, and one of affected siblings. One case has a de novo 21/21 translocation. Blood group, red cell and serum protein markers were also studied for linkage, gene exclusions, associations, and paternity testing. Thirty-one of the trisomy 21 cases were informative for parental origin of the extra chromosome and for stage of meiosis. The non-disjunctional event was of maternal origin in 24; 23 occurred in meiosis I, 1 in meiosis II. Seven were of paternal origin; 5 in meiosis I, and 2 in meiosis II. The translocation case was of paternal origin. A literature search revealed a total of 98 cases informative for the parent of origin of the extra chromosome, of >347 families tested. In addition, 3 de novo translocation cases, of 7 tested, were informative. The data suggest that most cases result from an error in the first meiotic division in the mother, but that a significant proportion are paternal in origin.     

Results of estimation of mutation rates for translocation trisomy 21

Among 1332 cases of trisomy 21 born within 1979-1999 in St. Petersburg, 76(5.7%) were carriers of a translocation between chromosome 21 and other acrocentrics. Among 43 Dq; 21q translocations, 17 were inherited from the mother, and one was inherited from the father, 16 were of sporadic occurrence, and in 9 cases the mode of inheritance was not established. Out of 31 cases displaying Gq;21 translocation, 23 were mutants and 8 of unknown origin. One case of non-Robertsonian translocation 21;22 was maternal in origin. It was assumed that the proportion of sporadic cases among translocations of unknown origin is the same as that among translocations of the known origin. However, it is conceivable that the parents of a child with a sporadic anomaly, previously having an uncomplicated reproductive history and healthy children, tend to avoid cytogenetic examination more often than the carriers of translocation. Hence, the reported proportion of de novo cases (-0.6) might be underestimated. The analysis of pregnancy outcomes in mothers of children with Down syndrome, who inherited translocation (n = 12), sporadic translocation (n = 12) and translocation of unknown origin (n = 8), supports this suggestion. Analysis of the data from 8 reports, where the origin of Dq;21 was specified, revealed that in those samples, where the origin was traced in almost all families, the proportion of de novo cases (0.75-0.82) was higher than in samples where an appreciable part of families was not examined (0.46-0.73). Therefore, with the aim of correct determination of mutation rate for Dq;21 translocation, the true proportions in D;21 cases merit evaluation. Meanwhile, using average estimation from all the above mentioned reports (0.67), the mutation rate for translocations Dq;21 in St. Petersburg was calculated to be 1.2 x 10(-5) and 0.8 x 10(-5) in 1980-1989 and 1990-1999, respectively. For Gq;21 translocations/isochromosomes, the corresponding figures were 1.6 x 10(-5) and 1.5 x 10(-5).     

Parental origin and meiotic stage of non-disjunction in 139 cases of trisomy 21

The parental origin and the meiotic stage of non-disjunction have been determined in 139 Down syndrome patients with regular trisomy 21 and in their parents through the analysis of DNA polymorphism. The meiotic error is maternal in 91.60% cases and paternal in 8.39% of cases. Of the maternal cases, 72.41% were due to meiosis I errors (MMI) and 27.58% were due to meiosis II errors (MMII). Of the paternal cases, 45.45% were due to meiosis I (PMI) and 54.54% were due to meiosis II (PMII). The mean maternal ages were 31.6 +/- 5.3 (+/- SD) years in errors from MMI, 32.3 +/- 6.4 years in errors from MMII, 31.4 +/- 4.6 years in errors from PMI and 29.5 +/- 2.7 years in errors from PMII. No significant statistical differences were observed between maternal and paternal errors, further supporting the presence of a constant chromosome 21 non-disjunction error type.     

Karyological characteristics of Down's syndrome: clinical and theoretical aspects

These data have been collected from St. Petersburg Down Syndrome Register that comprises information on 1778 liveborn children with the Down syndrome, including three twin sets, ascertained within 1970-1996. Karyotypes were obtained in 1223 cases, of which 1119 (90.7%) displayed regular trisomy. Mosaicism was found in 44 cases (3.6%), including 21 males and 24 females, and among these one familial case of mosaicism in a daughter and in a healthy mother. Of 70 cases of translocations, 41(5.7%) were Robertsonian D ones. 21 (17 inherited, 16 de novo and 8 of unknown origin), 28 translocations of isochromosomes 21q; 21q (1 inherited translocation 21; 22, 22 de novo and 5 of unknown origin). One child received the anomaly from his 46XX/45XX, t(D;G) mother-carrier. In 6 cases, free trisomy 21 was associated with structural or numerical anomalies: 46XY,t(13;14)mat + 21 in twins, 47XY,t(C;C) + 21, 47XY,t(10;15)pat + 21, 47XY,inv(19)mat + 21, 47XX + 21/48XX + 21 + ring, 48XXX + 21. In 12 families parental mosaicism was shown or suspected. In 6 families one parent had chromosome anomaly, in three cases it was not inherited: t(15;22) and t(6;21) in mothers and an additional small marker in a father. In cases confirmed cytogenetically an increased sex ratio was shown (679 males and 551 females, SR = 1.23), but it was not shown in patients not tested cytogenetically (264 males and 275 females, SR = 0.96, different from the expected 297 males and 242 females, P < 0.01).     

