Whereas in the great majority of autosomal duplications/deficiencies a clinically recognizable dysmorphic syndrome is present, distal 3p duplication is not associated with major dysmorphic signs. We present the clinical data and molecular cytogenetic findings in two non-related patients. Diagnosis was made in a female child at the age of 5 months because of psychomotor retardation and slight dysmorphism. She also presented hydronefrosis and develops no speech at the age of almost 4 years. Her partial trisomy is the result of an inverted duplication 3p22-->3pter (dup(3)(pter-->p26::p22(p26::p26-->ter)). An adult woman was diagnosed at the of 80 years only on the basis of mental retardation and poor speech development, but without evident dysmorphism. In this patient the partial 3p trisomy is the unbalanced product of a 3p/17p translocation: t(3;7)(p253;p133).Close

The prenatal and postnatal findings of a fetus with partial deletion of 3p25 -> pter and duplication of 2p25.3 -> pter are described. The proband postnatally displayed mental and growth retardation, psychomotor delay, microcephaly, ptosis, micrognathia, a narrow palate, and cryptorchidism. All of these anomalies were consistent with those described in 3p- and partial trisomy 2p syndromes, and also frequently seen in patients with other chromosomal disorders. However, the prenatal sonograms revealed unusual shortening of the long bones, a single umbilical artery, and normal development of the skull. Our case suggests that skeletal growth retardation of the long bones may occur earlier than that of the skull in fetuses associated with chromosomal aberrations such as del(3p)/dup(2p). Shortening of the long bones and a single umbilical artery together with other abnormalities detected by prenatal ultrasound thus warrant a fetal cytogenetic study.Close

Human chromosomes terminate with specialized telomeric structures including the simple tandem repeat (TTAGGG)n and additional complex subtelomeric repeats. Unique sequence DNA for each telomere is located 100-300 kilobases (kb) from the end of most chromosomes. A high concentration of genes and a number of candidate genes for recognizable syndromes are known to be present in telomeric regions. The human telomeric regions represent a major diagnostic challenge in clinical cytogenetics, because most of the terminal bands are G negative, and cryptic deletions and translocations in the telomeric regions are therefore difficult to detect by conventional cytogenetic methods. In fact, several submicroscopic chromosomal abnormalities in patients with undiagnosed mental retardation or multiple congenital anomalies have been identified by other molecular methods such as DNA polymorphism analysis. To improve the sensitivity for deletion detection and to determine whether such cryptic rearrangements represent a significant source of human pathology that has not been previously appreciated, it would be valuable to have specific FISH probes for all human telomeres. We report here the isolation and characterization of a complete set of specific FISH probes representing each human telomere. As most of these clones are at a known distance of within 100-300 kb from the end of the chromosome arm, this provides a 10-fold improvement in deletion detection sensitivity compared with high-resolution cytogenetics (2-3 Mb resolution). While testing these probes, we serendipitously identified a family with multiple members carrying a cryptic 1q;11p rearrangement in the balanced or unbalanced state.Close

We describe the first inverted duplication of the p21.3p26 region of chromosome 3 in a child with phenotypic features of the trisomy 3p syndrome. This uncommon type of aberration was verified by multicolour fluorescence in situ hybridisation (FISH) using yeast artificial chromosome (YAC) clones from chromosome 3 (CEPH library). With a newly constructed YAC clone from the 3p26 region an unexpected subtelomeric deletion was diagnosed in the aberrant chromosome 3. Using the primed in situ labelling (PRINS) method, telomeres were found to be present on the recombinant chromosome 3. The repeated appearance of concomitant distal deletions in inverted duplications suggests that an overall mechanism exists for the origin of such duplications/deficiencies.Close

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Telomere-specific clones are a valuable resource for the characterization of chromosomal rearrangements. We previously reported a first-generation set of human telomere probes consisting of 34 genomic clones, which were a known distance from the end of the chromosome ( approximately 300 kb), and 7 clones corresponding to the most distal markers on the integrated genetic/physical map (1p, 5p, 6p, 9p, 12p, 15q, and 20q). Subsequently, this resource has been optimized and completed: the size of the genomic clones has been expanded to a target size of 100-200 kb, which is optimal for use in genome-scanning methodologies, and additional probes for the remaining seven telomeres have been identified. For each clone we give an associated mapped sequence-tagged site and provide distances from the telomere estimated using a combination of fiberFISH, interphase FISH, sequence analysis, and radiation-hybrid mapping. This updated set of telomeric clones is an invaluable resource for clinical diagnosis and represents an important contribution to genetic and physical mapping efforts aimed at telomeric regions.Close

