Multiple recurrence of trisomy 21 Down syndrome

Summary A young family with four chromosomally documented cases of trisomy 21, at least two, further cases of Down syndrome diagnosed only clinically, and no healthy children among their offspring is reported. No sign of mosaicism was found in studies of lymphocytes and skin fibroblasts from the parents. In a biopsy from the mother's ovary a trisomic cell line was found, thus giving some, but not a complete explanation for this extraordinary family. Additional explanations are suggested.     

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.     

A patient with partial trisomy 21 and 7q deletion expresses mild Down syndrome phenotype

Backround

Down syndrome (DS) is the most common aneuploidy in live-born individuals and it is well recognized with various phenotypic expressions. Although an extra chromosome 21 is the genetic cause for DS, specific phenotypic features may result from the duplication of smaller regions of the chromosome and more studies need to define genotypic and phenotypic correlations.

Case report

We report on a 26 year old male with partial trisomy 21 presenting mild clinical symptoms relative to DS including borderline intellectual disability. In particular, the face and the presence of hypotonia and keratoconus were suggestive for the DS although the condition remained unnoticed until his adult age array comparative genomic hybridization (aCGH) revealed a 10.1 Mb duplication in 21q22.13q22.3 and a small deletion of 2.2 Mb on chromosomal band 7q36 arising from a paternal translocation t(7;21). The 21q duplication encompasses the gene DYRK1.

Conclusion

Our data support the evidence of specific regions on distal 21q whose duplication results in phenotypes recalling the typical DS face. Although the duplication region contains DYRK1, which has previously been implicated in the causation of DS, our patient has a borderline IQ confirming that their duplication is not sufficient to cause the full DS phenotype.     

Submicroscopic duplication of chromosome 21 and trisomy 21 phenotype (Down syndrome)

Summary A patient with the phenotype of trisomy 21 (Down syndrome) was found to have a normal karyotype in blood lymphocytes and fibroblasts. Assessment of the chromosome 21 markers SOD1, CBS, ETS2, D21S11, and BCEI showed partial trisomy by duplication of a chromosome segment carrying the SOD1, CBS, and ETS2 loci and flanked by the BCEI and D21S11 loci, which are not duplicated. This submicroscopic duplication at the interface of 21q21 and 21q22.1 reduces to about 2000–3000kb the critical segment the trisomy of which is responsible for the phenotype of trisomy 21.     

Equine half sibs with an unbalanced X;15 translocation or trisomy 28

Two unrelated chromosome abnormalities were found in equine half sibs. The proposita, Case 1, which was short in stature and infertile, had a de novo unbalanced X;15 translocation involving loss of Xp. Replication studies indicated that the translocated X was preferentially late replicating and that this late replication spread variably into the autosomal segment. Case 2, a half brother of the proposita, was short in stature, had cryptorchidism, and was trisomic for chromosome 28. Cytogenetic analysis of the dam, the sire of Case 1, and two other phenotypically normal half sibs revealed normal chromosome complements. Five further normal pregnancies were reported. The finding of two unrelated chromosome abnormalities is therefore probably fortuitous in this family. This is the first case of an unbalanced X-autosome translocation and the first case of an autosome trisomy to be reported in the horse.     

Physical mapping of the mitochondrial genome of Arabidopsis thaliana by cosmid and YAC clones

As part of the worldwide efforts at molecular analysis of Arabidopsis thaliana as a model plant the complete structure of the mitochondrial genome has been determined. The mitochondrial DNA molecules were mapped by restriction fragment analysis of more than 300 cosmid clones and purified mitochondrial DNA. The entire genome of 372 kb is contained in three different configurations of circular molecules and is split into two additional subgenomic molecules of 234 kb and 138 kb, respectively. These arrangements result from recombinations of the two sets of repeats present in combinations of inverted and/or direct orientation. Alignment of YAC clones confirms the in vivo presence of continuous DNA molecules of more than 300 kb in A. thaliana mitochondria. The presence of this comparatively large mitochondrial genome in a plant with one of the smallest nuclear genomes shows that different size constraints act upon the different genomes in plant cells.     

