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We report on genetic counseling and investigations in 36 families with inherited balanced translocations ascertained in different ways, with special regard to the completeness and reasons for incompleteness of family investigation. Quantitative evaluation of the results of cytogenetic investigations shows that non-directive genetic counseling was very effective in many families. Yet, in most of the families (34) genetic counseling and investigation remained incomplete in the sense that not all living potential translocation carriers could be counseled or investigated or that the origin of a fresh mutation could not be established by a normal karyotype in the parents of a carrier. Only in seven families could nearly all living potential carriers be counseled and investigated. The most frequent reason for incompleteness was the impossibility of transmitting or refusal to transmit information about the genetic risks to relatives (21 families), whereas direct rejection of investigation by a counseled individual was a rather rare event (18 adults). Families ascertained because of an unbalanced child seem to be more willing to transmit genetic information to relatives than families ascertained in other ways. Non-directive genetic counseling gave us an insight into the emotional problems arising during counseling of translocation families.

A 12.5-year-old male patient with a de novo derivative chromosome 22 is reported. A detailed description of the clinical features and comparison with the results of conventional cytogenetic banding methods indicated that the derivative chromosome might have been caused by a translocation between the short arms of chromosomes 12 and 22: der(22)t(12;22)(p12.1;p11.2). Fluorescence in situ hybridization with a chromosome 12-specific paint confirmed this supposition. The patient thus carries a pure duplication of 12pter-->p12.1. The phenotype of the patient described is compared to cases in the literature.

This report concerns two patients with clinical features typical for tetrasomy 18p syndrome. Chromosomal analysis revealed a male karyotype in both cases, with an additional small metacentric marker chromosome, putatively an i(18p). Fluorescent in situ hybridization with a chromosome 18-specific paint confirmed that the marker chromosome consisted of chromosome 18 material in both cases.

Clinical, cytogenetic and molecular studies were performed in three patients with Wolf-Hirschhorn syndrome (WHS). In all cases the altered chromosome 4 appeared to be the result of a de novo deletion. Cytogenetic investigations located the breakpoint at 4p15.3 and 4p13. With cytogenetic methods it was not possible to decide whether these deletions were terminal or interstitial. DNA methods also failed to define a distal breakpoint within the 4p16.3 region which might have indicated an interstitial deletion. According to the literature, the paternal chromosome 4 is preferentially deleted in most patients with WHS. DNA analysis with polymorphic markers out of the 4p16.3 region revealed that in two of the cases reported here the deleted segment was of paternal and in one case of maternal origin.

We report on a male patient with a de novo derivative chromosome 9. From clinical and conventional cytogenetic data, it was assumed that the derivative chromosome might be caused by a translocation between the short arms of chromosomes 7 and 9: der(9)t(7;9)(p21.2;p23.5). Fluorescence in situ hybridization with a chromosome 7-specific and a chromosome 9-specific paint confirmed this supposition. The phenotype of the patient described is compared to cases in the literature.

A boy is reported with mild retardation and minimal dysplasias, carrying a serial duplication of 10(q11q22). The possible origin of the aberrant chromosome is discussed in the context of similar cases from the literature.

DiGeorge syndrome (DGS) is a developmental field defect, characterised by absent/hypoplastic thymus and parathyroid, and conotruncal heart defects, with haploinsufficiency loci at 22q (DGS1) and 10p (DGS2). We performed fluorescence in situ hybridisations (FISH) and polymerase chain reaction (PCR) analyses in 12 patients with 10p deletions, nine of them with features of DGS, and in a familial translocation 10p;14q associated with midline defects. The critical DGS2 region is defined by two DGS patients, and maps within a 1 cM interval including D10S547 and D10S585. The other seven DGS patients are hemizygous for both loci. The breakpoint of the reciprocal translocation 10p;14q maps at a distance of at least 12 cM distal to the critical DGS2 region. Interstitial and terminal deletions described are in the range of 10-50 cM and enable the tentative mapping of loci for ptosis and hearing loss, features which are not part of the DGS clinical spectrum.

