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.     

Tandem duplication chromosome 21 in the offspring of a ring chromosome 21 carrier

A direct tandem duplication chromosome 21 was found in a boy with Down's syndrome. The proband's mother and grandmother both carried a ring chromosome 21. The observed duplication chromosome in the child may be explained either by recombination between the maternal ring and the mother's normal chromosome 21 or by break of a double-sized ring chromosome 21.     

Partial trisomy 9q syndrome with a de novo tandem duplication of 9q22.2-q31.1

A female with a de novo tandem duplication of 9q22.2-q31.1 is presented. Molecular delineation of the breakpoints was made by microarray CGH and fluorescent in situ hybridisation. Involvement of 9q22.2-q31.1 seems to be sufficient to produce the characteristic phenotype of partial trisomy 9q syndrome. A discussion on the recognizable clinical features of the condition is presented.     

Acrocallosal syndrome in a child with de novo inverted tandem duplication of 12p11.2-p13.3.

Report on the child of normal unrelated parents presenting the typical features of acrocallosal syndrome (craniofacial dysmorphy, mental deficiency, convulsive disorder, agenesis of corpus callosum, preaxial polydactyly "hallux duplex" of both feet, and in addition diabetes insipidus) in which a mirror duplication of nearly the entire short arm of chromosome 12 was discovered. Since the symptomatology of trisomy and tetrasomy 12p shows some overlap with acrocallosal syndrome a common origin of the monogenic disorder and the chromosomal phenotypes is discussed.     

Cytogenetic analysis in 139 Tunisian patients with de novo acute myeloid leukemia

This paper presents the results of a cytogenetic analysis in 139 Tunisian patients with de novo acute myeloid leukemia (AML), including 27 children aged 1-15 years and 112 adults. Mean age was 32 (range 1-75) and the M/F ratio was 1.43. Of our patients, 45% had apparently normal karyotypes. Acquired chromosome aberrations were found in 77 (55% ) patients. t(8;21) was identified in 27 patients (19%); t(15;17) in 13 patients (9%); deletion 7q or monosomy 7 in seven patients (5%); +8 in seven patients (5%); abnormal 16 in four patients (3%); 11q23 rearrangements in two patients (2%) and del(5q), in one patient (1%). The remaining 16 patients had miscellaneous clonal abnormalities. Specific translocations associated with the FAB type were found: t(8;21) with AML2 and t(15;17) with AML3. We concluded that our study in a Tunisian population confirmed the relation between some specific abnormalities and the FAB classification. We found a higher incidence for t(8;21) than usually described.     

Trisomy 6q syndrome: a case with a < de novo > 6q23 tandem duplication

In this study, we report the combined use of whole and partial chromosome 6 painting probe and YACS probes to define the unbalanced region of a de novo 6q+ marker chromosome. A male patient with peculiar features of < distal 6q trisomy syndrome > showed a direct duplication of 6q23 region. Comparing the phenotype of this child with the phenotype of other < de novo > partial 6q trisomy, we conclude that band 6q23 has an important role in defining 6q trisomy.     

The implication of de novo 21-hydroxylase mutation in clinical and prenatal molecular diagnoses

We studied 37 unrelated families with a history of 21-hydroxylase deficiency (CYP21D) for eight common mutations and gene deletions in the 21-hydroxylase (CYP21) gene. We found de novo mutations in the CYP21 gene in two CYP21D patients. Analysis for eight common mutations in the 21-hydroxylase gene as well as large gene deletions was accomplished using polymerase chain reaction (PCR) followed by amplified created restriction site (ACRS) or restriction fragment length polymorphism (RFLP) and Southern blot followed by hybridization to a CYP21-specific probe. Linkage analysis was performed using microsatellite markers flanking the CYP21 gene. Ten short tandem repeat (STR) markers were used to confirm parentage in the two de novo mutation cases. In two prenatal diagnosis cases, an intron 2-13A/C>G mutation was identified in the proband, but not in the fetus, although the proband and fetus had identical linkage markers. Subsequently, the mutation was confirmed to be absent in the parents' genome and misparentage was ruled out. Our findings are consistent with previous studies showing a de novo mutation frequency of approximately 1.0-1.5% in the CYP21 gene. This new mutation rate is high relative to the rate of approximately one in one million for other autosomal recessive disorders. Thus, the de novo mutation rate in the CYP21 gene is not negligible. It must be considered and discussed in prenatal diagnosis and genetic counseling for this relatively common inherited disorder.     

Interstitial "de novo" tandem duplication of 7(q31.1-q35): first reported case

A patient carrying a de novo 7q31-35 duplication is presented. The tandem duplication was confirmed by FISH analysis. The case seems to be the first in the literature and, in spite of the large size of the duplicated region, he shows mild facial dysmorphism and a moderate mental retardation. The clinical findings of the dup7q published cases are compared in order to define a possible common 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.     