Partial trisomy and monosomy 21 in an infant with an unusual de novo 21/21 translocation

A 3-month-old boy with a 46,XY,--21,+t(21;21)(pter leads to q22.3::q22.3 leads to q11::p11 leads to pter) karyotype, implicating trisomy for the 21q11 leads to 21q22.2 segment and monosomy for the 21q22.3 sub-band, is described. Most of the clinical features corresponded to Down syndrome ; other signs such as large ears, prominent nasal bridge and retromicrognathia were interpreted as the expression of 21q22.3 monosomy. The abnormal monocentric chromosome had satellites and stalks on both ends as a result of a 21q;21q translocation followed by deletion of one centromere region. Despite similar stalk size and NOR-Ag positiveness a significantly higher association frequency of the centrometric end as compared to the acentric end was found. This observation suggests that the satellite association phenomenon is not exclusively NOR-dependent, but that the centromeric and/or p11 regions of acrocentrics also play an important role.     

Characterization of familial partial 10p trisomy by chromosomal microdissection,FISH, and microsatellite dosage analysis

Unbalanced translocations are a frequent cause of multiple congenital anomalies in children. Translocations as small as 2–5 Mb of DNA are detectable by G-banding under optimal conditions. Some of these small translocations are visible but cannot be characterized cytogenetically due to the lack of characteristic banding on Giemsa preparations. We have combined chromosomal microdissection and fluorescence in situ hybridization (FISH) to identify the origin of a small translocated segment in three members of a family with a derivative chromosome 9 and multiple anomalies, including several ophthalmologic anomalies. We microdissected the abnormal region of the derivative 9 chromosome and used this DNA to generate a FISH probe. This probe hybridized to distal 10p on the metaphase spread of the proband, indicating the origin of the translocated segment. A whole 10p FISH probe confirmed the origin by hybridizing to the translocated segment of the derivative chromosome. FISH was then performed with a whole chromosome 9 painting probe and excluded the presence of a reciprocal, balancing translocation. We then studied the chromosome 10 partial duplication with microsatellite markers to better characterize the chromosomal segment that caused these phenotypic features. By examining the involved areas with distal 10p and 9p microsatellite markers, we were able to demonstrate a minimum of 9 Mb of trisomic 10p DNA with a chromosomal breakpoint between 10p14– 10p15. We then compared this family’s clinical findings to those of individuals with partial 10p trisomy who had been reported in the literature. The clinical phenotypes seen in this family are similar to, but milder than, the phenotypes of persons with the larger partial trisomies of 10p that were diagnosable by cytogenetic analysis alone. This study shows that microdissection and DNA markers can be used to precisely define small translocations that are difficult to identify by conventional G-banded chromosome analysis. Received: 29 February 1996 / Revised: 19 April 1996     

Mouse trisomy 16 as an animal model of human trisomy 21 (Down syndrome): production of viable trisomy 16 diploid mouse chimeras