We report on a girl with a de novo monosomy Xpter-->Xp22.3 and trisomy 3pter-->3p23, normal development and stature, mildly affected phenotype, and learning disabilities with a low normal level of intelligence. Late replication studies using BudR demonstrated that the entire der(X) was inactive in 30% of cells. In 62% of cells the inactivation did not spread to the autosomal segment in the der(X). The normal X was inactivated in 8% of cells. Quantitative X-inactivation studies using the human androgen receptor locus assay (HAR) on peripheral leukocytes and buccal epithelial cells showed extreme skewing of methylation (90.4% of the paternal allele). The correlation of cytogenetic and molecular data suggest that the mild phenotype of the proposita is most likely due to preferential inactivation of the entire der(X), which seems to be of paternal origin.Close

Deletion of the short arm of chromosome number 3, has been proposed as a distinctive syndrome, all cases are "de novo" deletions and the band 3p26 was systematically involved. The comparative study of the 21 reviewed cases (including one reported here) allows to conclude that there is no consistent association to delineate a typical clinical syndrome.Close

The C syndrome is a multiple congenital anomaly/mental retardation (MCA/MR) syndrome first described in sibs. The inheritance has been assumed to be autosomal recessive. Several authors have commented that the combination of anomalies found in the conditions suggest an underlying chromosomal anomaly and in a few apparent cases chromosome anomalies have been described. Our patient had findings consistent with the C syndrome and a duplication of 3p by use of subtelomere probes. This shows that new cytogenetic techniques continue to be important in defining the underlying cause of MCA/MR conditions.Close

Two profoundly mentally retarded brothers with partial trisomy for the distal part of the short arm of chromosome 3 (3p25 to 3pter) are described. Their anomaly arose as a segregation product of a balanced t(3p-;18q+) translocation in the mother. Compared with the other cases of partial 3p trisomy reported up to now, the present patients display a similar craniofacial dysmorphism with hypertelorism, broad nasal tip, short upper lip with prominent philtrum, and a large mouth with down-turned corners. Other stigmata, such as a prominent, high forehead with frontal bossing and full cheeks, were present during childhood but progressively disappeared.Close

A male newborn with partial deletion of the short arm of chromosome 3 is described. The patient shares most of the features with the previously reported cases. In addition, cardiac, skeletal and gastrointestinal anomalies not previously reported are described. These characteristics may help in further delineation of the syndrome.Close

Unbalanced submicroscopic subtelomeric chromosomal rearrangements represent a significant cause of unexplained moderate to severe mental retardation with and without phenotypic abnormalities. We investigated 254 patients (102 from Zurich, 152 from Liege) for unbalanced subtelomeric rearrangements by using fluorescence in situ hybridisation with probes mapping to 41 subtelomeric regions. Mental retardation combined with a pattern of dysmorphic features, with or without major malformations, and growth retardation and a normal karyotype by conventional G-banding were the criteria of inclusion. Selection criteria were more restrictive for the Zurich series in terms of clinical and cytogenetic pre-investigation. We found 13 unbalanced rearrangements and two further aberrations, which, following the investigation of other family members, had to be considered as variants without influence on the phenotype. The significant aberrations included three de novo deletions (two of 1pter, one of 5pter), three de novo duplications (8pter, 9pter, Xpter), one de novo deletion 13qter-duplication 4qter, and five familial submicroscopic translocations [(1q;18p), (2q;4p), (2p;7q), (3p;22q), (4q;10q), (12p;22q)], most of them with several unbalanced offspring with deletion-duplication. Although the incidence of abnormal results was higher (10/152) in the Liege versus the Zurich series (3/102), similar selection criteria in Zurich as in Liege would have resulted in an incidence of 7/106 and thus similar figures. In our series, submicroscopic unbalanced rearrangements explain the phenotype in 13/254 study probands. The most important selection criterion seems to be the presence of more than one affected member in a family. An examination of subtelomeric segments should be included in the diagnostic work-up of patients with unexplained mental retardation combined with physical abnormalities, when a careful conventional examination of banded chromosomes has yielded a normal result and a thorough clinical examination does not lead to another classification. The proportion of abnormal findings depends strongly on selection criteria: more stringent selection can eliminate some examinations but necessitates a high workload for experienced clinical geneticists. Once the costs and workload of screening are reduced, less selective approaches might finally be more cost-effective.Close

