Familial Down syndrome due to t(10;21) translocation: evidence that the Down phenotype is related to trisomy of a specific segment of chromosome 21.

This report deals with a reciprocal t(10;21) translocation which is observed in three generations of a family. Included are examples of the balanced translocation, adjacent-2 segregation producing three patients with trisomy of the distal long arm of chromosome 21 and the Down syndrome, and 3-1 disjunction producing trisomy of the proximal segment of chromosome 21 in a mildly mentally retarded boy without phenotypic features of the Down syndrome. These data provide evidence that the Down phenotype is attributable to trisomy of the distal long arm of chromosome 21.     

南宁地区唐氏综合征患者的细胞遗传学研究

为了探讨中国南宁地区唐氏综合征患者染色体核型分布及其特点, 对广西壮族自治区妇幼保健院1994年以来的500例疑似唐氏综合征(Down syndrome, DS)患者进行外周血染色体核型分析, 130例确诊为DS患者。其中, 单纯型21-三体为86.15%(112/130); 易位型为8.46%(11/130); 嵌合型为5.39%(7/130)。在单纯型21-三体中性别比为女∶男=1∶1.8; 93.08% 的唐氏综合征患儿由年轻母亲(<35岁)所生, 另有6.92% 由高龄产妇所生。结果表明, 南宁地区86% 以上唐氏综合征患者的染色体核型是单纯型21-三体, 男性唐氏综合征患儿明显高于女性患儿。     

The sequence of human chromosome 21 and implications for research into Down syndrome

The recent completion of the DNA sequence of human chromosome 21 has provided the first look at the 225 genes that are candidates for involvement in Down syndrome (trisomy 21). A broad functional classification of these genes, their expression data and evolutionary conservation, and comparison with the gene content of the major mouse models of Down syndrome, suggest how the chromosome sequence may help in understanding the complex Down syndrome phenotype.     

Origin of extra chromosome in Patau syndrome

Summary Five live-born infants with Patau syndrome were studied for the nondisjunctional origin of the extra chromosome. Transmission modes of chromosomes 13 from parents to a child were determined using both QFQ- and RFA-heteromorphims as markers, and the origin was ascertained in all of the patients. The extra chromosome had originated in nondisjunction at the maternal first meiotic division in two patients, at the maternal second meiosis in other two, and at the paternal first meiosis in the remaining one.Summarizing the results of the present study, together with those of the previous studies on a liveborn and abortuses with trisomy 13, nondisjunction at the maternal and the paternal meiosis occurred in this trisomy in the ratio of 14:3. This ratio is not statistically different from that inferred from the previous studies for Down syndrome. These findings suggest that there may be a fundamental mechanism common to the occurrence of nondisjunction in the acrocentric trisomies.     

A de novo reciprocal t(2;18) translocation with regular trisomy 21

A 4-year-old girl with Down syndrome exhibited an autosomal translocation t(2;18) in addition to trisomy 21. An evaluation of GTG-banded metaphases revealed the karyotype 47,XX,t(2;18),21 that was confirmed by using fluorescent in situ hybridization (FISH) probes. This case represents a very rare coincidence of an autosomal aneuploidy and a structural rearrangement. Her parents showed a normal chromosome complement. The translocation must have been an apparently "balanced" one as the proband presented with typical features of Down syndrome alone. The mechanism of origin of this rearrangement along with a nondisjunctional error and its significance are discussed.     

Mechanisms of ring chromosome formation in 11 cases of human ring chromosome 21

We studied the mechanism of ring chromosome 21 (r(21)) formation in 13 patients (11 unique r(21)s), consisting of 7 from five families with familial r(21) and 6 with de novo r(21). The copy number of chromosome 21 sequences in the rings of these patients was determined by quantitative dosage analyses for 13 loci on 21q. Nine of 11 r(21)s, including the 5 familial r(21)s, showed no evidence for duplication of 21q sequences but did show molecular evidence of partial deletion of 21q. These data were consistent with the breakage and reunion of short- and long-arm regions to form the r(21), resulting in deletion of varying amounts of 21q22.1 to 21qter. The data from one individual who had a Down syndrome phenotype were consistent with asymmetric breakage and reunion of 21q sequences from an intermediate isochromosome or Robertsonian translocation chromosome as reported by Wong et al. Another patient, who also exhibited Down syndrome, showed evidence of a third mechanism of ring formation. The likely initial event was breakage and reunion of the short and long arms, resulting in a small r(21), followed by a sister-chromatid exchange resulting in a double-sized and symmetrically dicentric r(21). The phenotype of patients correlated well with the extent of deletion or duplication of chromosome 21 sequences. These data demonstrate three mechanisms of r(21) formation and show that the phenotype of r(21) patients varies with the extent of chromosome 21 monosomy or trisomy.     