We have previously proposed that mice trisomic for chromosome 16 will provide an animal model of human trisomy 21 (Down syndrome). However, the value of this model is limited to some extent because trisomy 16 mouse fetuses do not survive as live-born animals. Therefore, in an effort to produce viable mice with cells trisomic for chromosome 16, we have used an aggregation technique to generate trisomy 16 diploid (Ts 16 2n) chimeras. A total of 79 chimeric mice were produced, 11 of which were Ts 16 2n chimeras. Seven of these Ts 16 2n mice were analyzed as fetuses, just prior to birth, and 4 were analyzed as live-born animals. Unlike nonchimeric Ts 16 mouse fetuses which die shortly before birth with edema, congenital heart disease, and thymic and splenic hypoplasia, all but 1 of the Ts 16 2n animals were viable and phenotypically normal. The oldest of the live-born Ts 16 2n chimeras was 12 months old at the time of necropsy. Ts 16 cells, identified by coat color, enzyme marker, and/or karyotype analyses, comprised 50-60% of the brain, heart, lung, liver, and kidney in the 7 Ts 16 2n chimeric fetuses and 30-40% of these organs in the 4 live-born Ts 16 2n animals. Ts 16 cells comprised an average of 40% of the thymus and 80% of the spleen in the Ts 16 2n chimeras analyzed as fetuses, with no evidence of thymic or splenic hypoplasia. However, we observed a marked deficiency to Ts 16 cells in the blood, spleen, thymus, and bone marrow of live-born Ts 16 2n chimeras as compared to 2n 2n controls. These results demonstrate that although the Ts 16 2n chimeras were, with one exception, viable and phenotypically normal, each animal contained a significant proportion of trisomic cells in a variety of tissues, including the brain. Furthermore, our results suggest that although the abnormal development of Ts 16 thymus and spleen cells observed in Ts 16 fetuses is largely corrected in Ts 16 2n fetuses, Ts 16 erythroid and lymphoid cells have a severe proliferative disadvantage as compared to diploid cells in older live-born Ts 16 2n chimeras. Ts 16 2n chimeric mice will provide a valuable tool for studying the functional consequences of aneuploidy and may provide insight into the mechanisms by which trisomy 21 leads to developmental abnormalities in man.     

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.     

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.     

Origin of trisomy 21 in Down syndrome cases from a Spanish population registry

We have carried out a population-based study on the origin of the extra chromosome 21 in 38 families with Down syndrome (DS) offspring in El Vallès (Spain). From 1991 to 1994, a higher prevalence of DS (22.7/10000 live births, stillbirths and induced abortions) was found compared to the majority of EUROCAT registries. The distribution of trisomy 21 by origin was 88% maternal (90.6% meiosis I, 6.2% meiosis II, 3.1% maternal mosaicism), 5.6% paternal (50% meiosis I, 50% meiosis II) and 5.6% mitotic. The percentage of parental mosaicism was 2.7%. These percentages are similar to those previously reported. Recombination study revealed a maternal meiosis I genetic map of 32.68 cM (approximately one-half the length of the normal female map). Mean maternal age among non-recombinant cases involving MI errors was significantly lower (31.1 years) than among those cases showing one observable crossover (36.1 years) (P<0.05); this could support the hypothesis that 'achiasmate' chromosomes may be subject to aberrant segregation regardless of maternal age.     

A partial trisomy 15q due to 15;17 translocation detected by conventional cytogenetic and FISH techniques

We report a case having multiple abnormalities including the simultaneous presence of the heart defect and central nerve system abnormalities, which has been reported in a few cases, and with a partial trisomy 15q. Partial trisomy 15q has been inherited from a balanced translocation carried by his phenotypically normal father, detected by traditional banding and fluorescence in situ hybridization (FISH). Application of FISH using whole chromosome specific library probes, locus specific and repetitive probes allowed us to detect the translocation between chromosomes 15q and 17q. Simultaneous application of probes revealed the position of the translocation. Interestingly, in addition to the chromosomes 15 pericentromeric signals, the use of chromosome 15 beta-satellite III probe demonstrated an extra signal on chromosome 14 in both metaphase, and lighted three signals interphase nuclei which was inherited from his father. This patient is compared with other partial trisomy 15q patients reported in the literature. The results are also discussed in relation to genetic counselling for the possible relation of chromosome abnormality and clinical findings.     

Sex ratio in Down syndrome. Studies in patients with confirmed trisomy 21

Male to female ratio (sex ratio, SR) for 1,329 liveborns with Down syndrome and for 178,160 newborns from the general population of St. Petersburg, Russia was determined as a function of a mother age. Male prevalence (an overall SR of 1.24) was found in children with all trisomy 21 variants except the cases with mosaicism (the ratio of 0.88). The most expressed male predominance was determined in children of mothers aged 20-24 years, where SR was 1.73 in the total group (p = 0.00003) and 1.61 in the cases with free trisomy (p = 0.0007). Some hypotheses concerning the male accumulation in this group are discussed including a suggestion that the SR deviations from the population value 1.06 might be due to different contribution of paternal chromosomal non-disjunction during spermatogenesis.     

