The associations of acrocentric chromosomes in the parents of Down's syndrome children (a review of the literature)]

A point of view has been recently maintained that, as data are accumulated, the role of the association activity as a cause of acrocentric chromosome nondisjunction is not confirmed. Data are reviewed concerning all the studies available in the literature on the frequency and pattern of acrocentric associations in parents of the Down's syndrome patients. From these data it is evident that the nucleolar organizing activity is an important factor in etiology of trisomy 21. Reasons of some negative results occasionally reported are discussed.     

Unusual genotypes in the COL6A1 gene in parents of children with trisomy 21 and major congenital heart defects

Collagen type VI is a candidate for a role in the pathogenesis of congenital heart defects (CHD) in Down's syndrome. Three restriction fragment length polymorphisms of the COL6A1 gene were used to determine COL6A1 genotypes in 50 families of affected children with trisomy 21 (29 with congenital heart defects and 21 without) and 37 unrelated volunteers. We found seven unusual genotypes in the parents of affected children with Down's syndrome, five being unique to the parents of children with trisomy 21 and CHD. There were no unusual genotypes associated with other chromosome 21 loci. No single COL6A1 genotype was associated with CHD. Thus, the unusual genotypes unique to parents of affected children suggest that genetic variation in the COL6A1 gene region contributes to the pathogenesis of CHD in Down's syndrome.     

Relationships between satellite association and the occurrence of non-disjunction in man.

It has been reported that there is an increased incidence of Down's syndrome among the children of parents who have been exposed to ionizing radiations for radiodiagnostic or radiotherapeutic reasons. Work with Drosophila, mice and human lymphocytes has shown that irradiation with X- or gamma-rays induces aneuploidy, presumably by non-disjunction. It has been suggested that in man the frequency of satellite association (s.a.) of acrocentric chromosomes may be involved in the causation of chromosomal non-disjunction. In the present work the effects of radiation on s.a. have, therefore, been investigated. The frequency of s.a. between acrocentric chromosomes was determined after the exposure of human blood from normal and chromosomally abnormal individuals to various small doses of Co-60 gamma-rays. The criteria of Zang and Back were used for the evaluation of s.a. complexes. No effects of radiation on the frequency of s.a. were apparent within the dose range investigated. The same result was obtained when s.a. was evaluated using the silver-staining technique in which physical connections between the associating satellites may be observed and the association complexes evaluated directly. The effects of other radiation sources have also been investigated.     

The origin of the extra chromosome 21 in Down syndrome. Studies of fluorescent variants and satelite association in 26 informative families.

Studies of fluorescence and other chromosomal variants were informative in 26 out of 72 families. Maternal nondisjunction was found in 19 and paternal in 7 cases. Satellite association studies of these parents and 94 controls from the same age group showed a highly significant increase in the satellite association index (AI) for chromosome 21 in the parents where the nondisjunctional event had taken place. The AI was also higher for chromosome 14. In addition, the parents who produced the normal gametes had significantly higher AI's for some acrocentrics than the controls. Exogenous factors increasing satellite association cannot be ruled out. The number of 21-21 association was significantly increased in the parents with nondisjunction in meiosis 1. The results indicate that satellite association may play a role in the etiology of Down syndrome.     

Double satellites do not increase the risk of chromosome 21 nondisjunction

The hypothesis concerning the increase of the risk of appearance of offsprings with trisomy 21 in parents having double satellite acrocentric chromosomes is checked. Chromosomes of 266 parents having offsprings with Down's disease were examined, including 73 donors of extrachromosome 21. The frequency of chromosomes with dNORs in the total and in the donor groups did not differ from that of the control group. From 42 donors of extrachromosome, who demonstrated a nondisjunction in the first meiotic division, double satellites were revealed only once. In addition, data on the frequency of Dp+ and Gp+ variants are presented and discussed.     

Evidence for the inheritance of silver-stained nucleolus organizer regions

Summary The inheritance of nucleolus organizer regions (NORs) was investigated by examining the degree of silver-staining in individual acrocentric chromosomes in two successive generations. The study was undertaken in six Down's syndrome children and their respective parents. Quinacrine fluorescent polymorphisms were used to identify individual acrocentrics and to determine which of the child's acrocentrics were informative as to parental homologue of origin. Of the 66 acrocentrics in the six children, 31 were informative. The correlation between the degree of silver-staining in the child's chromosomes and the respective parental chromosomes of origin was highly significant (P<0.001), with a correlation coefficient of 0.90. The results suggest that the degree of Ag-AS staining is characteristic for a particular chromosome and that this characteristic is an inherited property.     