Prenatal diagnosis of a rare de novo centromeric chromosome 6 variant

Cytogenetic heteromorphisms are described as heritable variations at specific chromosomal regions without phenotypic effect. Polymorphisms of the size of heterochromatic centromeric regions of chromosomes 1, 9 and 16 have been well documented in humans but only four previous reports described centromeric polymorphism of chromosome 6. We present a prenatal diagnosis of a rare de novo centromeric chromosome 6 variant. Cytogenetic and molecular techniques were used to characterize this variant and confirm the de novo nature of this event. This case illustrates the importance of reporting unusual variant chromosomes for genetic counseling and for determination of the frequency of variant chromosomes in the general population.     

Cytogenetic survey of 117 Tunisian patients with de novo myelodysplastic syndrome

Cytogenetic studies were performed on 117 Tunisian patients with de novo myelodysplastic syndromes (MDS). According to the French-American-British (FAB) criteria 40 patients presented with refractory anaemia (RA, 34%), eight with refractory anaemia with ringed sideroblasts (RARAS, 7%), 19 with refractory anaemia with excess of blasts (RAEB, 16%), 16 with refractory anaemia with excess of blasts in transformation (RAEB-t, 14%), 18 had chronic myelomonocytic leukaemia (CMML, 15%) and 16 unclassifiable MDS (14%). Seventy-five were men and forty-two were women. Five were children and 112 were adults with a median age of 58 years. Fifty-five per cent of the patients presented clonal chromosome abnormalities. Rates of abnormality varied from one FAB subtype to the other: 55% in RA, 75% in RARAS, 63% in RAEB, 75% in RAEB-t and 28% in CMML. The most frequent chromosome abnormalities were del(5q) (22 cases), monosomy 7 (12 cases), del(12p) (6 cases), and trisomy 8 (5 cases). Rare abnormalities were also found: ring of chromosome 12 and trisomy 15. Conventional cytogenetics remains the basic technique in identifying chromosomal abnormalities associated with MDS.     

Sequence optimization as an alternative to de novo analysis of tandem mass spectrometry data

MOTIVATION: Peptide identification following tandem mass spectrometry (MS/MS) is usually achieved by searching for the best match between the mass spectrum of an unidentified peptide and model spectra generated from peptides in a sequence database. This methodology will be successful only if the peptide under investigation belongs to an available database. Our objective is to develop and test the performance of a heuristic optimization algorithm capable of dealing with some features commonly found in actual MS/MS spectra that tend to stop simpler deterministic solution approaches. RESULTS: We present the implementation of a Genetic Algorithm (GA) in the reconstruction of amino acid sequences using only spectral features, discuss some of the problems associated with this approach and compare its performance to a de novo sequencing method. The GA can potentially overcome some of the most problematic aspects associated with de novo analysis of real MS/MS data such as missing or unclearly defined peaks and may prove to be a valuable tool in the proteomics field. We assess the performance of our algorithm under conditions of perfect spectral information, in situations where key spectral features are missing, and using real MS/MS spectral data.     

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.     

A new case of partial 2p trisomy due to de novo interstitial duplication 2p21-22

We report on a case of "de novo" interstitial duplication of bands 2p21-22 in a 31-month-old female with mild mental retardation and dysmorphism. Cytogenetic investigations were performed on peripheral blood by adding 5-BrdU and 5-FdU. Measurements of enzymatic activity of malate dehydrogenase, whose gene has been mapped on the band 2p23, added reliability to the identification of bands 2p21-22 as the duplicated segment. The authors suggest that the duplication of this segment is able to cause the clinical picture of the syndrome of partial 2p trisomy.     

Uniparental isodisomy due to duplication of chromosome 21 occurring in somatic cells monosomic for chromosome 21.

Uniparental disomy has been recently recognized as an important phenomenon in non-Mendelian inheritance of human genetic disorders. Several mechanisms for uniparental disomy, i.e., the presence of two homologous chromosomes derived from one parent, have been proposed. We studied two independent cases of abnormalities of chromosome 21 in which there were abnormal karyotypes at birth but blood cells with normal karyotype predominated later in life, and the cells with abnormalities disappeared. Uniparental isodisomy was observed in the normal cells in these individuals. The uniparental disomy in these families was the result of duplication of a chromosome in mitosis after the loss of the homologous abnormal chromosome. The duplication can be seen as mechanism for cell survival and is called here "compensatory" isodisomy, which provided a selective advantage for the cell population with the normal number of chromosomes 21.     

