Partial trisomies 13 and 22 due to nondisjunction of a maternal reciprocal translocation,t(13;22)(q22;q11)

Summary A family is reported in which the propositus has an extra G-like chromosome with an unusual G-banding pattern. Cytogenetic family studies showed that the mother is a carrier of a balanced reciprocal translocation t(13;22), which does not affect the size and morphology of the chromosomes involved. The propositus has a 47,XY,+der(22),t(13;22)(q22;q11) karyotype and is therefore partially trisomic for the distal third of the long arm of chromosome 13 and for a very small part of chromosome 22. The clinical findings are presented and compared with those of other reported cases of partial trisomies 13 and 22.     

Identification of G group anomalies in Down's syndrome by quinacrine dihydrochloride fluorescence staining

Summary 9 patients with regular trisomic Down's syndrome, 3 female carriers from different t (DqGq) families and 2 carriers from the same t (21q22q) family were examined by quinacrine dihydrochloride fluorescence microscopy. A G group chromosome with a highly fluorescent band on its long arm was found in triplicate in all patients. The same chromosome was missing in the (DqGq) translocation carriers being involved in the translocation with a D chromosome. It was also missing in the (21q22q) carriers. This supports the suggestion that it is always the same chromosome which is involved in both regular and translocation Down's syndrome.Quinacrine dihydrochloride is an easily available stain, which can be used for identification of human metaphase chromosomes.     

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.     

Familial transmission of a (21q22q) translocation.

A large family is described in which a (21q22q) Robertsonian translocation is segregating through three generations. The assessment of the risk of a translocation carrier producing an offspring with Down's syndrome is calculated from the data in this family and eight others reported in the literature. The risk when the translocation carrier is a female is approximately 6 in 100, or 0.06. For the male translocation carrier the risk can only be guessed, since the patients with Down's syndrome born to these parents were probands. The risk for Down's syndrome from the combined data of male and female translocation carriers in 3 is 100, or 0.03.     

The Chromosome Abnormality in Mongolism

In an examination of our present knowledge regarding chromosome anomalies in mongolism the anomalies of trisomy-21 (the commonest anomaly in association with mongolism), 13-15/21 translocation and 21-22/21 translocation were illustrated and discussed. The relatively uncommon chromosome translocations and chromosome mosaicisms found in association with mongolism have especial clinical importance. Translocation of either type may occur as an isolated finding in a mongoloid patient. However, the translocation chromosome is frequently also found in one of the phenotypically normal parents. This is associated with an increased incidence of mongolism in the offspring, though the actual risk figure is uncertain in view of the small number of families described to date. The occurrence of chromosome mosaicism in mongolism may be associated with incomplete manifestation of the syndrome, and the ultimate mental development in such patients has varied from normal to severely retarded in cases described in the literature.     

Trisomy 3p syndrome. Report of a new case, due to a chromosomal insertion

A new case of the trisomy 3p syndrome is described. The propositus showed mental and growth retardation and many of the congenital anomalies typical of this syndrome. Chromosome analysis in the propositus revealed an enlarged short arm of chromosome 4. In the mother a similar chromosome 4 was found and, in addition, an abnormal chromosome 3 with a deleted short arm. The karyotype of the mother was interpreted as resulting from a balanced insertional translocation. GTG bands p21 and p22 of chromosome 3 were inserted into the short arm of chromosome 4.     

A complex chromosomal rearrangement with a translocation 4;10;14 in a fertile male carrier: ascertainment through an offspring with partial trisomy 14q13-->q24.1 and partial monosomy 4q27-->q28 [corrected