Unbalanced submicroscopic subtelomeric chromosomal rearrangements represent a significant cause of unexplained moderate to severe mental retardation with and without phenotypic abnormalities. We investigated 254 patients (102 from Zurich, 152 from Liege) for unbalanced subtelomeric rearrangements by using fluorescence in situ hybridisation with probes mapping to 41 subtelomeric regions. Mental retardation combined with a pattern of dysmorphic features, with or without major malformations, and growth retardation and a normal karyotype by conventional G-banding were the criteria of inclusion. Selection criteria were more restrictive for the Zurich series in terms of clinical and cytogenetic pre-investigation. We found 13 unbalanced rearrangements and two further aberrations, which, following the investigation of other family members, had to be considered as variants without influence on the phenotype. The significant aberrations included three de novo deletions (two of 1pter, one of 5pter), three de novo duplications (8pter, 9pter, Xpter), one de novo deletion 13qter-duplication 4qter, and five familial submicroscopic translocations [(1q;18p), (2q;4p), (2p;7q), (3p;22q), (4q;10q), (12p;22q)], most of them with several unbalanced offspring with deletion-duplication. Although the incidence of abnormal results was higher (10/152) in the Liege versus the Zurich series (3/102), similar selection criteria in Zurich as in Liege would have resulted in an incidence of 7/106 and thus similar figures. In our series, submicroscopic unbalanced rearrangements explain the phenotype in 13/254 study probands. The most important selection criterion seems to be the presence of more than one affected member in a family. An examination of subtelomeric segments should be included in the diagnostic work-up of patients with unexplained mental retardation combined with physical abnormalities, when a careful conventional examination of banded chromosomes has yielded a normal result and a thorough clinical examination does not lead to another classification. The proportion of abnormal findings depends strongly on selection criteria: more stringent selection can eliminate some examinations but necessitates a high workload for experienced clinical geneticists. Once the costs and workload of screening are reduced, less selective approaches might finally be more cost-effective.Close

Whereas in the great majority of autosomal duplications/deficiencies a clinically recognizable dysmorphic syndrome is present, distal 3p duplication is not associated with major dysmorphic signs. We present the clinical data and molecular cytogenetic findings in two non-related patients. Diagnosis was made in a female child at the age of 5 months because of psychomotor retardation and slight dysmorphism. She also presented hydronefrosis and develops no speech at the age of almost 4 years. Her partial trisomy is the result of an inverted duplication 3p22-->3pter (dup(3)(pter-->p26::p22(p26::p26-->ter)). An adult woman was diagnosed at the of 80 years only on the basis of mental retardation and poor speech development, but without evident dysmorphism. In this patient the partial 3p trisomy is the unbalanced product of a 3p/17p translocation: t(3;7)(p253;p133).Close

Clinical descriptions of individuals with partial deletion of the distal short arm of chromosome three have been reported rarely. A characteristic phenotype has been proposed. We present another patient with this cytogenetic abnormality whose physical and developmental features show similarities with, as well as differences from, previously reported cases. This suggests that the clinical phenotype requires further definition. In addition, gene dosage studies were undertaken on several serum proteins in order to try to map the location of the responsible genes on chromosome three.Close

Minor abnormalities are described in an 11-month-old female in which a "de novo" trisomy 1q32 leads to lqter and a monosomy 3p25 leads to ter has been produced. The amount of the exceeding material in this case is less than that found in previous reports of partial trisomy 1q and in cases of parental 1q balanced translocations which has originated recurrent abortions.Close