Exclusion gene mapping utilizing patients with chromosome imbalance: the HL-A system as a prototype.

17 chromosomally unbalanced patients, their siblings and parents were tested for HL-A types and for up to 25 other polymorphic systems to determine whether there was gain or loss of an allele concurrent with the gain or loss of chromosome material. 5 patients had trisomy of part or all of a chromosome; 2 had trisomy of a segment and also deletion of chromosome material. All 7 were due to a familial translocation. The remaining patients had small deletions; 5 had ring chromosomes, 4 had rod deletions and 1 had missing chromosome material due to a heritable translocation. All cases were informative at the HL-A loci because of the high degree of polymorphism of the system whereas only some of the other systems were informative. None of the 17 patients showed unusual inheritance of HL-A or any other of the polymorphic systems examined. These results provide evidence excluding the HL-A and other loci from a number of possible locations in the human genome.     

Localization exclusion of the HL-A genes from the short arm of human chromosome 5

Summary A cri du chat patient with deletion of more than 3/4 of the short arm of one chromosome 5 was found to be heterozygous at both of the closely linked HL-A gene loci, thus demonstrating that the HL-A genes cannot be located on the missing segment.

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Zusammenfassung Bei einem Patienten mit Cri du chat-Syndrom und einer Chromosomendefizienz, die mehr als 3/4 des kurzen Armes eines Chromosoms 5 umfaßt, wurde Heterozygotie an beiden der enggekoppelten HL-A-Gene festgestellt. Damit können die HL-A-Gene nicht auf dem deletierten Abschmitt lokalisiert sein.

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Supported by the Deutsche Forschungsgemeinschaft.

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Supported by The Danish State Research Foundation and Einar Willumsen's Foundation.     

Ring chromosome 6: Case report and review of literature

Summary A ring chromosome 6 has been identified by GTG-banding in a male with microcephaly, growth retardation, seizures, epicanthus, hypertelorism, micrognathia, and other congenital anomalies. Cytogenetic studies indicate the instability of the ring chromosome. The most common findings in subjects with ring 6 include: profound to moderate mental retardation, microcephaly, prenatal growth failure, retarded bone age, epicanthal folds, flat nasal bridge, short neck, ears low-set or malformed, microphthalmia, and micrognathia. Linkage studies, including HLA, are consistent with reported maps of chromosome 6.This study was supported in part by grant number 1-442 from the National Foundation — March of Dimes     

Chromosome 7 short arm deletion and craniosynostosis a 7p-syndrome

Summary A patient with craniosynostosis and a small deletion of part of the short arm of chromosome 7 is described. A review of the literature indicates that craniosynostosis has occurred in at least four of the five infants (the fifth having microcephaly) affected by structural changes (resulting in deletion) within the terminal region of the short arm of chromosome 7.Supported by: National Foundation March of Dimes Grant CA-90, National Institutes of Health Grants, No. 5S01 RR05655-07 and No. P01 GM 15 253-08     

Central limit theorems of pedigrees

Summary Two multivariate central limit theorems are proved for polygenic trait values over a pedigree or collection of pedigrees. These theorems presuppose Hardy-Weinberg and linkage equilibrium for all loci, absence of assortative mating and epistasis, and a small variance for each locus compared to the total variance over many loci. To prevent clustering of loci, an upper bound is also imposed on the number of loci per chromosome. In the case of zero dominance variance for each locus, arbitrary inbreeding is allowed. Otherwise inbreeding is not permitted. Further technical conditions are spelled out in the text. This research was supported by the University of California at Los Angeles, NIH Division of Facilities and Resources Grant RR-3, and National Foundation March of Dimes Grant 6-55.     

Possible linkage of HL-A and GLO

Summary In 21 informative families with 60 children, a possible linkage between HL-A and GLO was found (recombination fraction approximatively 0.15). The sequence of the loci on chromosome 6 might be GLO, HL-A, PGM₃, MNSs.

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Zusammenfassung Koppelungsuntersuchungen bei 21 informativen Familien mit 60 Kindern zeigten, daß die Loci HL-A und GLO möglicherweise gekoppelt sind (Rekombinationsfrequenz ca. 15%). Die Reihenfolge der Loci am Chromosom 6 kann wie folgt angenommen werden: GLO, HL-A, PGM₃, MNSs.