Complex chromosomal rearrangements (CCRs) are usually associated with infertility or subfertility in male carriers. If fertility is maintained, there is a high risk of abnormal pregnancy outcome. Few male carriers have been identified by children presenting with mental retardation/congenital malformations (MR/CM) or by spontaneous abortions of the spouses. We report a de novo CCR with five breakpoints involving chromosomes 4, 10 and 14 in a male carrier who was ascertained through a son presenting with MR/CM due to an unbalanced karyotype with partial trisomy 14 and partial monosomy 4. The child has a healthy elder brother. In the family history no abortions were reported. No fertility treatment was necessary. Cytogenetic analysis from the affected son showed a reciprocal translocation t(4;10) with additional chromosomal material inserted between the translocation junctions in the derivative chromosome 10. The father showed the same derivative chromosome 10 but had additionally one aberrant chromosome 14. Further molecular cytogenetic analyses determined the inserted material in the aberrant chromosome 10 as derived from chromosome 14 and revealed a small translocation with material of chromosome 4 inserted into the derivative chromosome 14. Thus the phenotype of the son is supposed to be associated with a partial duplication 14q13-->q24.1 and a partial monosomy 4q27-->q28. Including our case we are aware of eleven CCR cases with fertile male carriers. In eight of these families normal offspring have been reported. We propose that exceptional CCRs in fertile male carriers might form comparatively simple pachytene configurations increasing the chance of healthy offspring.     

Cytogenetic studies in a Y-to-X translocation observed in three members of one family,with evidence of infertility in male carriers

Summary A family is reported in which the mother and two sons are carriers of a Y-to-X translocation, der(X)t(X;Y) (p22;q11). All of the three carriers have short statute and disproportion of extremities, but otherwise normal phenotype. One of the sons, the propositus, has been affected with schizophrenia. Evidence was obtained that male carriers are probable sterile; both sons aged 26 and 30 years had azoospermia and the biopsied specimens of the testis had histologic pictures showing spermatogenetic arrest. The mother was H-Y weakly positive, and the normal X chromosome was inactivated in the majority of the cells analyzed. Dermatoglyphics of the three carriers were unusual and dissimilar to the features of Turner's syndrome. The clinical and cytogenetic findings in the present study are compared with those of the previously reported familial cases, and the genetic background causing phenotypic abnormalities in the male and female carriers is discussed.     

Increased risk of trisomy 21 in offspring of carriers of balanced non-contributing autosomal rearrangements is not explained by interchromosomal effect

Only relatively recently the suggestion that interchromosomal effect (ICE) may be present in man had stopped to be argued. At once it became evident that this phenomenon is inherent to a proportion of balanced chromosome rearrangement carriers, predominantly to patients with fertility problems. It is important to establish whether ICE operates in genome of fertile rearrangement carriers and to determine what kind of rearrangement and how far increases a risk of aneuploidy offspring. Using own and literature data 1) we have assessed rates of inherited non-contributing balanced rearrangements in patients with trisomy 21 (T21) and rates of both mutant and inherited non-contributing balanced rearrangements in parents of offspring with T21 and 2) we have analyzed a parental origin of T21 in affected offspring of carriers of balanced rearrangement. We have found that carriers of balanced reciprocal translocation or inversion, but not robertsonian translocation, are at increased risk of T21 offspring. However these data do not support the existence of ICE in its common sense, i.e. as an effect of rearrangement on other chromosome’s segregation at the carrier’s meiosis. Probably the data obtained suggest an effect of paternal rearrangements on maternal chromosomes segregation after fertilization.     

Prenatal diagnosis and carrier detection of a cryptic translocation by using DNA markers from the short arm of chromosome 5.

DNA markers from the short arm of chromosome 5 were used to examine a large family in which a microscopically undetectable translocation was segregating. In addition to confirming that three retarded children were hemizygous for loci distal to 5p14, these analyses identified five individuals as being carriers of the balanced translocation. The use of molecular probes provided informed genetic counseling to the family for the first time. With the DNA markers from 5p, prenatal diagnosis was performed on two fetal chorionic villus samples, both of which were found to have unbalanced karyotypes. The identification of translocation carriers was complicated by recombination between the small translocated segment of 5p and the corresponding region on the normal homologue, which changed the haplotype of the translocated 5p segment.     