A somatic cell hybrid panel was constructed consisting of seven hybrids with translocation breakpoints spanning the region 17q23→q25. Hybrid clones carrying the long-arm derivative of chromosome 17 in the absence of the normal chromosome 17 and of the derivative 17 were initially identified by PCR typing for a proximal and distal 17q marker. The translocation breakpoints of the hybrids were then mapped in more detail by PCR analysis for a number of microsatellite markers from chromosome 17q as well as for five gene loci (CACNLG, GH1, SOX9, TIMP2, TK1) previously mapped to the region 17q23→q25. In addition, the locus for GDIA1 was mapped by FISH to 17q25.3 and fine mapped with the help of the hybrid panel. These seven new hybrids complement the existing somatic cell hybrid panel for the long arm of chromosome 17q.

In this collaborative study we report on 2 prenatally and 5 postnatally diagnosed cases with a 47,X,i(Xq),Y chromosomal constitution. Excepting tall stature, the 5 adult patients showed all typical manifestations of Klinefelter syndrome. Taken together with previously reported cases, these data suggest that Klinefelter syndrome with isochromosome Xq has a favorable prognosis with normal mental development, and with normal-to-short stature. The prevalence of this Klinefelter variant is calculated to be between 0.3-0.9% in males with X chromosome polysomies.

Voiculescu I, Toder R, Back E, Osswald P, Schempp W. A retrospective CISS hybridization analysis of a case with de novo translocation t(18;22) resulting in an 18p—syndrome. Clin Genet 1993: 43: 318–320. © Munksgaard, 1993 An unbalanced de novo translocation t(18;22) leading to a severely malformed liveborn girl with 18p—syndrome is described. Using the chromosomal in situ suppression (CISS) hybridization technique on 4-year-old G-banded chromosome preparations, it could be demonstrated that the translocation chromosome is composed of the long arm including the centromere of a chromosome 22 and the long arm of a chromosome 18. Consequently, the patient described here has lost the short arm including the centromere of chromosome 18. The possibility of restudying cytogen-etically unsolved cases in clinical cytogenetics using older G-banded chromosome preparations with the fluorescence in situ hybridization techniques is pointed out.

A rare BrdU-sensitive fragile site, designated FRA12C*RQ24.2 has a relatively high frequency in the normal population. It can be demonstrated in a heterozygous and homozygous condition. There is no evidence that a phenotypic abnormality is associated with the expression of this site. A comparison with the fragile site FRA10B*RQ25.2 has revealed common features with FRA12C*RQ24.2.

In five healthy family members of three generations a reciprocal translocation, t(6;12)(q27;q21), combined with an inverted insertion inv ins (7;8)(p14;q22q13), has been demonstrated. Neither offspring with unbalanced karyotypes nor descendants with isolated translocations or insertions were observed. Five simultaneously occurring chromosomal breaks are considered to be the reason for the new rearrangement.

We studied the influence of the method used in cultivating and preparing lymphocyte cultures on the quantitative and qualitative association patterns of the acrocentric chromosomes in the same individual. We compared the results obtained by macrocultures with medium TC 199 (method a), by macrocultures with McCoy’s medium 5A (method b) and by microcultures with McCoy’s medium 5A and 20% fetal calf serum (method c). These comparisons were made under two conditions: (1) fixation with glacial acetic acid/methanol 1:3 and (2) subsequent resuspension in 70% acetic acid. For cultures that were not resuspended, no marked differences could be observed in the quantitative association types {i.e., the number of associating chromosomes). As regards the qualitative association types (i.e., the relative frequency of participation of D and G chromosomes), however, an increasing deviation from the expected D-D:D-G:G-G ratio from method a to b to c, caused by an increase in G-G associations, could be demonstrated. In cultures resuspended in 70% acetic acid subsequent to the usual fixation process a significant increase in associations (primarily in associating G chromosomes) could be observed for all methods. Mechanical factors possibly responsible for these results are discussed.

A pericentric inversion in one of the chromosomes 12, found in two families living in the same region, is described. This inversion was detected during routine chromosomal analysis in two separate laboratories. The breakpoints were at 12p112 and 12q13. The inverted segment represented approximately 20% of the length of chromosome 12. Twenty nine descendants of carriers of the inversion were investigated, and the inversion was present in 23 of them. The other six descendants showed a normal karyotype. After correction for sample bias with the single selection scheme, a segregation ratio of 3:1 was estimated, indicating that the inverted chromosome 12 was preferentially transmitted. All the carriers of the inversion were phenotypically normal, without noticeable fertility disturbances.