Maternal balanced translocation (4;21) leading to an offspring with partial duplication of 4q and 21q without phenotypic manifestations of Down syndrome

We describe an 8-years old female with supernumerary chromosome der(21)t(4;21)(q25;q22) resulting in partial trisomy 4q25-qter and partial trisomy 21(pter-q22). The extra material was originated from a reciprocal balanced translocation carrier mother (4q;21q). Karyotyping was confirmed by FISH using whole chromosome painting probes for 4 and 21q and using 21q22.13-q22.2 specific probe to rule out trisomy of Down syndrome critical region. Phenotypic and cytogenetic findings were compared with previously published cases of partial trisomy 4q and 21q. Our patient had the major criteria of distal trisomy 4q namely severe psychomotor retardation, growth retardation, microcephaly, hearing impairment, specific facies (broad nasal root, hypertelorism, ptosis, narrow palpebral fissures, long eye lashes, long philtrum, carp like mouth and malformed ears) and thumbs and minor feet anomalies. In spite of detection of most of the 3 copies of chromosome 21, specific features of Down syndrome (DS) were lacked in this patient, except for notable bilateral symmetrical calcification of basal ganglia. This report represents further delineation of the phenotype-genotype correlation of trisomy 4q syndrome. It also supports that DS phenotype is closely linked to 21q22. Nevertheless, presence of basal ganglia calcification in this patient may point out to a more proximal region contributing in its development in DS, or that genes outside the critical region may influence or control manifestations of DS features.     

Molecular cytogenetic study of Robertsonian translocation 13;14 and Down syndrome in a 3-year-old infant

We describe here a rare case of Robertsonian translocation 13;14 of maternal origin combined with regular trisomy 21 (46,XX,der(13;14)(q10;q10)mat,+21) with Down syndrome phenotype. Molecular cytogenetic studies allowed us to determine the maternal origin of additional chromosome 21 and the non-disjunction of chromosome 21 to occur in meiosis I. On the basis of data obtained we discuss the possible involvement of structural alterations of chromosomes 13 and 14 in the chromosome 21 non-disjunction.     

Double autosomal aberration: trisomy 21 and familial reciprocal translocation t(10;12)(p14;q21)]

A child with the Down syndrome revealed besides a regular trisomy 21, an enlargment of the short arm of chromosome 10, and the deletion of the long arm of chromosome 12. The proband's mother, who was phenothypically normal woman, appeared to be a carrier of the reciprocal translocation, her karyotype being: 46, XX, rep (10;12) (10qter leads to leads to 10p14; 12q21 leads to 12qter; 12pter leads to 12q21 : 10p14 leads to 10pter). Hence, the proband had double chromosomal aberration 47, XX, +21, rcp (10; 12) (10qter leads to 10p14 : 12q21 leads to leads to 12qter; 12pter leads to 12q21 : 10p14 leads to 10pter) mat. There is no reason to relate hard manifistation of the Down syndrome with the detected translocation. The influence of the mathernal non-devision in the meiosis and the rise of the trisomy 21 is discussed. In the following pregnancies it is advisable to amniocentesis.     