Familial pericentric and paracentric inversions of chromosome 1

Summary We investigated 33 individuals (21 carriers) from one family with a pericentric inversion involving a large part of chromosome 1 (1p36.11q32). In addition, we investigated 15 individuals (10 carriers) from another family with a paracentric inversion of a small part of chromosome 1(1p321p36.1). In each family, the index patient was ascertained because three miscarriages had occurred. Each carrier of these inversions was phenotypically normal. If the miscarriages of the index patients are excluded, the frequency of recognized miscarriages among the carriers of childbearing age was 9% (4 of 46) for the family with pericentric inversion and 17% (4 of 23) for the family with paracentric inversion. One of the pericentric inv(1) carriers had had a stillborn daughter. The carriers of the pericentric inversion who were of childbearing age had 41 children; carriers of the paracentric inversion who were of childbearing age had 19 children. No live-born children with birth defects were observed in either family. This evidence, together with the low frequency of miscarriages, suggests that crossover within the inversion loop occurs much less frequently than might be expected from the large size of this inversion. Our investigation suggests that the risk of recognized miscarriages, stillbirths, and live-born children with recombinant chromosomes who have birth defects may be much lower for inv(1) carriers than previously reported. The risk of having a malformed child because of a recombinant chromosome is probably less than 3% for carriers of the pericentric inversion and less than 6% for the carriers of the paracentric inversion.     

Inheritance of a translocation between chromosomes 12 and 16 in a family with recurrent miscarriages and a newborn with Down syndrome carrying the same translocation

Reciprocal translocation carriers have reduced fertility, increased risk of spontaneous abortion or unbalanced karyotype in their offspring. Here, we report the inheritance of a translocation between chromosomes 12 and 16 in a family with recurrent miscarriages and a newborn with Down syndrome carrying the same translocation. Chromosomal analysis from fetal amniotic fluid and peripheral blood lymphocytes from the family were performed at the Cukurova university hospital in Turkey. We assessed a family in which the translocation between chromosomes 12 and 16 segregates; one of the eight progenies with the karyotype 47,XY,+21,t(12;16)(q24;q24) was heterozygote for the translocation and presented with Down syndrome. His mother is phenotypically normal, one brother and one sister were also carrying the same translocation. Apparently, this rearrangement occurred due to the unbalanced chromosome segregation of the mother [t(12;16)(q24;q24)mat]. This case will enable us to explain the behavior of segregation patterns and the mechanism for each type oftranslocation from carrier to carrier and their effects on reproduction and numerical aberrations. The t(12;16) is also associated with fetal wastage and may play a role in the etiology of the family's miscarriages. These findings can be used in clinical genetics and may be used as an effective tool for reproductive guidance and genetic counseling.     

Inherited (13; 14) translocation and reproduction

Summary An inherited translocation chromosome t(13;14) was found in three unrelated families which showed strikingly different types of reproductive disturbances possible associated with the translocation chromosome. Two translocation carrier sisters on the first family had four pregnancies of which one yielded a severely malformed child with a translocation D trisomy and three pregnancies terminated in spontaneous abortions. In the second family the translocation carrier mother had had seven spontaneous abortions, one induced abortion and no normal pregnancies. The foetus of the induced abortion had, unexpectedly, a balanced translocation karyotype identical to the mother's. No obvious ill effects of the translocation chromosome were encountered in the third family, in which the translocation was first detected in a girl with typical Down's syndrome. She had 21-trisomy and the t(13;14) translocation. Special attention was paid to the morphology of the translocation chromosome and to the structure of the centromeres using the G-, C- and Q-banding techniques. The translocation chromosome was, however, identical in all three families and it was considered to be a result of an unequal reciprocal translocation of the affected D chromosomes; t(13;14) (q12;p12). The need of prenatal chromosome analyses in pregnancies of D/D-translocation carriers is briefly discussed.