A BrdU-requiring fragile site, fra(12)(q24.2), on human chromosome 12 of some individuals is reported. This fragile site is inherited in a Mendelian codominant fashion and does not seem to be associated with any physical or mental abnormality in carriers. It was mostly observed as a chromatid gap: no acentric fragments, triradials or deleted chromosomes were found. The fra(12)(q24.2) was expressed in 34%–48% of metaphases in lymphocyte cultures from carriers when BrdU and FdU were added 6.5 h before harvest, while the expression ranged between 5% and 20% when the cultures were treated with BrdU alone. The fra(12)(q24.2) represents the second BrdU-requiring rare fragile site described on human chromosomes.

Ring (20) chromosomal mosaicism defined by two cell lines (one normal and the other with the ring) has been demonstrated in lymphocyte and fibroblast cultures from three members of a family through two generations. Two carriers of the ring chromosome were affected and showed the typical signs of r(20) syndrome including mental retardation, microcephaly, behavioral disorders, and epilepsy. The epilepsy is characterized by complex partial seizures sometimes evolving secondarily into generalized tonic-clonic seizures and is poorly controlled by or resistant to medical treatment. The mother of the two patients, also a carrier of ring (20) chromosomal mosaicism, was clinically and phenotypically normal and did not exhibit any signs of epilepsy. Lymphocyte and fibroblast cultures from the most severely affected sib, the proband, contained the highest percentage of cells with ring (20) chromosome and revealed the greatest instability of the ring. Though it is assumed that the ring (20) chromosome arose from terminal breakage and reunion in both arms, no loss of genetic material could be documented cytogenetically. Yet the question arises of how ring chromosomal mosaicism can be passed on. One explanation might be that a chromosome 20 predisposed to terminal lesions or breaks is transmitted from the mother to her offspring. Inherited instability of this type might lead to de novo formation of the ring.

A case of complete trisomy 22 in a live-born female child with multiple malformations is reported. The karyotype of the index patient had 46 chromosomes, with one chromosome 22 missing and one supranumerary metacentric chromosome. Different banding methods and in situ hybridization revealed that the extra chromosome consists of the long arms and a part of the short arms of two chromosomes 22. Our report supplies further proof that a fetus with complete trisomy 22 can occasionally survive to term, but the condition is not compatible with life over a long period.

A family is reported with a segregating t(5;10)(q15;q11) translocation resulting in a child carrying trisomy 10p. The clinical findings of the patient are compared with trisomy 10p and the Cri-du-Chat syndrome.

A search for Y-specific DNA sequences has been performed in a sample of seven 46,XX true hermaphrodites and one 45,X mixed gonadal dysgenesis case and compared with a sample of 11 XX males. Using six Y-specific DNA probes no hybridization signal was obtained in the hermaphrodite group; in contrast, all XX males gave a positive signal with at least one probe. This difference is statistically highly significant. We conclude that the aetiology of true hermaphroditism is different from that of the XX male syndrome. As all cases of the hermaphrodite group are positive for the serological sex-specific antigen (Sxs) it is concluded that this antigen can be present even in the absence of Y-specific DNA.

The association pattern of the acrocentric chromosomes shows no significant difference between a population of mothers of mongoloid children and male and female controls of the same age-group. It could only be demonstrated that the associations of the mothers were interconnected by thread-like structures in a higher percentage. However, no significance could be deduced from for this phenomenon (P ≊ 0.1).

Balanced translocations affecting the paternal copy of 15q11--q13 are a rare cause of Prader-Willi syndrome (PWS) or PWS-like features. Here we report on the cytogenetic and molecular characterization of a de novo balanced reciprocal translocation t(X;15)(q28;q12) in a female patient with atypical PWS. The translocation breakpoints in this patient and two previously reported patients map 70-80 kb distal to the SNURF-SNRPN gene and define a breakpoint cluster region. The breakpoints disrupt one of several hitherto unknown 3' exons of this gene. Using RT--PCR we demonstrate that sequences distal to the breakpoint, including the recently identified C/D box small nucleolar RNA (snoRNA) gene cluster HBII-85 as well as IPW and PAR1, are not expressed in the patient. Our data suggest that lack of expression of these sequences contributes to the PWS phenotype.