Localization of human c-mos to chromosome band 8q11 in leukemic cells with the t(8;21) (q22;q22)

Summary Chromosome in situ hybridization studies locate c-mos to chromosome band 8q11 in leukemic cells carrying the t(8;21) (q22;q22). This amends the previous assignment of c-mos to chromosome band 8q22 and conforms with its recent assignment to 8q11 in normal cells and in a cell line with a structurally abnormal chromosome 8. C-mos lies proximally to, and distant from, the breakpoint at 8q22 in the t(8;21) and is unlikely to have a role in the onset of acute myeloid leukemia characterized by this translocation.     

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.     

Interchange trisomy 21 by t(1;21)(p22;q22)mat

Interchange trisomy 21 by t(1:21)(p22:q22)mat: Interchange trisomy 21 by t(1;21)(p22;q22)mat was identified in a sporadic patient with Down syndrome. With a 21q22 specific probe, we observed signals on both normal 21 chromosomes and on the der. We reviewed the 23 published reports of families with reciprocal translocations leading to viable offspring with interchange trisomy 21. The breakpoints in chromosome 21 were mainly located in 21q (19/24 instances, including the present report) and in 19/23 cases the other chromosome involved in the translocation was (pairs 1-12). The underlying 3:1 segregation occurred mainly in carrier mothers; only one patient presented a de novo imbalance and in another case the father was the carrier. In addition, there were 4 instances of concurrence with another unbalanced segregation (adjacent-1 or tertiary trisomy) and 3 families with recurrence of interchange trisomy 21. The mean age of 14 female carriers at birth of interchange trisomy 21 offspring (24.8 yr) was lower that the mean (28.3 yr) found in a larger sample of mothers of unbalanced offspring due to 3:1 segregation (mostly tertiary trisomics) and was not increased with respect to the general population average. Overall, these data agree with previous estimates regarding recurrence risk (9-15%) and abortion rate (about 28%) in female carriers ascertained through an interchange trisomic 21 child.     

Pachytene analysis in males heterozygous for a familial translocation (9;12;13) (q22; q22; q32) ascertained through a child with partial trisomy 9

A family with four male and three female heterozygotes for a three-way translocation (9;12;13) (q22; q22; q32) in three generations was ascertained through a chromosomally imbalanced newborn with an additional derivative chromosome 9 resulting from nondisjunction. Three heterozygous males from two generations with apparent differences in their fertility status were investigated using pachytene spreads and testicular histology. Pachytene analysis in all three individuals, the fertile (II-2) as well as the subfertile (III-7) and infertile (III-9), showed a hexavalent with central nonpairing around the translocation breakpoints in nearly all spermatocytes. Thus, the observed hexavalent configurations in pachytene do not seem to have caused impaired fertility. This rather may have been the result of sperm carrying unbalanced chromosome sets. However, the observed difference in fertility between the heterozygous fertile male in generation II and his two heterozygous sons remains unexplained.     

Unexpected Inheritance of a Balanced Homologous translocation t(22q;22q) from father to a phenotypically normal daughter

Rearrangements between homologous chromosomes are extremely rare and manifest mainly as monosomic or trisomic offsprings. There are remarkably few reports of balanced homologous chromosomal translocation t (22q; 22q) and only two cases of transmission of this balanced homohologous rearrangement from mother to normal daughter are reported. Robersonian translocation carriers in non-homologous chromosomes have the ability to have an unaffected child. However, it is not possible to have an unaffected child in cases with Robersonian translocations in homologous chromosomes. Carriers of homologous chromosome 22 translocations with maternal uniparental disomy do not have any impact on their phenotype. We are presenting a family with a history of multiple first trimester miscarriages and an unexpected inheritance of balanced homologous translocation of chromosome 22 with paternal uniparental disomy. There are no data available regarding the impact of paternal UPD 22 on the phenotype. We claim this to be the first report explaining that paternal UPD 22 does not impact the phenotype.     

