Inherited translocations in two families (t(14q+;10q−) and t(13q−;21q+))

Summary Two families with reciprocal translocations (t(14q+;10q–) and t(13q–;21q+)) are described. In both families the proband had multiple congenital anomalies and an unbalanced karyotype, 46,XY,14q+ and 46,XX,21q+ respectively. Routine, autoradiographic and fluorescence techniques were used for analysis of karyotype of probands and their relatives. The probands' phenotypes and the results of their family members' dermatoglyphic analysis are presented in detail.

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Zusammenfassung Zwei Familien mit reziproker Translokation (t(14q+;10q–) und t(13q–;21q+)) werden beschrieben. In beiden Familien weist der Proband multiple angeborene Mißbildungen und einen unbalancierten Karyotyp (46,XY,14q+ bzw. 46,XX,21q+) auf. Für die Analyse aller untersuchten Personen wurden neben der Routine-Methode autoradiographische und Fluorescenz-Methoden verwendet. Die Phänotypen der Probanden sowie die Ergebnisse einer Analyse der Dermatoglyphen bei ihren Familienangehörigen werden genau beschrieben.

     

Characterisation of interstitial duplications and triplications of chromosome 15q11–q13

Chromosome 15 is frequently involved in the formation of structural rearrangements. We report the molecular characterisation of 16 independent interstitial duplications, including those of one individual who carried a duplication on both of her chromosomes 15, and three interstitial triplications of the Prader-Willi/Angelman syndrome critical region (PWACR). In all probands except one, the rearrangement was maternal in origin. In one family, the duplication was paternal in origin, yet appeared to segregate in a sibship of three with an abnormal phenotype that included developmental delay and a behavioural disorder. Ten duplications were familial, five de novo and one unknown. All 16 duplications, including two not visible by routine G-banding, were of an almost uniform size and shared the common deletion breakpoints of Prader-Willi syndrome and Angelman syndrome. Like deletions, the formation of duplications can occur in both male and female meiosis and involve both inter- and intrachromosomal events. This implies that at least some deletions and duplications are the reciprocal products of each other. We observed no instances of meiotic instability in the transmission of a duplication, although recombination within the PWACR occurred in two members of the same family between the normal and the duplicated chromosome 15 homologues. All three triplications arose de novo and included alleles from both maternal chromosomes 15. Triplication breakpoints were more variable and extended distally beyond the PWACR. The molecular characteristics of duplications and triplications suggest that they are formed by different mechanisms.     

Retinoblastoma,gross internal malformations,and deletion 13q14→q31

Summary A male patient with an interstitial deletion 13q14q31 is described. Our necropsy findings included a left retinoblastoma and several gross internal malformations. In this paper we reaffirm that band 13q14 is involved in cases of retinoblastoma and we propose, after studying accompanying cases of total or partial long arm trisomies 13, that the loss of specific 13q bands, from 13q14 to 13q31 is responsible for the congenital defects we are describing.     

Two reciprocal translocations t(9p+;13q−) and t(13q−;21q+)

Summary Two reciprocal balanced translocations 46,XY,t(9;13)(p23;q21) and 46,XX,t(13;21)(q21;q21), identified by RFA- and GTG-banding, are presented along with a complete study of both families.In the second case a 3:1 segregation is associated with an unbalanced 2:2 segregation, as demonstrated in the two surviving sons: one with interchange trisomy 21 and the other with partial trisomy 13 and partial monosomy 21. This suggests that the presence of this translocation, and possibly of other translocations involving morphologically similar chromosomes, could signify a high risk of having chromosomal disorders in offspring.     

Partial 3q duplication syndrome and assignment of D3S5 to 3q25–3q28

Summary We report a girl with a de novo duplication of the distal part of the long arm of chromosome 3 and review the literature. Our patient had the facial characteristics and many other anomalies of the partial 3q duplication syndrome. As a hitherto undescribed symptom in partial 3q trisomy syndrome, she had microphthalmia. The karyotype of this girl was interpreted as an inverse duplication of the terminal portion of chromosome 3: 46,XX,inv dup (3)(pter-q28::q28–q25::q28-qter). Quantitative hybridisation studies with 3p and 3q probes gave a consistent 32 ratio of the relative intensities of the q bands in relation to the p bands between patient and control. This confirmed the presence of a 3q duplication and delineated the location of D3S5 to 3q25–3q28.     

