Molecular analysis of a reciprocal translocation t(5;11)(q11;p13) in a WAGR patient

Summary Most patients with the complex association aniridia — predisposition to Wilms' tumor (WAGR syndrome) present with a de novo constitutional deletion of band 11p13. We report a patient with WAGR syndrome and a reciprocal translocation between chromosomes 5 and 11 t(5;11)(q11;p13). High resolution banding cytogenetic analysis and molecular characterization using 11p13 DNA markers showed a tiny deletion encompassing the gene for CAT but sparing the gene for FSHB. This suggests that syndromes associated with apparently balanced translocations may be due to undetectable loss of material at the breakpoint(s) rather than to breakage in the gene itself.     

An azoospermic male with reciprocal translocation t(1;15)(q11;p11)

Summary The authors report on a case of 1;15 translocation and request contact with any colleagues who have observed similar cases.     

Paternal reciprocal translocation t(11;16)(p13;q24.3) in a Silver-Russel syndrome patient

We describe a 7-month-old male child with Silver-Russel syndrome (SRS) phenotype, presented with two major clinical features: low birth weight, short stature, and minor features, such as macrocephaly, clinodactyly, essential for the diagnosis of SRS. Routine cytogenetic studies with GTG-banding showed 46,XY,t(11;16)(p13;q24.3). Fluorescence in situ hybridisation (FISH) with single copy probes BAC (11p13) and PAC (16q24.3), showed a reciprocal translocation. Chromosomal analysis of the mother was normal and the phenotypically normal father had apparently identical translocation t(11;16)(p13;q24.3). The disruption of growth factor genes at 11p and 16q breakpoint regions due to reciprocal translocation in the father might have caused SRS phenotype in the child.     

Sperm chromosome analysis of two males heterozygous for a t(2;17)(q35;p13) and t(3;8)(p13;p21) reciprocal translocation

Summary Sperm chromosome complements from two males, one heterozygous for the reciprocal translocation t(2;17)(q35;p13) (n = 18) and one for t(3;8) (p13;p21) (n = 73), were analyzed. Only 2:2 segregations were observed with t(2;17): alternate, 56%; adjacent-I, 33%; adjacent-II, 11%. Both 2:2 and 3:1 meiotic segregations occurred in t(3;8): alternate, 34.2%; adjacent-I, 43.8%; adjacent-II, 20.5% and 3:1, 1.4%. A significant excess of chromosomally normal versus balanced sperm complements was observed with both translocation heterozygotes. The frequencies of other chromosome aberrations unrelated to the translocations were 16.7% for t(2;17) and 8.2% for t(3;8). The ratio of X-bearing to Y-bearing sperm was not different from the theoretically expected ratio of 1:1.     

Breakpoint mapping of a novel de novo translocation t(X;20)(q11.1;p13) by positional cloning and long read sequencing

Disease associated chromosomal rearrangements often have break points located within disease causing genes or in their vicinity. The purpose of this study is to characterize a balanced reciprocal translocation in a girl with intellectual disability and seizures by positional cloning and whole genome sequencing. The translocation was identification by G- banding and confirmed by WCP FISH. Fine mapping using BAC clones and whole genome sequencing using Oxford nanopore long read sequencing technology for a 1.46 X coverage of the genome was done. The positional cloning showed split signals with BAC RP11-943 J20. Long read sequencing analysis of chimeric reads carrying parts of chromosomes X and 20 helped to identify the breakpoints to be in intron 2 of ARHGEF9 gene on Xp11.1 and on 20p13 between RASSF2 and SLC23A2 genes. This is the first report of translocation which successfully delineated to single base resolution using Nanopore sequencing. The genotype-phenotype correlation is discussed.     

A maternal inherited translocation t(1;22)(q11;p11) in two infertile brothers

We report two infertile brothers presenting with azoospermia and oligozoospermia. Cytogenetic studies using G-banding and FISH analysis on lymphocyte cultures revealed an autosomal balanced reciprocal translocation t(1;22)(q11;p11) in both males. The same translocation was found in their mother, but not in a third fertile brother and maternal uncle suggesting that this translocation might compromise the male but not the female gametogenesis in this family.     