Inv21p12q22del21q22 and intellectual disability

Chromosomal rearrangements are common in humans. Pericentric inversions are among the most frequent aberrations (1–2%). Most inversions are balanced and do not cause problems in carriers unless one of the breakpoints disrupts important functional genes, has near submicroscopic copy number variants or hosts “cryptic” complex chromosomal rearrangements. Pericentric inversions can lead to imbalance in offspring. Less than 3% of Down syndrome patients have duplication as a result of parental pericentric inversion of chromosome 21. We report a family with an apparently balanced pericentric inversion of chromosome 21. The proband, a 23-year-old female was referred for prenatal diagnosis at 16 weeks gestation because of increased nuchal translucency. She has a familial history of Down's syndrome and moderate intellectual disability, a personal history of four spontaneous abortions and learning difficulties. Peripheral blood and amniotic fluid samples were collected to perform proband's and fetus' cytogenetic analyses. Additionally, another six family members were evaluated and cytogenetic analysis was performed. Complementary FISH and MLPA studies were carried out. An apparent balanced chromosome 21 pericentric inversion was observed in four family members, two revealed a recombinant chromosome 21 with partial trisomy, and one a full trisomy 21 with an inverted chromosome 21. Array CGH analysis was performed in the mother and the brother's proband. MLPA and aCGH studies identified a deletion of about 1.7 Mb on the long arm of inverted chromosome 21q22.11. We believe the cause of the intellectual disability/learning difficulties observed in the members with the inversion is related to this deletion. The recombinant chromosome 21 has a partial trisomy including the DSCR with no deletion. The risk for carriers of having a child with multiple malformations/intellectual disability is about 30% depending on whether and how this rearrangement interferes with meiosis.     

Predisposition for breast cancer in carriers of constitutional translocation 11q;22q.

A translocation between the long arms of chromosomes 11 and 22, t(11;22)(q23;q11), is the most frequent constitutional reciprocal translocation in man. This chromosome abnormality has not previously been reported to be associated with an increased risk for neoplasia. The observation of one patient with a constitutional translocation t(11q;22q) and breast cancer prompted us to study the relationship between these two conditions. The incidence of breast cancer was determined in carriers of t(11q;22q). The karyotypes were determined by QFQ-banding, and the breakpoints were then further characterized by fluorescent in situ hybridization. Eight families with a total of 22 balanced carriers were found. In five of these families there was one case of breast cancer each. In another family a case of an unknown malignancy was reported in one member. No other malignancies were found among these patients. The number of breast cancer cases was significantly higher than expected among the translocation carriers (P < .001). The chromosomal breakpoints showed the same localization with the markers used, in the seven families studied. The association of constitutional translocation t(11q;22q) and breast cancer identifies a subset of patients with a highly increased risk for breast cancer who would benefit from counseling and screening. It also suggests the involvement of genes on 11q and/or 22q, in the tumorigenesis of breast cancer.     

A novel translocation,t(9;21)(q13;q22) rearranging the RUNX1 gene in acute myelomonocytic leukemia

A novel translocation t(9;21)(q13;q22) associated with trisomy 4 has been detected in a patient with acute myelomonocytic leukemia (AML,M4) in relapse. The chromosomal translocation results in rearrangement of the RUNX1 gene at 21q22. The DNA sequence rearranged on chromosome 9 remains unidentified. The diversity of the partners involved in translocations implicating RUNX1 suggests that the functional consequences of the abnormality are more due to the truncation of RUNX1 than to the identity of its partner in the rearrangement.     

Evidence that chromosome band 22q12 is concerned with cell proliferation in chronic myeloid leukaemia

Summary A man and two of his three children carried an abnormally short chromosome 22 resembling the Philadelphia chromosome (Ph¹). Giemsa banding showed that the abnormal chromosome resulted from a translocation t(11;22) (q25;q13). The breakpoint on chromosome 22 was at the q12/q13 band interface compared with the breakpoint of Ph¹ at the q11/q12 band interface. The absence of leukaemia or haematological disorder in members of this family suggests that the critical genetic site on chromosome 22 concerned with abnormal myeloid cell proliferation in human leukaemia is contained in the 22q12 band.     

47,XY,+der(11;22)(q23;q12) following balanced translocation t(11;22)(q23;q12)mat

Summary Report of a supernumerary extra chromosome der(11;22)(q23; q12) resulting from a balanced translocation in the mother. The propositus suffers from mental deficiency, deafness and extreme muscular weakness and exhibits cleft palate, a labial lymphangioma and an atrial septum defect. Since the features of partial trisomy 11q23 frequently associated with a translocation t(11q;22q) bear similarities with the cases of so called trisomy 22 one might conjecture that some of these observations are in fact products of translocations including partial 11q.     