Pure monosomy and trisomy 2q24.2→q3105 due to an inv ins(7;2)(q21.2;q3105q24.2) segregating in four generations

Summary An inv ins(7;2)(q21.2;q3105q24.2) was found to segregate through four generations of a family. Adjacent-1 segregation aneusomies were ascertained in five patients: three monosomics and two trisomics; and the corresponding syndromes were delineated. The comparative analysis between these and other previously described 2q aneusomic individuals led to the conclusion that a large cleft between first and second toes is a constant feature in monosomy 2q24q31. No other trait could plausible be mapped. Risks of 7.9 to 31.9% for aneusomic children and of 26.3% for abortion were estimated in the present family.     

3q26.31–q29 duplication and 9q34.3 microdeletion associated with omphalocele,ventricular septal defect,abnormal first-trimester maternal serum screening and increased nuchal translucency: Prenatal diagnosis and aCGH characterization

We present prenatal diagnosis and array comparative genomic hybridization characterization of 3q26.31–q29 duplication and 9q34.3 microdeletion in a fetus with omphalocele, ventricular septal defect, increased nuchal translucency, abnormal first-trimester maternal screening and facial dysmorphism with distinct features of the 3q duplication syndrome and Kleefstra syndrome. The 26.61-Mb duplication of 3q26.31–q29 encompasses EPHB3, CLDN1 and CLDN16, and the 972-kb deletion of 9q34.3 encompasses EHMT1. We review the literature of partial trisomy 3q associated with omphalocele and discuss the genotype–phenotype correlation in this case.     

Comparative analysis of vertebrate EIF2AK2 (PKR) genes and assignment of the equine gene to ECA15q24–q25 and the bovine gene to BTA11q12–q15

The structures of the canine, rabbit, bovine and equine EIF2AK2 genes were determined. Each of these genes has a 5'' non-coding exon as well as 15 coding exons. All of the canine, bovine and equine EIF2AK2 introns have consensus donor and acceptor splice sites. In the equine EIF2AK2 gene, a unique single nucleotide polymorphism that encoded a Tyr329Cys substitution was detected. Regulatory elements predicted in the promoter region were conserved in ungulates, primates, rodents, Afrotheria (elephant) and Insectifora (shrew). Western clawed frog and fugu EIF2AK2 gene sequences were detected in the USCS Genome Browser and compared to those of other vertebrate EIF2AK2 genes. A comparison of EIF2AK2 protein domains in vertebrates indicates that the kinase catalytic domains were evolutionarily more conserved than the nucleic acid-binding motifs. Nucleotide substitution rates were uniform among the vertebrate sequences with the exception of the zebrafish and goldfish EIF2AK2 genes, which showed substitution rates about 20% higher than those of other vertebrates. FISH was used to physically assign the horse and cattle genes to chromosome locations, ECA15q24–q25 and BTA11q12–15, respectively. Comparative mapping data confirmed conservation of synteny between ungulates, humans and rodents.     

New gene in the homologous human 11q13–q14 and mouse 7F chromosomal regions

Alterations in the chromosomal region 11q13–11q14 are involved in several pathologies in which most of the key genes remain to be identified. In an effort to isolate as many candidates as possible, we are cloning genes from this region. We report here the mapping for a new sequence from 11q13.5–11q14. This sequence, designated D11S833E, putatively encodes a new gene, provisionally named GARP. We cloned its homologous sequence in the mouse and located it on Chromosome (Chr) 7, region F. The human and mouse genes belong to a conserved group of synteny. This, together with the similar conservation of the FGF and TYR genes, indicates that the human 11q13–q14 and mouse 7E-7F regions share homology.     