The trisomy 18 syndrome with an E/G translocation

Summary An infant with a typical Edwards syndrome and a modal chromosome number of 46 is reported. In all cells analyzed one chromosome G was missing and an additional chromosome similar to a pair No. 16 was present. The phenotype of the child indicates that the extra element is a translocation between G and 18 chromosomes as in one case described previously.     

Double aneuploidy: partial trisomy 21 and XO/XXX in a family with 12/21 translocation.

A female patient with mild mental retardation with spatial perceptual difficulties, microcephaly, depressed nasal root, receding chin, webbed neck, low hairline, shield chest, cubitus valgus, scoliosis and dermatoglyphic findings not characteristic of Down's syndrome is reported. In addition to X/XXX, she had a partial trisomy 21 of the short arm-centromere-proximal long arm segment due to maternal t(12;21) translocation. Two phenotypically normal siblings carried the balanced translocation.     

Risk of Down syndrome in relatives of trisomy 21 children. A case-control study

We conducted a case-control study in families of Down syndrome children with classical trisomy 21 (n = 188) and in a control group of families of children referred to the same hospital for benign diseases (n = 185). The low sibling number does not allow any conclusion about the risk for sibs but our results do not support an increased incidence of Down syndrome among second and third degree relatives of trisomy 21 children. The choice of the control group and the restriction to close relatives protect us against biases which may have interfered in previous studies reporting recurrence in families.     

The ratio of de novo unbalanced translocation to 47, trisomy 21 Down syndrome. A new method for human mutation surveillance and an apparent recent change in mutation rate resulting in human interchange trisomies in one jurisdiction.

The Down syndrome phenotype may be associated with, among other genotypes, an unbalanced Robertsonian translocation producing an "interchange trisomy" with 46 chromosomes, or 47, trisomy 21. Translocations, like specificlocus point mutations, result from a direct change in structural chromosome elements. In contrast 47, trisomy 21 results from meiotic non-disjunction. Mutation rates for interchange trisomies may be followed indirectly by determining the ratio of instances of Down syndrome associated with a new translocation mutation to those produced by 47, trisomy 21, which accounts for the bulk of the Down syndrome phenotype. This genotypic ratio can be analyzed in data from cytogenetic laboratories, clinics, and chromosome registries and does not depend upon intensive chromosome screening of newborn populations. A similar approach can be adopted to follow trends in Patau syndrome. The genotypic ratio, stratified by maternal age, may in addition, provide a sentinel index for changes in human specific-locus mutations and perhaps other adverse health consequences. Analysis of data from the New York State-North-eastern chromosome registry revealed a two- to three-fold increase in the genotypic ratio for both Down syndrome and Patau syndrome for individuals born in 1973, 1974 and 1975 compared to those born in earlier years.     

Altered calcium currents in cultured sensory neurons of normal and trisomy 16 mouse fetuses, an animal model for human trisomy 21 (Down syndrome)

Down syndrome is determined by the presence of an extra copy of autosome 21 and is expressed by multiple abnormalities, with mental retardation being the most striking feature. The condition results in altered electrical membrane properties of fetal dorsal root ganglia (DRG) neurons, as in the trisomy 16 fetal mouse, an animal model of the human condition. Cultured trisomic DRG neurons from human and mouse fetuses present faster rates of depolarization and repolarization in the action potential compared to normal controls and a shorter spike duration. Also, trisomy 16 brain and spinal cord tissue exhibit reduced acetylcholine secretion. Therefore, we decided to study Ca2+ currents in cultured DRG neurons from trisomy 16 and age-matched control mice, using the whole-cell patch-clamp technique. Trisomic neurons exhibited a 62% reduction in Ca2+ current amplitude and reduced voltage dependence of current activation at -30 and -20 mV levels. Also, trisomic neurons showed slower activation kinetics for Ca2+ currents, with up to 80% increase in time constant values. Kinetics of the inactivation phase were similar in both conditions. The results indicate that murine trisomy 16 alter Ca2+ currents, which may contribute to impaired cell function, including neurotransmitter release. These abnormalities also may alter neural development.