No significant effect of monosomy for distal 21q22.3 on the Down syndrome phenotype in “Mirror” duplications of chromosome 21

Three Down syndrome patients for whom karyotypic analysis showed a "mirror" (reverse tandem) duplication of chromosome 21 were studied by phenotypic, cytogenetic, and molecular methods. On high-resolution R-banding analysis performed in two cases, the size of the fusion 21q22.3 band was apparently less than twice the size of the normal 21q22.3, suggesting a partial deletion of distal 21q. The evaluation of eight chromosome 21 single-copy sequences of the 21q22 region--namely, SOD1, D21S15, D21S42, CRYA1, PFKL, CD18, COL6A1, and S100B--by a slot blot method showed in all three cases a partial deletion of 21q22.3 and partial monosomy. The translocation breakpoints were different in each patient, and in two cases the rearranged chromosome was found to be asymmetrical. The molecular definition of the monosomy 21 in each patient was, respectively, COL6A1-S100B, CD18-S100B, and PFKL-S100B. DNA polymorphism analysis indicated in all cases a homozygosity of the duplicated material. The duplicated region was maternal in two patients and paternal in one patient. These data suggest that the reverse tandem chromosomes did not result from a telomeric fusion between chromosomes 21 but from a translocation between sister chromatids. The phenotypes of these patients did not differ significantly from that of individuals with full trisomy 21, except in one case with large ears with an unfolded helix. The fact that monosomy of distal 21q22.3 in these patients resulted in a phenotype very similar to Down syndrome suggests that the duplication of the genes located in this part of chromosome 21 is not necessary for the pathogenesis of the Down syndrome features observed in these patients, including most of the facial and hand features, muscular hypotonia, cardiopathy of the Fallot tetralogy type, and part of the mental retardation.     

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.     

Severe psychomotor retardation in a boy with a supernumerary derivative chromosome resulting in partial trisomy 21 and partial trisomy 7p

We report on a 12-year-old boy with a supernumerary chromosome der(21)t(7; 21)(p21; q21.3)mat, resulting in a partial trisomy 21 and a partial trisomy 7p. The patient has a severe psychomotor retardation. Although he has most of chromosome 21 in three copies, he does not have a phenotype of Down syndrome (DS). In addition to cytogenetic analysis, molecular analysis confirmed that the "DS critical region" on chromosome 21 (21q22) is not present in three copies, since the breakpoint of the partial trisomy 21 was found to be located distal to the marker locus D21S145 but proximal to D21S226. The patient's severe mental retardation is probably due to the small telomeric 7p trisomy, having the breakpoint between markers D7S507 and D7S488. In comparison with previously published cases of partial trisomy 7p, the phenotype of this patient indicates that there is a region around the distal part of band 7p21 that in three copies might contribute to many of the facial features common to patients with partial trisomy 7p.     

18q部分单体患儿的细胞和分子遗传学研究

临床发现1例智力低下伴轻度发育迟缓的女性患儿,对患儿进行G显带高分辨染色体核型分析, 发现18q21→qter缺失, 经多色荧光原位杂交和双色荧光原位杂交证实, 确定其核型为46,XX,del(18)(pter→q21:),ish del(18)(D18Z1+, qter-)。用DNA多态性方法分析, 该患儿从18q22.1至18qter区域内至少有8.7 Mbp丢失, 有MBP基因和GALNR基因缺失。缺失的18号染色体源自父亲。患者的智力低下和生长发育迟缓是18q21→qter缺失的结果, 或许与MBP基因和GALNR基因的缺失有关。     

Molecular definition of a region of chromosome 21 that causes features of the Down syndrome phenotype