A novel genetic locus for familial febrile seizures and epilepsy on chromosome 3q26.2–q26.33

Febrile seizures (FS) are common in children, and the incidence is 2–5% before the age of 5 years. A four-generation Chinese family with autosomal dominant febrile seizure and epilepsy was studied by genome-wide linkage analysis. Significant linkage was identified with markers on chromosome 3q26.2–26.33 with a maximum pairwise LOD score of >3.00. Fine mapping defined the new genetic locus within a 10.7-Mb region between markers D3S3656 and D3S1232. A maximum multipoint LOD score of 5.27 was detected at marker D3S1565. A previously reported CLCN2 gene for epilepsy was excluded as the disease-causing gene in the family by mutational analysis of all exons and exon–intron boundaries of CLCN2 and by haplotype analysis. Mutation analysis of KCNMB2 and KCNMB3, which were two potassium-channel genes in this linkage region, did not reveal a disease causing mutation. Our results identified another novel locus on chromosome 3q26.2–26.33, and future studies of the candidate genes at the locus will identify a new gene for combined FS and idiopathic epilepsies. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users. X.-H. Dai, W.-W. Chen, and X. Wang contributed equally to this work.     

Prenatal diagnosis of de novo interstitial deletions involving 5q23.1–q23.3 and 18q12.1–q12.3 by array CGH using uncultured amniocytes in a pregnancy with fetal interrupted aortic arch and atrial septal defect

We present prenatal diagnosis of de novo interstitial deletions involving 5q23.1–q23.3 and 18q12.1–q12.3 by aCGH using uncultured amniocytes in pregnancy with interrupted aortic arch and atrial septal defect in a fetus. The fetus postnatally manifested facial dysmorphisms and long slender fingers. We discuss the genotype–phenotype correlation and the consequence of haploinsufficiency of FBN2, DTNA and CELF4 in this case.     

10q(q23→qter) duplication: GOTs,HK1, and other gene markers

Summary Gene marker analyses have been carried out in a patient with 10q(q23qter) duplication. The observed elevation of red cell glutamic oxaloacetic transaminase activity is compatible with earlier somatic cell hybridization studies that mapped the locus to this region. Hexokinase-1 activity in the red cells was normal, which is consistent with its prior assignment to the unaffected part of chromosome 10 (10pterq23).     

Duplication 15q22»15qter and its phenotypic expression

Summary Two infants with dysmorphism and aortic stenosis were trisomic for the distal part of 15q. Similar to seven other published cases, the facial dysmorphism was characteristic: prominent nose, narrow palpebral fissures, slight anti-mongoloïd slant, low-set ears, long upper lip, and a pronounced philtrum. Laboratory studies failed to demonstrate a gene-dose effect for the enzymes coded by chromosome 15 (PK 3 and MPI) and chromosome 21 (SOD 1).     

Triplex gene dosage effect for β-glucronidase and possible assignment to band q22 in a partial duplication 7q

Summary A 2-year-old girl had a de novo duplication in the long arm of one chromosome 7 and an increased level of the enzyme -glucuronidase in cultured fibroblasts. The phenotype of the girl partly overlaps those of two presumptive syndromes due to secondary partial trisomies 7q. The ratio of the enzyme activity was 1.43 to the controls, and 1.37 to her parent's values. We could not define the abnormality but suggest two alternatives: either the patient is trisomic for region q112 to q22 or for the region q22 to q34. If the second alternative is correct the locus for -glucuronidase is possibly assigned to band 7q22.     

Linkage and LOH studies in 19 cylindromatosis families show no evidence of genetic heterogeneity and refine the CYLD locus on chromosome 16q12–q13

Familial cylindromatosis is an autosomal dominant predisposition to multiple neoplasms of the skin appendages. The susceptibility gene has previously been mapped to chromosome 16q12-q13 and has features of a recessive oncogene/tumour suppressor gene. We have now evaluated 19 families with this disease by a combination of genetic linkage analysis and loss of heterozygosity in cylindromas from affected individuals. All 15 informative families show linkage to this locus, providing no evidence for genetic heterogeneity. Recombinant mapping has placed the gene in an interval of approximately 1 Mb. There is no evidence, between families, of haplotype sharing that might be indicative of common founder mutations.     