     

Familial trisomy 20p five cases and two carriers in three generations a review.

A clinically normal mother of three retarded children has been determined by G-banding to have a balanced translocation 46,XX,t(13;20) (q34;p11.2). The children each have an unbalanced form of the translocation with partial trisomy for 20p. Extensive gene marker studies have been unable to affix any specific gene locus onto the short arm of chromosome 20. The balanced translocation was inherited from the maternal grandfather. Two phenotypically abnormal deceased members of the family are believed to have had the unbalanced trisomy 20p condition. An increases number of spontaneous abortions were possibly due to lethal unbalanced 20p deletions. The moderate to mild mental retardation and somewhate unusual features (round face, prominent cheeks and nose, short mandible) in the three siblings and two other affected relatives suggest that trisomy of the short arm of chromosome 20 may cause a distinguishable clinical syndrome. Vertebral abnormalities and abnormal dermatoglyphics are part of the picture. Clinical and cytogenetic findings of all reported cases are compared.     

Linkage group HL-A-MLC-BF (properdin factor B). The site of the Bf locus at the immunogenetic linkage group on chromosome 6.

Genetic linkage between the HL-A and Bf loci could be confirmed in 43 families with 168 offspring. In 4 families, 5 recombinants out of 82 informative meiotic divisions were observed (r = 6.1%). The localisation of the Bf marker system was studied in 3 families with crossovers between HL-A and MLC. From these data the following map order of human chromosome 6 can be proposed: HL-A (1st locus) -- HL-A (2nd locus)--MLC-Bf---PGM(3). The fact that important components of the classical and alternate pathway of complement activation are governed by genes closely linked with HL-A and MLC loci leads to the proposition to include the Bf system into the Major Histocompatibility Complex in man.     

Parental origin of the extra chromosome in Down's syndrome

Summary Chromosome 21 fluorescent heteromorphisms were studied in 42 patients with Down's syndrome, their parents and their siblings. Included in this number are two instances of an aunt and niece affected with trisomy 21, and one of affected siblings. One case has a de novo 21/21 translocation. Blood group, red cell and serum protein markers were also studied for linkage, gene exclusions, associations, and paternity testing. Thirty-one of the trisomy 21 cases were informative for parental origin of the extra chromosome and for stage of meiosis. The non-disjunctional event was of maternal origin in 24; 23 occurred in meiosis I, 1 in meiosis II. Seven were of paternal origin; 5 in meiosis I, and 2 in meiosis II. The translocation case was of paternal origin. A literature search revealed a total of 98 cases informative for the parent of origin of the extra chromosome, of >347 families tested. In addition, 3 de novo translocation cases, of 7 tested, were informative. The data suggest that most cases result from an error in the first meiotic division in the mother, but that a significant proportion are paternal in origin.     

46,XX,t(15;21)/47,XX,15p-,+21 mosaicism in a child with Down's syndrome

We report here the first case of a mosaic Down's syndrome in which both clones are trisomic for chromosome 21, one of them (90%) by a Robertsonian translocation (15;21) appearing de novo, and the other (10%) by an additional chromosome 21. Three hypotheses can explain the appearance of such a mosaic: that of a chimera formed by the fusion of two trisomy 21 zygotes, one of which had a Robertsonian translocation, the other an additional trisomy 21 zygote; that of a fusion between a chromosome 15 and a chromosome 21 in one of the early segmentation blastomeres of a trisomy 21 zygote; the more probable hypothesis of the occurrence of a fission at the break-attachment point of a Robertsonian translocation (15;21) in one of the cells arising from the early postzygotic divisions of a zygote which was a trisomy 21 by Robertsonian translocation (15;21).     

Induced chromosome aberrations in early embryogenesis of mice

Summary A 28-year-old man, whose infant son died of multiple malformations, was shown to have a balanced 13q-/18q+ translocation. He was phenotypically and mentally normal. Studies of the pedigree revealed the presence of bilateral microtia on the side of the spouse of the proband, transmitted in a dominant mode through four generations. Occasional cells from the proband and his mother exhibited an elongated long arm of a chromosome 16.This work was supported by a grant from the National Swiss Foundation for Scientific Research (Credit No. 3.211.69).Supported by Grant 64-411A from the Ford Foundation Population Program.     