Familial reciprocal translocation t(9;13)(p11;p12) investigated by silver staining and in situ hybridisation

Summary A maternal de novo reciprocal translocation between the short arms of chromosomes 9 and 13 is reported. Using C-, Q- or G-banding, it was not possible to determine the precise breakpoint on 13, but a combination of silver staining and in situ hybridisation was used to do so on the two chromosomes, and it was demonstrated that the break on chromosome 13 had occurred within the NOR.     

The offspring of marriage between two first cousins with the same reciprocal translocation t(2;7)(p11;q31)

Summary A marriage between two first cousins who have the same 2/7 balanced translocation is reported. The chromosome rearrangement was primarily detected in amniotic fluid cells cultured for prenatal chromosome analysis because of advanced maternal age. The translocation was also found in the couple's two normal children and in three other members of the family. The possible zygotic chromosome constitutions following 2:2 meiotic segregation in consanguineous parents with the same translocation are discussed.     

4p- syndrome in a girl with translocation t(1;4)(q11;p16)mat

Summary A newborn girl had features of the 4p- syndrome. Cytogenetic studies of the mother showed a translocation t(1;4)(q11;p16). The proband had the translocation, but the band 4p16 had been lost.     

Fine mapping of the constitutional translocation t(11;22)(q23;q11)

Translocation t(11;22)(q23;q11) is the most common constitutional reciprocal translocation in man. Balanced carriers are phenotypically normal, except for decreased fertility, an increased spontaneous abortion rate and a possible predisposition to breast cancer in some families. Here, we report the high resolution mapping of the t(11;22)(q23;q11) breakpoint. We have localised the breakpoint, by using fluorescence in situ hybidisation (FISH) walking, to a region between D11S1340 and WI-8564 on chromosome 11, and D22S134 and D22S264 on chromosome 22. We report the isolation of a bacterial artificial chromosome (BAC) clone spanning the breakpoint in 11q23. We have narrowed down the breakpoint to an 80-kb sequenced region on chromosome 11 and FISH analysis has revealed a variation of the breakpoint position between patients. In 22q11, we have sequenced two BACs (BAC2280L11 and BAC41C4) apparently mapping to the region; these contain low copy repeats (LCRs). Southern blot analysis with probes from BAC2280L11 has revealed different patterns between normal controls and translocation carriers, indicating that sequences similar/identical to these probes flank the translocation breakpoint. The occurrence of LCRs has previously been associated with genomic instability and "unclonable" regions. Hence, the presence of such repeats renders standard translocation breakpoint cloning techniques ineffective. Thus, we have used high resolution fiber-FISH to study this region in normal and translocation cases by using probes from 22q11, LCRs and 11q23. We demonstrate that the LCR containing the gap in 22q11 is probably substantially larger than the previous estimates of 100 kb. Using fiber-FISH, we have localised the breakpoint in 22q11 to approximately 20-40 kb from the centromeric border of the LCR (i.e. the telomeric end of AC006547) and have confirmed the breakpoint position on 11q23.     

First trimester abortions associated with a translocation t(1;20)(p36;p11)

Summary A large family with a high rate of spontaneous abortions was found also to have a high incidence of a reciprocal translocation.     

Familial aniridia and translocation t(4;11)(q22;p13) without Wilms' tumor

A family with dominantly inherited aniridia in three generations is presented. All three patients had an apparently balanced chromosome translocation t(4;11)(q22;p13). The patients were otherwise clinically normal and without signs of Wilms' tumor; their erythrocyte catalase activities were within the normal range. We suggest that in this family aniridia is caused either by a submicroscopic deletion at the translocation breakpoint 11p13 or by a position effect on the same chromosome segment. Furthermore, the loci for aniridia and Wilms' tumor susceptibility are separate. It follows that the WAGR complex is caused by a mutation of more than one gene located at 11p13. The theoretical implications of a presumably defective allele causing a mendelian dominant phenotype are discussed.     