Down syndrome (DS) is a major cause of mental retardation and heart disease. Although it is usually caused by the presence of an extra chromosome 21, a subset of the diagnostic features may be caused by the presence of only band 21q22. We now present evidence that significantly narrows the chromosomal region responsible for several of the phenotypic features of DS. We report a molecular and cytogenetic analysis of a three-generation family containing four individuals with clinical DS as manifested by the characteristic facial appearance, endocardial cushion defect, mental retardation, and probably dermatoglyphic changes. Autoradiograms of quantitative Southern blots of DNAs from two affected sisters, their carrier father, and a normal control were analyzed after hybridization with two to six unique DNA sequences regionally mapped on chromosome 21. These include cDNA probes for the genes for CuZn-superoxide dismutase (SOD1) mapping in 21q22.1 and for the amyloid precursor protein (APP) mapping in 21q11.2-21.05, in addition to six probes for single-copy sequences: D21S46 in 21q11.2-21.05, D21S47 and SF57 in 21q22.1-22.3, and D21S39, D21S42, and D21S43 in 21q22.3. All sequences located in 21q22.3 were present in three copies in the affected individuals, whereas those located proximal to this region were present in only two copies. In the carrier father, all DNA sequences were present in only two copies. Cytogenetic analysis of affected individuals employing R and G banding of prometaphase preparations combined with in situ hybridization revealed a translocation of the region from very distal 21q22.1 to 21qter to chromosome 4q. Except for a possible phenotypic contribution from the deletion of chromosome band 4q35, these data provide a molecular definition of the minimal region of chromosome 21 which, when duplicated, generates the facial features, heart defect, a component of the mental retardation, and probably several of the dermatoglyphic changes of DS. This region may include parts of bands 21q22.2 and 21q22.3, but it must exclude the genes S0D1 and APP and most of band 21q22.1, specifically the region defined by S0D1, SF57 and D21S47.     

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.     

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.     

Distribution of meiotic recombination along nondisjunction chromosomes 21 in Down syndrome determined using cytogenetics and RFLP haplotyping

Summary Ten families (Down syndrome children and their parents) showing evidence of meiotic recombination between intraparental chromosomes transmitted after nondisjunction were studied. Cytogenetic polymorphisms and a cassette of RFLP markers distributed along chromosome 21 were used to analyze these families to localize the regions of meiotic recombination. Results indicated that only one crossover occurred per meiotic division and that nine of ten nondisjunctions appeared to be of maternal origin. In one family the crossover had taken place in the pericentromeric region, proximal to marker D21S13, which is quite exceptional. A chance of meiotic recombination within region 21q21, flanked by marker D21S72 and the amyloid gene, could be demonstrated in seven of the ten families. Most strikingly, this chance significantly decreased distal to q21, with frequencies of 0.3 and 0.1 in regions q22.2 and q22.3-qter, respectively. It is hypothesized that decreased chiasmata formation in the most distal part of chromosome 21q might promote nondisjunction. Furthermore, data from the ten crossovers made it possible to map provisionally two previously undefined markers, D21S24 and D21S82, to regions q21-qter and q22.1-qter, respectively.     

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.     

Two Down syndrome patients with rec(21),dupq,inv(21)(p11;q2109) from a familial pericentric inversion

Aneusomie de recombinaison arose from a familial pericentric inversion of a chromosome 21. Two female patients had a typical Down syndrome; one of them had slight psychomotor retardation. There was partial trisomy 21q2109----qter in these two patients but ZnCu SOD activity was normal.     

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.     

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.     

Partial trisomy 21

Summary Cytogenetic analysis of a 6-year-old girl with moderate mental retardation revealed 46 chromosomes with a tandem translocation (21;21) resulting in a partial trisomy 21. Only the terminal band 21q22 was not in triplicate. G-, Q-, R-, and C-banding techniques and silver nitrate staining of the nucleolus organizer regions (NORs) were used to identify this chromosome fully.The phenotype of the patient was not typical for Down's syndrome, providing additional evidence that trisomy of band 21q22 is pathogenetic for the phenotype of Down's syndrome. This is also a new example in human pathology of a stable dicentric chromosome in which one of the centromeric constrictions appears to be nonfunctional.     