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Zusammenfassung In drei nicht miteinander verwandten Familien wurde ein vererbtes Translokationschromosom gefunden, wobei die Familien auffallend verschiedene Typen von Fortpflanzungsstörungen aufwiesen, die möglicherweise mit dem Translokationschromosom zusammenhängen. Zwei Schwestern der ersten Familie waren Translokationsträger und hatten vier Schwangerschaften, von denen eine ein schwer mißgebildetes Kind mit einer Translokations D-Trisomie erbrachte. Die drei anderen Schwangerschaften endeten mit Fehlgeburten. In der zweiten Familie hatte die Mutter als Translokationsträgerin sieben Fehlgeburten gehabt, davon einen induzierten Abort und keine normalen Schwangerschaften. Der Fetus aus der Schwangerschaftsunterbrechung hatte unerwarteterweise eine balancierte Translokation analog zu der der Mutter. In der dritten Familie, in der die Translokation zuerst bei einem Mädchen mit typischem Down-Syndrom entdeckt worden war, konnte kein schädlicher Effekt des Translokationschromosoms nachgewiesen werden. Das Mädchen hatte eine Trisomie 21 und die t(13;14)-Translokation. Besondere Aufmerksamkeit wurde der Morphologie des Translokationschromosoms und der Struktur der Zentromeren gewidmet. Die G-, C- und Q-Bandentechnik zeigte, daß das Translokationschromosomen in allen drei Familien identisch war. Es war als Ergebnis einer ungleichen reziproken Translokation der betroffenen D-Chromosomen; t(13;14) (q12;p12) anzusehen. Die Frage der Notwendigkeit der pränatalen Chromosomendiagnostik bei Schwangerschaften von D/D-Translokationsträgern wird kurz besprochen.

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Supported by grants from the Foundation for Pediatric Research, the Sigrid Jusélius Foundation, and the National Research Council for Medical Sciences, Finland.     

Partial trisomy of chromosome 21 by maternal translocation t(15;21) (q26.2; q21)]

A balanced reciprocal translocation, t(15;21) (q262;q21) was observed in the mother and maternal grandfather of two patients. The propositus, who received the abnormal chromosome 15 from his mother, is trisomic for the distal part of chromosome 21, and his phenotype is that of classical trisomy 21. His sister, who is trisomic for the proximal part of 21q, is slightly retarded but developmentally normal otherwise.     

Use of somatic cell nuclear transfer to study meiosis in female cattle carrying a sex-dependent fertility-impairing X-chromosome abnormality

Animal models have played an important part in establishing our knowledge base on reproduction, development, and the occurrence and impact of chromosome abnormalities. Translocations involving the X chromosome and an autosome are unique in that they elicit sex-dependent infertility, with male carriers rendered sterile by synaptic anomalies during meiosis, whereas female carriers conceive but repeatedly abort. Until now the limited access to relevant fetal oocytes has precluded direct study of meiotic events in female carriers. Because somatic cell nuclear transfer (SCNT) circumvents meiotic problems associated with fertility disturbances in translocation carriers, we used SCNT to generate embryos, fetuses, and calves from a cell line derived from a deceased subfertile X-autosome translocation carrier cow to study the meiotic configurations in carrier oocytes. Data from 33 replicates involving 2470 oocyte-donor-cell complexes were assessed for blastocyst development and of these, 42 blastocysts were transferred to 21 recipients. Fourteen pregnancies were detected on day 35 of gestation. One of these was sacrificed for ovary retrieval on day 94 and three went to term. Features of oocytes from the fetal ovary and from the newborn ovaries were examined. Of the pachytene spreads analyzed, 16%, 82%, and 1.5% exhibited quadrivalent, trivalent/univalent, and bivalent/univalent/univalent structures, respectively, whereas among the diakinesis/metaphase I spreads, 16% ring, 75% chain, and 8.3% bivalent/bivalent configurations were noted, suggesting that the low fertility among female carriers may be related to synaptic errors in a predominant proportion of oocytes. Our results indicate that fibroblasts carrying the X-autosome translocation can be used for SCNT to produce embryos, fetuses, and newborn clones to study such basic aspects of development as meiosis and to generate carriers that cannot easily be reproduced by conventional breeding.     

Inv(10)(p11.2q21.2), a variant chromosome

We present 33 families in which a pericentric inversion of chromosome 10 is segregating. In addition, we summarise the data on 32 families in which an apparently identical inv(10) has been reported in the literature. Ascertainment was through prenatal diagnosis or with a normal phenotype in 21/33 families. In the other 12 families, probands were ascertained through a wide variety of referral reasons but in all but one case (a stillbirth), studies of the family showed that the reason for referral was unrelated to the chromosome abnormality. There has been, to our knowledge, no recorded instance of a recombinant chromosome 10 arising from this inversion and no excess of infertility or spontaneous abortion among carriers of either sex. We propose that inv(10)(p11.2q21.2) can be regarded as a variant analogous to the pericentric inversion of chromosome 2(p11q13). We conclude that prenatal chromosome analysis is not justified for inv(10) carriers. In addition, family investigation of carrier status is not warranted in view of the unnecessary concern this may cause parents and other family members. Received: 7 July 1997 / Accepted: 4 August 1997     