Trisomy 20p due to a paternal reciprocal translocation

A mentally retarded boy with multiple malformations was found to have trisomy for the distal two-thirds of the short arm of chromosome 20 (trisomy 20p), resulting from a paternal translocation (5;20)(p15;p11). The patient had a cleft palate, a feature not present in other trisomy 20p patients. A review of the reported trisomy 20p patients indicates that their varied features do no constitute a readily recognizable clinical syndrome.     

Distribution of constitutive heterochromatin in Hela and HEp-2 cell lines

Summary Despite the fact that HeLa and HEp-2 cell lines have been established respectively from a female and a male patient, the frequent loss of the Y chromosome makes it difficult to discriminate the two cell types. The technique of centromeric localization of heterochromatin, however, facilitates more definite identification of the two cell types. Giemsa positive centromeric constitutive heterochromatin blocks were induced within the intact metaphase chromosome preparations of Hela and HEp-2 cells. The Hela cell population had a single heterochromatin marker chromosome, whereas the HEp-2 cell line was found to possess two types of heterochromatin markers. The distinctive patterns of distribution of constitutive heterochromatin of these three chromosomes served as the guides in tracing the presumptive cytological pathways for their orgin.

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Zusammenfassung Trotz der Tatsache, daß Hela- und HEp-2-Zellinien jeweils von einem weiblichen und einem männlichen Patienten stammen, erschwert der häufige Verlust des Y-Chromosoms eine Unterscheidung der beiden Zelltypen. Der Nachweis des zentromernahen Heterochromatins jedoch ermöglicht eine zuverlässigere Erkennung dieser beiden Zelltypen. Die Hela-Zellpopulation hat ein einzelnes, durch das Heterochromation gekennzeichnetes Marker-Chromosom, während die HEp-2-Zellinie deren 2 besitzt. Das distinkte Verteilungsmuster des konstitutiven Heterochromatons dieser 3 Chromosomen dient dazu, die vermutliche cytologische Herkunft zu interpretieren.

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Supported in part by the Robert A. Welch Foundation, The National Foundation —March of Dimes and USPHS Grant No. FR-05425.     

Non-reciprocal chromosomal bridge-induced translocation (BIT) by targeted DNA integration in yeast

Several experimental in vivo systems exist that generate reciprocal translocations between engineered chromosomal loci of yeast or Drosophila, but not without previous genome modifications. Here we report the successful induction of chromosome translocations in unmodified yeast cells via targeted DNA integration of the KAN^R selectable marker flanked by sequences homologous to two chromosomal loci randomly chosen on the genome. Using this bridge-induced translocation system, 2% of the integrants showed targeted translocations between chromosomes V-VIII and VIII-XV in two wild-type Saccharomyces cerevisiae strains. All the translocation events studied were found to be non-reciprocal and the fate of their chromosomal fragments that were not included in the translocated chromosome was followed. The recovery of discrete-sized fragments suggested multiple pathway repair of their free DNA ends. We propose that centromere-distal chromosome fragments may be processed by a break-induced replication mechanism ensuing in partial trisomy. The experimental feasibility of inducing chromosomal translocations between any two desired genetic loci in a eukaryotic model system will be instrumental in elucidating the molecular mechanism underlying genome rearrangements generated by DNA integration and the gross chromosomal rearrangements characteristic of many types of cancer.Electronic Supplementary Material Supplementary material is available for this article at     

Two sibs with duplication of 4q31-->qter due to 3:1 meiotic disjunction and mild phenotype

Two sibs with duplication of 4q31-->qter due to 3:1 meiotic disjunction and mild phenotype: Clinical and cytogenetic findings in two sibs with partial duplication of 4q31.3-->qter and 21q11.2-->pter are reported. These patients are rare cases of reoccurrence of those partial trisomies due to 3:1 segregation of a maternal balanced translocation. A review of the literature reporting cases of trisomy of the 4q31-->qter segment is also made; previously reported cases mostly in addition have deletions of other chromosomes resulting from adjacent segregation of balanced translocation. The findings of our study confirm the high risk for offspring with unbalanced rearrangements in women with reciprocal translocation involving acrocentric and short chromosome segments. The study also points out that duplication of 4q31-->qter may go along with only mild phenotypic findings if there is no significant additional aneuploidy of the other chromosome involved in the rearrangement.     