Trisomie 10 partielle par translocation familiale t(1;10) (q44;q22)

Résumé Chez une enfant anormale, on observe un excès de matériel chromosomique sur la paire 1:1q+, et une translocation t(1q+;10q-) est dépistée dans la famille.L'analyse du caryotype après «dénaturation thermique ménagée» a permis d'individualiser le chromosome C anormal (10q-), de définir l'emplacement exact des points de cassure et de lier essentiellement l'état pathologique du patient à une trisomie partielle du bras long du chromosome 10.Cette trisomie se traduit principalement par une arriération mentale, une hypotrophie, des anomalies oculaires, une fente palatine, une mal-implantation des oreilles, un micrognathisme, des anomalies du squelette et une cardiopathie.

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Partial trisomy 10 due to hereditary translocation t(1;10) (q44;q22)

Summary A chromosome 1q+was observed in an abnormal girl. A balanced t(1q+;10q-) was found in the family.Application of a controlled thermic denaturation technique allowed recognition of the abnormal C as a 10q-and localization of the break points (1q44 and 10q22).The partial trisomy 10q of the proband had induced mental retardation, severe retardation of growth, ocular anomalies, agenesis of the palate, low implantation of the ears, micrognathia bone anomalies and cardiac malformation.

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Zusammenfassung Bei einem Mädchen mit Mißbildungen wurde ein Chromosom 1q+beobachtet. Eine balancierte t(1q+, 10q-) fand sich in der Familie.Die Identifikation des abnormen C als 10q- wurde durch Anwendung kontrollierter Wärmedenaturierung erreicht; auf diesem Wege wurden auch die Bruchpunkte identifiziert.Die partielle Trisomie 10q hatte bei dem Probanden einen geistigen Entwicklungsrückstand, eine schwere Wachstumsstörung, Augenanomalien, Fehlen des Gaumens, tief ansetzende Ohren, eine Mikrognathie, Knochenanomalien und eine Herzmißbildung zur Folge.

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Chargée de Recherche I.N.S.E.R.M. Chef de Service à l'Institut Pasteur de Lyon.

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Chargés de Recherche C.N.R.S.     

Systemic mastocytosis associated with t(8;21)(q22;q22) acute myeloid leukemia

Although KIT mutations are present in 20–25% of cases of t(8;21)(q22;q22) acute myeloid leukemia (AML), concurrent development of systemic mastocytosis (SM) is exceedingly rare. We examined the clinicopathologic features of SM associated with t(8;21)(q22;q22) AML in ten patients (six from our institutions and four from published literature) with t(8;21) AML and SM. In the majority of these cases, a definitive diagnosis of SM was made after chemotherapy, when the mast cell infiltrates were prominent. Deletion 9q was an additional cytogenetic abnormality in four cases. Four of the ten patients failed to achieve remission after standard chemotherapy and seven of the ten patients have died of AML. In the two patients who achieved durable remission after allogeneic hematopoietic stem cell transplant, recipient-derived neoplastic bone marrow mast cells persisted despite leukemic remission. SM associated with t(8;21) AML carries a dismal prognosis; therefore, detection of concurrent SM at diagnosis of t(8;21) AML has important prognostic implications.     

A novel form of "central pouchlike" cataract, with sutural opacities, maps to chromosome 15q21-22

Congenital cataract is a clinically and genetically highly heterogeneous eye disorder, with autosomal dominant inheritance being most common. We investigated a large seven-generation family with 74 individuals affected by autosomal dominant congenital cataract (ADCC). The phenotype in this family can be described as "central pouchlike" cataract with sutural opacities, and it differs from the other mapped cataracts. We performed linkage analysis with microsatellite markers in this family and excluded the known candidate genes. A genomewide search revealed linkage to markers on chromosome 15, with a maximum two-point LOD score of 5.98 at straight theta=0 with marker D15S117. Multipoint analysis also gave a maximum LOD score of 5.98 at D15S117. Multipoint and haplotype analysis narrowed the cataract locus to a 10-cM region between markers D15S209 and D15S1036, closely linked to marker D15S117 in q21-q22 region of chromosome 15. This is the first report of a gene for a clinically new type of ADCC at 15q21-22 locus.     