A molecular genetic approach to the identification of isochromosomes of chromosome 21

Summary The largest class of de novo chromosomal rearrangements in Down syndrome are rea(21q21q). Classically, these rearrangements have been termed Robertsonian translocations, implying an attachment of two different chromosome 21 homologues. Additionally, a Robertsonian translocation between two chromosomes 21 cannot be distinguished from an isochromosome composed of genetically identical arms by cytogenetic analyses. Therefore, we have used molecular techniques to differentiate between true Robertsonian translocations and isochromosomes. Samples were obtained from 12 probands, ascertained for de novo rearrangements between homologous chromosomes 21 [11 rea(21q21q) and 1 rea (21;21)(q22;q22)], their parents (n = 24) and available siblings (n = 7). The parental origins of the de novo rearrangements were assigned using molecular and cytogenetic analyses. Although not statistically significant, there was a two-fold increase in the number of paternally derived de novo rearrangements (n = 8) as compared with maternally derived rearrangements (n = 4). To distinguish between rob(21q21q) and i(21q), we used restriction fragment length polymorphisms (RFLPs) spanning the length of chromosome 21. Using all informative and partially informative RFLPs, we used the method of maximum likelihood to assign the most likely rearrangement definition (i or rob) and parental origin in each family. The maximum likelihood estimates indicated that all rearrangements tested (n = 8) were isochromosomes. C-banding revealed two centromeres in three cases indicating that a U-type exchange occurred between sister chromatids in these rearrangements. Our results suggest that the majority of de novo rea(21q21q) are isochromosomes derived from a single parental chromosome 21.     

Prevalence and origin of de novo duplications in Charcot-Marie-Tooth disease type 1A: first report of a de novo duplication with a maternal origin.

Charcot-Marie-Tooth disease (CMT) is the most common inherited peripheral neuropathy. Sporadic cases of CMT have been described since the earliest reports of the disease. The most frequent form of the disorder, CMT1A, is associated with a 1.5-Mb DNA duplication on chromosome 17p11.2, which segregates with the disease. In order to investigate the prevalence of de novo CMT1A duplications, this study examined 118 duplication-positive CMT1A families. In 10 of these families it was demonstrated that the disease had arisen as the result of a de novo mutation. By taking into account the ascertainment of families, it can be estimated that > or = 10% of autosomal dominant CMT1 families are due to de novo duplications. The CMT1A duplication is thought to be the product of unequal crossing over between parental chromosome 17 homologues during meiosis. Polymorphic markers from within the duplicated region were used to determine the parental origin of these de novo duplications in eight informative families. Seven were of paternal and one of maternal origin. This study represents the first report of a de novo duplication with a maternal origin and indicates that it is not a phenomenon associated solely with male meioses. Recombination fractions for the region duplicated in CMT1A are larger in females than in males. That suggests that oogenesis may be afforded greater protection from misalignment during synapsis, and/or that there may be lower activity of those factors or mechanisms that lead to unequal crossing over at the CMT1A locus.     

Preferential maternal derivation in inv dup(15)

Summary Eight patients are reported with a de nov extra inverted duplicated chromosome 15. The abnormal chromosome was considered to be the same in all cases, but its precise delineation remained uncertain and was defined as either 15qter15q12::15q1215pter or 15pter15q11::15q1315pter. Analysis with various techniques of the satellite regions of the bisatellited chromosomes demonstrated maternal derivation in six and paternal derivation in one of the seven families. A nonsister chromatid exchange between the two homologous chromosomes 15 is considered a likely origin of the inv dup(15) in the cases with maternal derivation; in the only case of paternal derivation, however, the abnormal chromosome originated from one single chromosome 15. The clinical findings confirm that patients with inv dup(15) have mental and developmental retardation and are frequently affected by seizures, while severe physical malformations are absent.