Women heterozygous for deficiency of the (p21 leads to pter) region of the X chromosome are fertile

A woman balanced carrier of a X/15 translocation gave birth to a balanced infertile son and three unbalanced Xp--fertile daughters. This family and the other eleven cases of Xp--fertile women found in the literature demonstrate that loss of the p21 leads to pter region of the X chromosome is compatible with fertility, probably because it leaves on Xp the region which is never inactivated.     

Familial translocation t(10;21)(q22;q22)

Summary A family is described with a translocation t(10;21)(q22;q22) transmitted through three generations. This family was studied for the apparition of several miscarriages and two sisters with multiple malformations. Both children had a probably partial trisomy of chromosome 10 and a monosomy of chromosome 21 due to a maternal adjacent-2 meiotic segregation.     

Additional evidence of the formation of unbalanced embryos in cattle with the 7/21 Robertsonian translocation

To confirm the effect of the 7 21 Robertsonian translocation on fertility in Japanese Black Cattle, cytogenetic studies were performed on embryos collected from the following 3 mating groups: normal bull cross normal cow, translocation carrier bull cross normal cow, and normal bull cross translocation carrier cow. All the analyzable embryos showed normal chromosome complements when the parents had a normal karyotype. In the group sired by the 7 21 translocation heterozygous bulls, a total of 56 embryos had metaphases suitable for chromosome analyses. Out of these embryos, 28 had normal chromosome complements and 25 were embryos with a balanced karyotype. However, 3 (5.4%) were monosomic and trisomic embryos, presumably resulting from the fertilization of normal ova by aneuploid spermatozoa. Unbalanced embryos were also observed in the chromosome analyses of embryos derived from the 7 21 translocation heterozygous cows. These results suggest that the 7 21 translocation in the heterozygous state may be associated with a slight reduction in reproductive efficiency.     

Is there an interchromosomal effect in reciprocal translocation carriers? Sperm FISH studies

Chromosome translocations have been known to affect disjunction of chromosomes unrelated to the translocation in the mouse and in Drosophila. However, in humans, an interchromosomal effect in chromosome translocations has not been demonstrated. The availability of techniques that allow the study of nondisjunction in sperm cells has permitted us to evaluate the possibility of an interchromosomal effect in male translocation heterozygotes. In this study, multicolor fluorescence in situ hybridization was used to determine levels of disomy for the clinically relevant chromosomes X, Y, 13, 18, and 21 in 332,858 spermatozoa from nine reciprocal translocation heterozygotes and nine controls with normal karyotypes. The specific translocations studied were as follows: t(10;12)(p26.1;p13.3), t(2;18)(p21;q11.2), t(3;19)(p25;q12), t(5;8)(q33;q13), t(11;22)(q23;q11), t(3;4)(p25;p16), t(8;9) (q24.2;q32), t(10;18)(q24.1;p11.2), and t(4;10)(q33;p12.2). Comparisons of disomy rates between carriers and controls were performed by using the Mann-Whitney test. Our results showed that the rates of sex chromosome hyperhaploidy were similar in controls (0.21%) and in translocation carriers (0.19%). Similarly, the frequencies of disomy for chromosomes 13, 18, and 21 did not differ significantly between controls and carriers (0.05% versus 0.08%, 0.07% versus 0.03%, and 0.14% versus 0.20%, respectively). Sex chromosome nondisjunction was more common than nondisjunction of chromosomes 13 and 18 both in controls (P=0.0057) and in carriers (P=0.0008). Similarly, the rates of chromosome disomy for chromosome 21 were higher than those for chromosomes 13 and 18 in both controls (P=0.0031) and translocation carriers (P=0.0057). In our study, the excess of chromosome 21 disomy versus disomy of the other autosomes was more pronounced in carriers than in controls. Thus, although the difference of disomy 21 between controls and carriers was not statistically significant, it is worthy of attention.