Interchange trisomy 21 by t(1;21)(p22;q22)mat

Interchange trisomy 21 by t(1:21)(p22:q22)mat: Interchange trisomy 21 by t(1;21)(p22;q22)mat was identified in a sporadic patient with Down syndrome. With a 21q22 specific probe, we observed signals on both normal 21 chromosomes and on the der. We reviewed the 23 published reports of families with reciprocal translocations leading to viable offspring with interchange trisomy 21. The breakpoints in chromosome 21 were mainly located in 21q (19/24 instances, including the present report) and in 19/23 cases the other chromosome involved in the translocation was (pairs 1-12). The underlying 3:1 segregation occurred mainly in carrier mothers; only one patient presented a de novo imbalance and in another case the father was the carrier. In addition, there were 4 instances of concurrence with another unbalanced segregation (adjacent-1 or tertiary trisomy) and 3 families with recurrence of interchange trisomy 21. The mean age of 14 female carriers at birth of interchange trisomy 21 offspring (24.8 yr) was lower that the mean (28.3 yr) found in a larger sample of mothers of unbalanced offspring due to 3:1 segregation (mostly tertiary trisomics) and was not increased with respect to the general population average. Overall, these data agree with previous estimates regarding recurrence risk (9-15%) and abortion rate (about 28%) in female carriers ascertained through an interchange trisomic 21 child.     

Down syndrome and the genes of human chromosome 21: current knowledge and future potentials. Report on the Expert workshop on the biology of chromosome 21 genes: towards gene-phenotype correlations in Down syndrome. Washington D.C., September 28-October 1, 2007

Down syndrome (DS), trisomy of human chromosome 21, is the most common genetic cause of intellectual disability. With an incidence in some countries as high as one in approximately 700 live births, and a complex, extensive and variably severe phenotype, Down syndrome is a significant medical and social challenge. In recent years, there has been a rapid increase in information on the functions of the genes of human chromosome 21, as well as in techniques and resources for their analysis. A recent workshop brought together experts on the molecular biology of Down syndrome and chromosome 21 with interested researchers in other fields to discuss advances and potentials for generating gene-phenotype correlations. An additional goal of the workshop was to work towards identification of targets for therapeutics that will correct features of DS. A knowledge-based approach to therapeutics also requires the correlation of chromosome 21 gene function with phenotypic features.     

Unbalanced Robertsonian translocations associated with Down's syndrome or Patau's syndrome: Chromosome subtype,proportion inherited,mutation rates,and sex ratio

Summary Summary data are presented on 168 D/21 and 131 G/21 translocation trisomies reported to the New York State Chromosome Registry. By combining these data with others from the literature it is estimated that about 59% of D/21 cases are the result of mutation in the parental generation; the rest are translocations inherited from parental carriers (39% maternal, 3% paternal). The proportion of mutants is about 10% greater for 14/21 cases and significant lower for 13/21 cases. Of G/21 cases 93% are mutant, about 6% of maternal origin, and 1% of paternal origin. All the mutant cases involve 21/21 rearrangements. Estimated mutation rates per 10⁵ gametes for translocation trisomies in affected livebirths are 0.1 for 21/13, 0.5 to 0.9 for 21/14, and 1.1 to 1.4 for 21/21. The rates for 21/15 and 21/22 translocation trisomies are probably all conservatively less than 0.1 per 10⁵ gametes. Of interchange trisomy Patau's syndrome, about 60% of cases are mutant; the rest are translocations inherited from a parental carrier (about 25% for 13/13 cases and about 45% for 13/14 cases. The estimated mutation rates for 13/13 and 13/14 interchange trisomies are each about 0.5 per 10⁵ gametes; the rate for 13/15 interchange trisomies is less than 0.1 per 10⁵ gametes. A male excess is observed for D/21 (sex ratio=1.70), and G/21 (sex ratio=1.38) interchange Down's syndrome, and a female excess for D/13 interchange Patau's syndrome (sex ratio =0.77), trends similar to those seen in the respective 47, trisomies associated with these phenotypes.     

Mutation rates for unbalanced Robertsonian translocations associated with Down syndrome. Evidence for a temporal change in New York State live births 1968--1977.

The mutation rate for translocation Down syndrome was investigated for New York State live births for each of the years 1968--1977 using data from the New York State Chromosome Registry. The overall rate was 2.5 X 10(-5) per gamete (1.4 X 10(-5) for G/21 and 1.0 X 10(-5) for D/21 rearrangements), about 20% higher than rates previously reported by two other studies. For the first 5-year period, 1968--1972, the rate was 1.8 X 10(-5), and for the second 5-year period, 3.1 X 10(-5); there was an abrupt change in 1973 and 1974 to rates more than twice that in the 3 preceding years. These rates were derived by applying completeness estimates for all cases of Down syndrome, mostly 47,trisomy 21, in the jurisdiction to cases with translocation Down syndrome mutations. If completeness corrections are ignored and only the minimum boundaries of rates are considered, however, the increase in 1973 and 1974 was even greater compared with the previous 3 years. The trends, if not attributable to an undetected artifact, may have been caused by an increased frequency of mutant zygotes and/or enhanced intrauterine survival of mutant translocations.     