Human CD28 and CTLA-4 Ig superfamily genes are located on chromosome 2 at bands q33–q34

CD28 is a cell surface molecule present on most peripheral T cells which has been implied in the amplification of the T-cell response in vitro. Using in situ hybridization on human prometaphase cells, we have found that the human CD28 gene maps to chromosome 2 at bands q33–q34, as shown previously for the CTLA-4 gene. CD28 and CTLA-4 are both members of the Ig superfamily, where they define a subgroup of membrane-bound single V domains. Their chromosomal proximity and their close structural relationship suggest that these two genes could be the result of the duplication of a common evolutionary precursor and may share some functional properties. Address correspondence and offprint requests to: M. Lafage-Pochitaloff.     

Gαq allosterically activates and relieves autoinhibition of p63RhoGEF

Gα_q directly activates p63RhoGEF and closely related catalytic domains found in Trio and Kalirin, thereby linking G_q-coupled receptors to the activation of RhoA. Although the crystal structure of Gα_q in complex with the catalytic domains of p63RhoGEF is available, the molecular mechanism of activation has not yet been defined. In this study, we show that membrane translocation does not appear to play a role in Gα_q-mediated activation of p63RhoGEF, as it does in some other RhoGEFs. Gα_q instead must act allosterically. We next identify specific structural elements in the PH domain that inhibit basal nucleotide exchange activity, and provide evidence that Gα_q overcomes this inhibition by altering the conformation of the α6–αN linker that joins the DH and PH domains, a region that forms direct contacts with RhoA. We also identify residues in Gα_q that are important for the activation of p63RhoGEF and that contribute to Gα subfamily selectivity, including a critical residue in the Gα_q C-terminal helix, and demonstrate the importance of these residues for RhoA activation in living cells.     

Juvenile open angle glaucoma: fine mapping of the TIGR gene to 1q24.3–q25.2 and mutation analysis

Autosomal dominant juvenile open angle glaucoma (JOAG) is an early-onset form of primary open angle glaucoma (POAG), which has been linked to chromosome 1q21–q31. Recently, mutations in the trabecular meshwork inducible glucocorticoid response gene (TIGR), one of the candidate genes mapped in this region, were identified in glaucoma patients of several families. We screened for mutations of the TIGR gene in two German families with JOAG and in 100 unselected sporadic cases of POAG. In the first family we identified a Pro370Leu mutation and in the second family a Gly367Arg mutation cosegregating with the glaucoma phenotype. No pathogenic mutation was found in 100 sporadic cases but a Tyr347Tyr polymorphism was found in two patients. Furthermore, fluorescence in situ hybridization (FISH) analysis was used to map a TIGR-specific yeast artificial chromosome to 1q24.3–q25.2. Received: 19 June 1997 / Accepted: 12 August 1997     

Deletion 14q(q24.3 to q32.1) syndrome: significance of peculiar facial appearance in its diagnosis,and deletion mapping of (α1-antitrypsin)

Summary A 10-month-old Japanese boy who had interstitial deletion of the long arm of chromosome No. 14; 46,XY, del(14)(pter»q24.3::q32.1»qter) is reported. A peculiar facial appearance, including round face, frontal hypertrichosis with thick eyebrows, horizontal narrow palpebral fissures, a short bulbous nose with a flat nasal root, and mild micrognathia, appeared to be common with the two previously reported cases. We stress the significance of this peculiar facial appearance in the diagnosis of 14q-(q24.3 to q32.1) syndrome. The level of ₁-antitrypsin in the patient was only about half of that of his parents and controls, and the Pi locus was tentatively assigned to band 14q32.1.     

Transposition of 9q34 and 22 (q11→qter) regions has a specific role in chronic myelocytic leukemia

Summary Six cases are reported of variant Ph translocations found among 240 patients with Ph-positive CML. Five cases had a three-chromosome rearrangement involving, in addition to chromosomes 9 and 22, chromosomes 7, 4, 2(two), and 3 respectively, and one case had a two-chromosome rearrangement 22/5. A review of the literature revealed that three- and two-chromosome variant Ph translocations are observed with equal frequency. It is postulated that all variant translocations are indeed three-chromosome rearrangements, that the specific event for the formation of the Ph chromosome is the reciprocal translocation 9/22, and that the transposition of regions 9q34 and 22 (q11qter), plays a major role in the development of CML.