Segregation of acrocentric chromosome association in familial dicentric Robertsonian translocation t(14p;22p), aneuploidy (trisomy-21) and heteromorphism

The frequency and types of acrocentric chromosome association were quantitatively analysed in a Down syndrome child with unusual karyotype, 46, XX, -14, -22, t dic (14p;22p), +21, 21S+. Father and 4 sibs were heterozygous carriers for t dic (14p;22p). The variant 21S+ was inherited from the mother. The occurrence of translocation and trisomy in the same individual is extremely rare. Acrocentric chromosome association was analysed in this interesting family to understand the interrelationship of acrocentric chromosome association, Robertsonian translocation and heteromorphism, as possible predisposing factors for nondisjunction. Our findings suggest that acrocentric chromosome association is a heritable and nonrandom phenomenon. Heterozygous carriers for translocations and variants are likely to be at increased risk of nondisjunction. Long term family studies will enable to ascertain the causal-relationship of these factors more precisely.     

RHG-band polymorphism of the short arms of human acrocentric chromosomes and relationship of variants to satellite associations

Summary The extent of RHG-band variation of short arms of human acrocentric chromosomes was investigated in a group of 100 subjects by visually comparing the variants with the size of reference bands 7p22, 21q22 and 11q13. Marked differences were found among the chromosomes in the distribution of variants; the largest mean size of RHG-band was associated with chromosome 21, whereas the variants of chromosome 22 had the smallest band size. The study further showed that the involvement of acrocentric chromosomes in satellite association did not depend upon the size of RHG-band variants.     

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.     

The “happy puppet” syndrome in two siblings

Summary Disomic and trisomic cells of a patient with Down syndrome mosaic were used to study the effect of the additional chromosome 21 against an identical genetic background. The frequency of Ag staining and the participation in satellite associations were determined for each pair of acrocentric chromosomes. The additional chromosome 21 of the trisomic cells and its homologues proved to be regularly Ag positive. Therefore the trisomic cells showed more Ag positive chromosomes and more satellite associations per cell than the diploid cells. Thus, no compensation for the additional rRNA-gene dose could be found in the cells of the trisomic line.     

The occurrence of a ring 18, an accessory bisatellited fragment,and trisomy 21 within one sibship

Summary A family is presented in which there were three different chromosome abnormalities in the children although the parents were cytogenetically normal. The proband had the karyotype 46,XX,r(18)(p11q23), a phenotypically normal brother was 47,XY,+mar, and another brother was a typical case of Down's syndrome, karyotype 47,XY,+21. There is nothing in the parents' history that provides grounds for a hypothesis to explain the coincidence of the abnormalities.     

Translocation (14;21)(q11;q22) in a woman with history of abortions and a child with Down's syndrome

A translocation (14;21)(q11;q22) was observed in a woman with history of abortions and in her child with Down's syndrome. This appears to be the first report of such a translocation with no centric fusion between the acrocentric chromosomes leading to a count of 45 chromosomes in the carrier and giving birth to a Down's syndrome child.     

A family with three sibs carrying trisomy 21.

A family with three sibs, including a pair of dizygotic twins, all affected by Down's syndrome with regular trisomy 21, is described. The chromosome counts carried out on prolonged fibroblasts cultures of the mother, revealed the presence of the trisomy 21 in 6 out of 688 scored mitoses. The cytological findings give support to the hypothesis of a chromosome mosaicism in one of the normal parents, as a cause of the recurrence of the trisomy 21.     

人类核仁形成区结构性变异与随体联合的研究

本文以硝酸银染色法研究了200对正常夫妇及200对唐氏综合征(DS)患者双亲淋巴细胞染色体核仁形成区(NOR)。结果发现双核仁形成区(dNOR)的检出率在两组人群中均为0.5％;随体联合(SA)的结果表明,负有dNOR染色体的SA频率并不随其核糖体RNA(rRNA)基因含量的明显增加而上升,提示除rRNA基因含量及其活性外,尚有其他因素影响SA的形成。dNOR携带者与DS的发生亦无明显关系。     

Molecular cytogenetic characterization of 17 rob(13q14q) Robertsonian translocations by FISH, narrowing the region containing the breakpoints.

We have characterized 17 rob(13q14q) Robertsonian translocations, using six molecular probes that hybridize to the repetitive sequences of the centromeric and shortarm regions of the five acrocentric chromosomes by FISH. The rearrangements include six de novo rearrangements and the chromosomally normal parents, five maternally and three paternally inherited translocations, and three translocations of unknown origin. The D21Z1/D13Z1 and D14Z1/D22Z1 centromeric alpha-satellite DNA probes showed all rob(13q14q) chromosomes to be dicentric. The rDNA probes did not show hybridization on any of the 17 cases studied. The pTRS-47 satellite III DNA probe specific for chromosomes 14 and 22 was retained around the breakpoints in all cases. However, the pTRS-63 satellite III DNA probe specific for chromosome 14 did not show any signals on the translocation chromosomes examined. In 16 of 17 translocations studied, strong hybridization signals on the translocations were detected with the pTRI-6 satellite I DNA probe specific for chromosome 13. All parents of the six de novo rob(13q14q), including one whose pTRI-6 sequence was lost, showed strong positive hybridization signals on each pair of chromosomes 14 and 13, with pTRS-47, pTRS-63, and pTRI-6. Therefore, the translocation breakpoints in the majority of rob(13q14q) are between the pTRS-47 and pTRS-63 sequences in the p11 region of chromosome 14 and between the pTRI-6 and rDNA sequences within the p11 region of chromosome 13.     