Pericentric inversions of chromosome 12 in two families

Summary Two cases of pericentric inversion of chromosome 12 are presented, one 46,XX,inv(12)(p13;q11) and the other 47,XX,+21,inv(12)(p13;q13). In both cases one of the parents was also a heterozygotic carrier of the inversion. These inversions were detected among 4035 cytogenetic analyses carried out in patients with psychosomatic retardation and/or malformations (357 with a Down phenotype) and in patients with histories of miscarriages, sterility, or growth failure.In cases studied from a review of the literature together with our own we found that among 3235 cases of Down syndrome there were 7 patients with trisomy 21 and inherited balanced reciprocal translocation involving chromosomes other than pair 21. The frequent participation of some chromosomes in these balanced reciprocal translocations, above all those of group A (1–3), suggests that these and probably other rearrangements could make the segregation of chromosome 21 easier.     

Sex ratio in Down syndrome

Data from 55 publications providing the sex ratio (SR), i.e. ratio between male and female cases of Down syndrome (DS), are presented. In general, SR was skewed toward an excess of males in the majority of studied populations, either in populations with a high level of cases ascertainment (epidemiological studies) or in selected groups. No significant correlation involving the age of either patients or mothers was found. Some other factors which might influence the sex ratio in DS at birth are mentioned. Meta-analysis of data from epidemiological studies suggests the phenomenon is not restricted to free trisomy 21 alone but appears in translocation cases, both in mutant and inherited translocation carriers (SR = 1.31 and 1.36, respectively). In contrast to nonmosaic 47, +21 cases, where SR is close to 1.3, an excess of females was observed in mosaics 46/47, +21 (SR = 0.83). No male predominance was found among patients with DS not tested cytogenetically (SR = 0.98), which may be explained by female predominance in false-positive cases. In populations with a fraction of clinically diagnosed cases of 30% and over, SR has intermediate value of 1.1. The ratio showed a tendency to increase since 1940's, reaching a mean value of 1.35 in 1980's varying from 1.3 to 1.62 in different populations), which might be a consequence of the growing use of karyotyping to confirm diagnosis and of a real increase in proportion of males. In the 1990's, the ratio fell to 1.22 varying from 1.03 to 1.27. As SR is assumed to reflect a proportion of paternal contribution, the discrepancy between the proportions of paternal errors in cytogenetic studies on parental origin of the extra chromosome (24% in the 1980's) and in molecular studies (5-10% in the 1990's) discussed in the literature might be explained by temporal changes alone. Genetic mechanisms of male predominance in trisomy 21 are reviewed, among them models for joint segregation of chromosome 21 and Y chromosome in spermatogenesis, and the chromosome 21 nondisjunction during 2nd meiotic division of oogenesis caused by Y chromosome-bearing spermatozoa.     

Trisomy 21 mosaicism in two subjects from two generations.

In the course of a chromosome fragility investigation on the cancer prone hereditary disorder xeroderma pigmentosum, a low proportion of cells with a 47,XY,+21 karyotype was found in lymphocyte cultures of a patient not showing any Down syndrome symptom. The presence of trisomy 21 mosaicism was demonstrated also in peripheral blood of the healthy father and confirmed by "chromosome painting" that allowed a rapid detection of chromosomes 21 on metaphase cells and interphase nuclei. The trisomic cell line was not detected in fibroblast cultures. The analysis of chromosome 21 heteromorphism indicated that in both subjects the mosaic could result from either a diploid or an aneuploid zygote. Since in the trisomic cell line of the father and the son the extra chromosome 21 seems to be the same, a predisposition toward mitotic errors (non-disjunction or anaphase lagging) may be postulated, leading to the recurrent gain or loss of a specific chromosome 21. In order to test the hypothesis of an abnormal mitotic behaviour of the chromosome 21, we investigated the centromere separation index and the DNA restriction pattern in Southern blots probed with satellite DNA sequences specific for chromosome 21 centromere. Both the approaches did not reveal any peculiar feature that may account for the genetically determined proneness to mitotic error observed in the family.     

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.