Cloning of the cDNA for a human homolog of the rat PEP-19 gene and mapping to chromosome 21q22.2–q22.3

Exon trapping was used to identify fragments of genes on human chromosome 21. One trapped sequence, hmc18h10 (GenBank no. X88329), showed homology to a sequence (GenBank no. S65225) that includes the first three codons of the rat PEP-19 gene and 5′ untranslated leader region. We have cloned the corresponding cDNA for a human homolog of the rat PEP-19 gene and mapped it to the region between markers ERG and D21S56 of chromosome 21q22.2–q22.3. Rat PEP-19 is a neuron-specific polypeptide expressed in several regions of the central nervous system. It serves as a cell-specific marker in Purkinje cells and its expression is developmentally regulated in the cerebellum, but its precise function is unknown. It is also presently unknown whether overexpression of the PEP-19 gene is involved in certain phenotypes of Down syndrome. Received: 3 May 1996 / Revised: 2 July 1996     

Partial trisomy for the segment 21(q11----qter) resulting from a de novo translocation between chromosomes 5 and 21

A 3 1/2-year-old boy is described whose Down syndrome resulted from partial 21 trisomy through unbalanced de novo translocation between the long arm of chromosome 21 and the short arm end of a No. 5: 46,XY,t(5;21)(p15;q11). This case is discussed and compared with 17 others collected from the literature, some of which derived from a maternal balanced translocation.     

Cytogenetic,FISH and DNA studies in 11 individuals from a family with two siblings with dup(21q) Down syndrome

A Spanish family has previously been described with two siblings with dup(21q) Down syndrome. The father has a normal karyotype. The mother has a microchromosome. Cytogenetic, fluorescence in situ hybridization and DNA studies have now been carried out on the family. Findings include that the mother has three different chromosome anomalies, viz. (1) a chromosome 22 with an unusual pericentromeric region that contains alphoid DNA from chromosomes 21/13 and chromosome 22, (2) an isochromosome 21p in the frequent cell line and (3) an isochromosome 21q in a rare second cell line. A possible explanation is that the mother developed from a zygote with trisomy 21 and that mitotic error in early development resulted in the formation of two cell lines with karyotypes of 47,XX,+i(21p) and 47,XX,+i(21q), respectively. The unusual chromosome 22 represents a hitherto undescribed chromosome anomaly and one possible explanation is a translocation of the short arms between chromosomes 21/13 and 22 in the ancestry of the family. The relationship between the unusual chromosome 22 and the isochromosome formation in the mother is not known. However, all three chromosome anomalies involve the alphoid DNA of chromosome 21/13, indicating that this is not a chance finding.     

Partial trisomy 8p (8p11.2-->pTER) and deletion of 13q (13q32-->qTER): case report

We report a female infant with partial trisomy 8p (8p11.2-->pter) and deletion of 13q (13q32-->qter). She was born with mild hypotonia, intrauterine growth retardation, microcephaly, micrognathia, large low set ears, pectus excavatum, anteriorly placed anus, and bilateral clinodactyly. Echocardiography showed left ventricular hypertrophy, bicuspid aortic valve, dilatation of the aorta and pulmonary artery, and prolapse of atrio-venticular valve leaflets. Cytogenetic investigation of her sister and her father showed that the altered region resulted from a balanced translocation between the part of the long arm of chromosome 13 and short arm of chromosome 8. In partial trisomy 8p, the clinical picture of the patients comprises hypotonia, structural brain abnormalities, facial anomalies including a large mouth with a thin upper lip, a high arched palate, a broad nasal bridge, an abnormal maxilla or mandible, malformed, low set ears, and orthopedic anomalies. Although patients with proximal deletions of 13q that do not extend into band q32 have mild to moderate mental and growth delays with variable minor anomalies, patients with more distal deletions including at least part of band q32 usually have major malformations such as retinoblastoma, mental-motor growth retardation, malformation of brain and heart, anal atresia, and anomalies of the face and limbs. To our knowledge partial trisomy 8p and partial monosomy of 13q have not been reported previously in the same person.