Parental origin of chromosomes in Down's syndrome

Summary The number of 21 chromosomes of 15 individuals with Down's syndrome and their parents were examined in an attempt to determine the parental origin of the extra number 21 chromosome and the stage of meiosis at which nondisjunction occurred. Chromosomes were stained with quinacrine hydrochloride and photographed; serial prints were made ranging from underexposed to overexposed. Twelve of the 15 families (80%) were informative: nondisjunction occurred in maternal meiosis I in eight (66.7%) families, in paternal meiosis I in two (16.7%) families, and in paternal meiosis II in two (16.7%) families. The production of serial exposures of chromosomes at the time of printing proved to be a valuable method of enhancing slight differences in short arm and satellite structure of the number 21 chromosomes and thereby increasing the number of informative families.     

Dermatoglyphics of the relatives of children with congenital defects in development]

The localization of an axial triradius and the flexor creases were studied in 173 phenotypically normal mothers and 104 fathers of congenitally malformed children. The most pronounced changes ofdermatoglyphics were found in the parents of children with polygenic determined defects, less pronounced ones-- in the parents of children with multiple congenital non-chromosomal defects and with Down's syndrome. The frequency of the pathological features studied was similar both in children with polygenically determined isolated defects and with Down's syndrome. The frequency of the pathological determined isolated defects and in their parents. In multiple congenital defects and in Down's syndrome the abnormalities ofof the localization of an axial triradius and of the flexor creases were found in children more frequently than in the parents. It is suggested that the above mentioned peculiarities of parental dermatoglyphics may be useful for the genetic counsleling.     

Preferential association of nucleolar organizing human chromosomes as revealed by silver staining technique at mitosis

Summary The frequency of different types of satellite associations of nucleolar organizing human chromosomes (i.e. acrocentric chromosomes; 13, 14, 15, 21, and 22) is reported using 10 normal individuals by Ag-staining technique. The preferential involvement of acrocentric chromosomes in satellite association is suggested. Only acrocentric chromosomes with active NORs (i.e. Ag-stained) were found in association while unstained (inactive NORs) chromosomes were never seen in satellite association. In general as number of NORs expression increase, the frequency of association per cell was also increased. A possible mechanism and the clinical consequences of such an unusual phenophenon is described.     

Reexamination of paternal age effect in Down's syndrome

Summary The recent discovery that the extra chromosome in about 30% of cases of 47, trisomy 21 is of paternal origin has revived interest in the possibility of paternal age as a risk factor for a Down syndrome birth, independent of maternal age. Parental age distribution for 611 Down's syndrome 47,+21 cases was studied. The mean paternal age was 0.16 year greater than in the entire population of live births after controlling for maternal age. There was no evidence for a significant paternal age effect at the 0.05 level. For 242 of these Down's syndrome cases, control subjects were selected by rigidly matching in a systematic manner. Paternal age was the variable studied, with maternal age and time and place of birth controlled. There was no statistically significant association between paternal age and Down's syndrome. After adjustment for maternal age, these two studies were not consistent with an increase of paternal age in Down's syndrome.     

Homologous alpha satellite sequences on human acrocentric chromosomes with selectivity for chromosomes 13, 14 and 21: implications for recombination between nonhomologues and Robertsonian translocations.

We report a new subfamily of alpha satellite DNA (pTRA-2) which is found on all the human acrocentric chromosomes. The alphoid nature of the cloned DNA was established by partial sequencing. Southern analysis of restriction enzyme-digested DNA fragments from mouse/human hybrid cells containing only human chromosome 21 showed that the predominant higher-order repeating unit for pTRA-2 is a 3.9 kb structure. Analysis of a "consensus" in situ hybridisation profile derived from 13 normal individuals revealed the localisation of 73% of all centromeric autoradiographic grains over the five acrocentric chromosomes, with the following distribution: 20.4%, 21.5%, 17.1%, 7.3% and 6.5% on chromosomes 13, 14, 21, 15 and 22 respectively. An average of 1.4% of grains was found on the centromere of each of the remaining 19 nonacrocentric chromosomes. These results indicate the presence of a common subfamily of alpha satellite DNA on the five acrocentric chromosomes and suggest an evolutionary process consistent with recombination exchange of sequences between the nonhomologues. The results further suggests that such exchanges are more selective for chromosomes 13, 14 and 21 than for chromosomes 15 and 22. The possible role of centromeric alpha satellite DNA in the aetiology of 13q14q and 14q21q Robertsonian translocations involving the common and nonrandom association of chromosomes 13 and 14, and 14 and 21 is discussed.