Retained heterodisomy for chromosome 12 in atypical lipomatous tumors: implications for ring chromosome formation

Atypical lipomatous tumor (ALT) is an intermediate malignant mesenchymal tumor that is characterized by supernumerary ring chromosomes and/or giant rod-shaped marker chromosomes (RGMC). Fluorescence in situ hybridization (FISH) and molecular genetic analyses have disclosed that the RGMCs always contain amplified sequences from the long arm of chromosome 12. Typically, RGMCs are the sole clonal changes and so far no deletions or other morphologic aberrations of the two normal-appearing chromosomes 12 that invariably are present have been detected. The mechanisms behind the formation of the RGMCs are unknown, but it could be hypothesized that RGMC formation is preceded by trisomy 12 or, alternatively, that ring formation of one chromosome 12 is followed by duplication of the remaining homolog. The latter scenario would always result in isodisomy for the two normal-appearing chromosomes 12, whereas the former would yield isodisomy in one-third of the cases. In order to investigate these possible mechanisms behind ring formation, we studied polymorphic loci on chromosome 12 in 14 cases of ALT showing one or more supernumerary ring chromosomes and few or no other clonal aberrations at cytogenetic analysis. The molecular genetic analyses showed that the tumor cells always retained both parental copies of chromosome 12, thus refuting the trisomy 12 and duplication hypotheses.     

An unusually proximal deletion on the short arm of chromosome 3 in a patient with small cell lung cancer.

The tumors of patients with small cell lung carcinoma (SCLC) frequently exhibit the loss of alleles at polymorphic loci on the short arm of chromosome 3. We report the genotype analysis of six SCLC patients obtained using 15 chromosome 3 probes that identified 19 restriction fragment length polymorphisms (RFLPs). Five of the six patients were reduced to homozygosity in the tumor DNA at every informative 3p locus, and thus did not serve to delineate the deletion. However, the RFLP analysis of the tumor DNA of the sixth patient demonstrated both heterozygous and hemizygous loci on 3p and allowed the definition of an interstitial deletion that extends proximal to the D3S2 locus at 3p14.2-p21 to include at least 3p13-p14. The exclusion of the D3F15S2 locus from the deleted region, observed in this patient, is an uncharacteristic feature of SCLC deletions. This deletion includes the location of D3S30 and D3S4, and thus serves to map these loci within the proximal half of chromosome 3.     

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.     

Characterization of three VNTR systems at D21S112.

D21S112 is a highly polymorphic marker on the long arm of chromosome 21. Our analysis of this locus indicated the presence of three VNTR systems. We estimated the heterozygosity of each system and sequenced one of the repetitive regions. Utilizing PCR, we demonstrated that the sequenced VNTR is responsible for the system with the highest level of heterozygosity. Combining data from the three systems makes D21S112 one of the most informative loci on the chromosome.     

Monosomy for the centromeric and juxtacentromeric region of chromosome 21

Summary A boy with partial monosomy 21 is described. The child has an unbalanced 20/21 translocation with deletion of the centromeric and juxtacentromeric region of chromosome 21. Examination by C-banding technique shows that the translocation is of maternal origin. Investigation of a number of genetic marker systems shows that the HL-A, AcP, and GPT loci are not located in the deleted segment.

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Zusammenfassung Es wird ein Junge mit partieller Monosomie Nr. 21 beschrieben. Das Kind hat eine unbalancierte 20/21-Translokation mit einer Deletion der Zentromer-und Juxtazentromer-Region des Chromosomes Nr. 21. Untersuchung mit der C-Band-Technik zeigt, daß die Translokation mütterlichen Ursprungs ist. Untersuchung einer Reihe genetischer Markersysteme zeigt, daß die HL-A-, AcP- und GPT-Loci nicht in dem deletierten Segment liegen.