Heterozygous submicroscopic inversions involving olfactory receptor-gene clusters mediate the recurrent t(4;8)(p16;p23) translocation

The t(4;8)(p16;p23) translocation, in either the balanced form or the unbalanced form, has been reported several times. Taking into consideration the fact that this translocation may be undetected in routine cytogenetics, we find that it may be the most frequent translocation after t(11q;22q), which is the most common reciprocal translocation in humans. Case subjects with der(4) have the Wolf-Hirschhorn syndrome, whereas case subjects with der(8) show a milder spectrum of dysmorphic features. Two pairs of the many olfactory receptor (OR)-gene clusters are located close to each other, on both 4p16 and 8p23. Previously, we demonstrated that an inversion polymorphism of the OR region at 8p23 plays a crucial role in the generation of chromosomal imbalances through unusual meiotic exchanges. These findings prompted us to investigate whether OR-related inversion polymorphisms at 4p16 and 8p23 might also be involved in the origin of the t(4;8)(p16;p23) translocation. In seven case subjects (five of whom both represented de novo cases and were of maternal origin), including individuals with unbalanced and balanced translocations, we demonstrated that the breakpoints fell within the 4p and 8p OR-gene clusters. FISH experiments with appropriate bacterial-artificial-chromosome probes detected heterozygous submicroscopic inversions of both 4p and 8p regions in all the five mothers of the de novo case subjects. Heterozygous inversions on 4p16 and 8p23 were detected in 12.5% and 26% of control subjects, respectively, whereas 2.5% of them were scored as doubly heterozygous. These novel data emphasize the importance of segmental duplications and large-scale genomic polymorphisms in the evolution and pathology of the human genome.     

Partial trisomy 4q: Two cases resulting from a familial translocation t(4;18)(q27;p11)

Summary Partial trisomy of the long arm of chromosome 4 was observed in two related patients, a child aged 2 years and a woman aged 42. Cytogenetic investigation revealed that their chromosome anomalies were due to segregation of a familial balanced translocation t(4;18)(q27;p11). Some clinical and cytogenetic considerations are noted.     

Multicolor fluorescence in situ hybridization analysis of the spermatozoa of a male heterozygous for a reciprocal translocation t(11;22)(q23;q11)

A reciprocal translocation between chromosomes 11 and 22 is a site-specific translocation that has been seen in many families with no common ancestry. This translocation is of particular interest because balanced carriers have a 0.7–3.7% risk of having children with the supernumerary der(22), resulting from a 3:1 segregation. We have used a three color fluorescence in situ hybridization (FISH) with specific DNA probes to determine the chromosome segregation pattern of a male carrier of a translocation t(11;22)(q23;q11). The probes selected included a centromeric marker for chromosome 11, a marker closely linked to the centromere of chromosome 22, and a third probe distal to the translocation breakpoint of chromosome 22. The results showed that 3 : 1 segregation is preferential in this patient, with 40.1% of spermatozoa belonging to this segregation type. Alternate segregation followed with 27.4% of analyzed spermatozoa; 17.6% resulted from adjacent 1 and 12.5% resulted from adjacent 2 segregation. We detected 0.5% of presumably diploid spermatozoa. Complementary adjacent 1 products were observed at statistically different frequencies (P = 0.02). Complementary adjacent 2 products without recombination in the interstitial segments were also seen at different frequencies (P = 0.002). In 3 : 1 segregation, the products containing one chromosome were observed more frequently than those with three chromosomes (P = 0.0001). The 24,+der(22) gamete was seen more frequently than all of the other gametes combined which had 24 chromosomes resulting from 3 : 1 segregation. The results of this study demonstrate that in this t(11;22) carrier, 3 : 1 segregation is preferential but not exclusive. Received: 9 December 1998 / Accepted: 1 March 1999     

Balanced reciprocal whole-arm translocation t(1;19) in three generations

Summary Seven carriers of a balanced reciprocal whole-arm translocation of chromosomes 1 and 19 were found in 19 members investigated in three generations of one family. The apparent lack of a carrier of an unbalanced form of the translocation and of a history of miscarriages are discussed.