22q11.2 deletion mosaicism in patients with conotruncal heart defects

BACKGROUND: Some patients with conotruncal heart defects (CTDs) have a chromosome 22q11.2 deletion, but we do not know whether patients with CTDs who are missing the peripheral blood-cell chromosome 22q11.2 deletion are also missing the 22q11.2 deletion in myocardial cells, and whether patients with the 22q11.2 deletion can show a different 22q11.2 deletion in peripheral blood cells and myocardial cells due to a postzygotic mutation during the embryonic period. METHODS: A total of 32 Chinese pediatric nonsyndromic CTD patients (21 with tetralogy of fallot [TOF], 9 with double outlet right ventricle [DORV], 1 with pulmonary artery atresia with ventricular septal defect [PAA/VSD], and 1 with congenitally corrected transposition of the great arteries [CCTGA]), 12 females and 20 males ranging in age from 5 months to 7 years, were included in our study. We used fluorescence in situ hybridization (FISH) to find the chromosome 22q11.2 deletion in peripheral blood cells and compared genotypes of 15 short tandem repeat (STR) markers within 22q11.2 between peripheral blood cells and myocardial cells to search for genetic mosaicism of the chromosome 22q11.2 deletion. RESULTS: Three patients, 2 with TOF and 1 with DORV, were determined to have the peripheral blood cell chromosome 22q11.2 deletion. There was no STR genotypic difference observed between peripheral blood cells and myocardial cells in patients with or without the chromosome 22q11.2 deletion. CONCLUSIONS: Genetic mosaicism may not play a major role in the etiology of isolated CTDs.     

Linear order of the four BCR-related loci in 22q11

It has recently been shown the a probe for the 3' end of the BCR gene recognizes a family of four BCR-like genes that map to 22q11. Using a panel of somatic cell hybrids with rearrangement of chromosome 22, we have determined their order within 22q11: BCR-2, BCR4, BCR1, BCR-3, with BCR-2 the most centromere proximal. All of the BCR-like genes map proximal to the 22q11-q12 breakpoint of a t(11;22) in a Ewing sarcoma.     

Cloning of the Human Monocarboxylate Transporter MCT3 Gene: Localization to Chromosome 22q12.3–q13.2

Lactate transport across cell membranes is mediated by a family of proton-coupled monocarboxylate transporters (MCTs). The retinal pigment epithelium (RPE) expresses a unique member of this family, MCT3. A portion of the human MCT3 gene was cloned by polymerase chain reaction using primers designed from rat RPE MCT3 cDNA sequence. The human genomic sequence was used to design primers to clone human MCT3 cDNA and to identify a bacterial artificial chromosome clone containing the human MCT3 gene. The human MCT3 cDNA contained a 1512-nucleotide open reading frame with a deduced amino sequence 85% identical to rat MCT3. Comparison of the cDNA and genomic sequences revealed that the MCT3 gene was composed of five exons distributed over 5 kb of DNA. The exon–intron borders were conserved between the human and the chicken MCT3 genes. Using radiation hybrid mapping, the MCT3 gene was mapped to chromosome 22 between markers WI11639 and SGC30687. A search of chromosome 22 in the Sanger Centre database confirmed the location of the human MCT3 gene at 22q12.3–q13.2.     

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.     

Chronic myelogenous leukemia with translocations (3q-;9q+) and (17q-;22q+). Possible crucial cytogenetic events in the genesis of CML

Summary Two reciprocal translocations involving chromosomes 3, 9, 17, and 22 were found in a patient with seemingly Ph¹-negative chronic myelogenous leukemia (CML). The two translocations were t(3;9)(q21;q34) and t(17;22)(q21;q11); the breakage in chromosomes 9 and 22 apparently occurred at the same point as in the usual Ph¹ translocation, t(9;22)(q34;q11).From the present evidence and a review of the literature it appears that the breakage on both chromosomes 9 and 22 at the special regions and the separation of the fragments are present in practically all standard and variant Ph¹ translocations, even those in which the terminal region of the long arm of chromosome 9 (9q) does not seem to be involved in the rearrangement; however, a translocation between chromosomes 9 and 22 is not an obligatory result of the rearrangement, as seen in the present case. Thus, we postulate that the breakage on both chromosomes 9 and 22 at the special regions and separation of the fragments are the crucial cytogenetic events in the genesis of CML and stress the importance of paying careful attention to the terminal region of 9q, particularly when chromosome 9 does not seem to be involved in the rearrangement.This work was supported in part by grants (Nos. 401001 and 401071) from the Ministry of Education, Science and Culture of Japan     

An infant with trisomy 9pter yields 9q22 resulting from 3:1 segregation in a 46,XX t(1;9) (p36;q22) mother.

A newborn infant with a 47,XY,+ der(.),t(1;9) (p36;q22)mat chromosome complement and the clinical features of the 9p trisomy is described. A review of the reproductive histories of five cases with trisomy 9pter yields 9q21 or 22 indicate that the balanced translocation mothers of these infants may have as high as a 23% chance of producing a chromosomally unbalanced offspring due to 3:1 disjunction.