Clinical and molecular cytogenetic studies in a case with partial trisomy 12p due to a de novo supernumerary ring chromosome

Clinical and molecular cytogenetic studies in a case with partial trisomy 12p due to a de novo supernumerary ring chromosome: We report on a girl with a mosaic karyotype containing a supernumerary ring chromosome. Fluorescence in situ hybridization (FISH) studies showed that this marker chromosome was derived from chromosome 12, resulting in partial trisomy 12p13.1-->12q11. The girl showed developmental delay, cerebral visual impairment, obesity and mild dysmorphic features. Her clinical data at 6 months, 3 years, and 6 years of age were compared with the clinical data on other trisomy 12p patients.     

Obligate short-arm exchange in de novo Robertsonian translocation formation influences placement of crossovers in chromosome 21 nondisjunction

Robertsonian translocations (ROBs) involving chromosome 21 are found in approximately 5% of patients with Down syndrome (DS). The most common nonhomologous ROB in DS is rob(14q21q). Aberrant recombination is associated with nondisjunction (NDJ) leading to trisomy 21. Haplotype analysis of 23 patients with DS and de novo rob(14q21q) showed that all translocations and all nondisjoined chromosomes 21 were maternally derived. Meiosis II NDJ occurred in 21 of 23 families. For these, a ROB DS chromosome 21 genetic map was constructed and compared to a normal female map and a published trisomy 21 map derived from meiosis II NDJ. The location of exchanges differed significantly from both maps, with a significant shift to a more distal interval in the ROB DS map. The shift may perturb segregation, leading to the meiosis II NDJ in this study, and is further evidence for crossover interference. More importantly, because the event in the short arms that forms the de novo ROB influences the placement of chiasmata in the long arm, it is most likely that the translocation formation occurs through a recombination pathway in meiosis. Additionally, we have demonstrated that events that occur in meiosis I can influence events, such as chromatid segregation in meiosis II, many decades later.     

Characterization of three de novo derivative chromosomes 16 by “Reverse chromosome painting” and molecular analysis

We have analyzed three de novo chromosome 16 rearrangements—two with a 16p+ chromosome and one a 16q+—none of which could be fully characterized by conventional cytogenetics. In each case, flow karyotypes have been produced, and the aberrant chromosome has been isolated by flow sorting. The origin of the additional material has been ascertained by amplifying and labeling the DNA of the abnormal chromosome by degenerate-oligonucleotide-primer–PCR and hybridizing it in situ to normal metaphase spreads (reverse chromosome painting). Both 16p+ chromosomes contain more than 30 Mb of DNA from the short arm of chromosome 9 (9p21.2-pter), while the 16q+ contains approximately 9 Mb of DNA from 2q37. The breakpoints on chromosome 16 have been localized in each case; the two breakpoints on the short arm are at different points within the terminal band, 16p13.3. The breakpoint on the long arm of chromosome 16 is very close to (within 230 kb of) the 16q telomere. Determination of the regions of monosomy and trisomy allowed the observed phenotypes to be compared with other reported cases involving aneuploidy for these regions.     

Constitutional duplication 11q23 de novo involving the MLL gene

We report a child with mental retardation, brain anomalies and congenital heart defect. His karyotype, after G-banding and FISH with a whole chromosome probe for chromosome 11 and a locus-specific probe for the MLL gene, was 46,XY,dup(11)(q23q23).ish dup(11)(q23q23)(wcp11+, MLL++) de novo; i.e., he had a pure partial 11q23 duplication. Clinical and cytogenetic findings of the present case were compared with the 7 previously reported cases with pure partial trisomy 11q; in 6/8 cases the region 11q23 was involved. We conclude that the scarce number of cases and their heterogeneity do not allow to establish a reliable genotype-phenotype correlation.     

Prognostic significance of chromosome analysis in de novo acute myeloid leukemia (AML)

Between 1981 and 1986 cytogenetic studies of bone marrow and/or blood cells in 139 patients with de novo acute myeloid leukemia (AML) were performed. The overall incidence of chromosomal aberrations was 53%, and this was not significantly influenced by sex, age nor the FAB classification. The aberrations most often found were: complex anomalies (n = 13), t(8; 21) (n = 10), trisomy 8 (n = 9), monosomy 7 (n = 6), monosomy 5, 5q-, trisomy 11, 12p- (n = 4) and trisomy 6, 11q-, inv (n = 3). The prognostic significance of chromosomal findings was evaluated in 112 patients treated by combination chemotherapy. The chromosomal status NN, AN, AA did neither significantly influence complete remission rate (NN: 68%, AN: 71%, AA: 60%) nor mean survival (NN: 24, AN: 26.6, AA: 35.6 months). On the other hand, certain types of chromosomal anomalies were of prognostic value. CR was obtained in all 10 patients with t(8; 21) but only in 2 out of 9 patients with complex aberrations. Median duration of CR in patients with t(8; 21) was significantly longer than in patients with a normal karyotype (30 vs 7 months).