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We report a boy with multiple congenital anomalies compatible with trisomy for the distal region of the long arm of chromosome 10 and a male karyotype with one 18p+. In situ hybridisation with a cDNA for ornithine aminotransferase (OAT), whose locus maps to 10q26, confirmed the clinical suspicion of distal trisomy 10q. Subterminal localisation of the labelling signals on chromosome 10 and on the der(18) indicated the localisation of the OAT locus in the proximal part of 10q26. Two clusters of labelling signals were also found on the pericentromeric and proximal portion of the X chromosome short arm, thus confirming the presence in this region of two non-adjacent OAT pseudogenes. The phenotypic similarities of this patient to previously reported cases provide further support for the delineation of trisomy 10qter as a specific, clinically recognisable syndrome.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

A 3 1/2 year old girl was evaluated because of developmental delay. Short stature was evident with height between the 3rd and 10th centiles, while weight and head circumference were on the 50th centile. Dysmorphic features consisted of a high bossed forehead, pointed short ear lobes, small nose, bilateral convergent strabismus, left simian crease, a gap between the first and second toes bilaterally, mild clinodactyly, and a broad, barrel shaped thorax. Cytogenetic investigations showed an unbalanced karyotype, 46,XX,10q+, which was de novo in origin. Fluorescence in situ hybridisation (FISH) using three library probes (from chromosomes 10, 19, and 19q) and a YAC probe (from 10q telomere) showed that the additional material on 10q was derived from chromosome 19q. The patient had an unbalanced translocation, 46,XX,-10,+der(10)t(10;19)(q26.3; q13.3), which resulted in distal trisomy 19q. Few other cases of proven distal trisomy 19q are available for comparison of clinical features.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 the clinical findings in an adolescent male with a de novo terminal deletion of chromosome 10 del(10)(q26.1). This young man is one of the oldest known patients reported with this condition. His condition is compared with that of 11 reported cases of de novo terminal deletion of 10q at band 26. Individuals with chromosome 10q26 deletion have some findings and medical complications in common. Our patient has chronic renal failure due to urinary tract obstruction from posterior urethral valves. Similar anomalies have been reported in cases of 10q26 deletion, suggesting a careful renal/urinary tract evaluation should be completed in individuals with this condition.Close

A male patient is reported with terminal 10q26 deletion and clinical findings suggesting Prader-Willi syndrome during the infancy. These findings included decreased fetal movements, neonatal hypotonia, need for tube feeding, characteristic facial dysmorphism with dolichocephaly, narrow bifrontal diameter, almond-shaped eyes and epicanthus, hypogenitalism and developmental retardation. However, during the further evolution there was neither hyperphagia nor obesity and chromosomal and molecular investigations failed to confirm the diagnosis of Prader-Willi syndrome. Special behavioural abnormalities became evident with notably hyperactivity, hyperkinesis and destructive tendency. Finally, at the age of 17 years high resolution chromosome studies revealed a terminal 10q26.3 deletion. A review of the literature is made on previously reported patients with either a Prader-Willi-like syndrome or a terminal 10q deletion with behavioural problems.Close

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We present genotype-phenotype correlations in two patients with distal 10q deletion. A patient with a small terminal deletion presented mild mental retardation and behavioral difficulties with hyperactivity, whereas the patient with a larger deletion, had multiple congenital anomalies and moderate mental retardation. Our observation confirms the previous suggestion that larger deletions of distal chromosome 10q are associated with a more severe clinical presentation, whereas hyperactive behavior may be a specific feature of small terminal deletions of chromosome 10q26.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

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Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant myopathy, clinically characterized by asymmetric weakness of muscles in the face, shoulder girdle and upper arm. Deletion of an integral number of 3.3 kb repeated units within a highly polymorphic EcoRI fragment at chromosome 4q35, generating a relatively short EcoRI fragment (< 35 kb), has been shown to cause FSHD1. Probe p13E-11 detects these short fragments in FSHD1 patients, and has therefore been used for diagnostic DNA analysis. However, the reliability of this analysis has been hampered by cross-hybridization of p13E-11 to chromosome 10q26-linked EcoRI fragments of comparable size, which also contain a variable number of 3.3 kb repeated units. Recently, a BinI restriction site was identified within each of the repeated units derived from chromosome 10q26, which enables differentiation of the two polymorphic p13E-11 loci in most cases without haplotype analysis. Remarkably, applying the differential analysis to screen DNA of 160 Dutch cases referred to us for FSHD1 diagnosis, we obtained evidence for subtelomeric exchange of 3.3 kb repeated units between chromosomes 4q35 and 10q26 in affected and unaffected individuals. Subsequently, analysis of 50 unrelated control samples indicated such exchange between chromosomes 4q35 and 10q26 in at least 20% of the population. These subtelomeric rearrangements have generated a novel interchromosomal polymorphism, which has implications for the specificity and sensitivity of the differential restriction analysis for diagnostic purposes. Moreover, the high frequency of the interchromosomal exchanges of 3.3 kb repeated units suggests that they probably do not contain (part of) the FSHD1 gene, and supports position effect variegation as the most likely mechanism for FSHD1.Close

The subtelomeric region of human chromosome 4q contains the locus for facioscapulohumeral muscular dystrophy (FSHD). The FSHD mutation is a deletion within an array of 3.3-kb tandem repeats (D4Z4). The disease mechanism is unknown but is postulated to involve position effect. A closely related 3.3-kb array on chromosome 10qter, in contrast, is not associated with a disease phenotype. We show here that the 4q homology on chromosome 10 is not confined to the 3.3-kb repeats but extends both proximally (42 kb) and distally to include the telomere. We have also identified the most distal expressed gene on 10q known so far, mapping only 96 kb from the 3.3-kb repeat array. A 4q variant has also been identified; there is 92%nucleotide identity between the two 4q forms, 4qA and 4qB. The 4qter and 10qter forms show homology to other chromosome ends, including 4p, 21q, and 22q, and these regions may represent a relatively common subtelomeric domain.Close

A YAC library enriched for telomere clones was constructed and screened for the human telomere-specific repeat sequence (TTAGGG). Altogether 196 TYAC library clones were studied: 189 new TYAC clones were isolated, 149 STSs were developed for 132 different TY-ACs, and 39 P1 clones were identified using 19 STSs from 16 of the TYACs. A combination of mapping methods including fluorescence in situ hybridization, somatic cell hybrid panels, clamped homogeneous electric fields, meiotic linkage, and BLASTN sequence analysis was utilized to characterize the resource. Forty-five of the TYACs map to 31 specific telomere regions. Twenty-four linkage markers were developed and mapped within 14 proterminal regions (12 telomeres and 2 terminal bands). The polymorphic markers include 12 microsatellites for 10 telomeres (1q, 2p, 6q, 7q, 10p, 10q, 13q, 14q, 18p, 22q) and the terminal bands of 11q and 12p. Twelve RFLP markers were identified and meiotically mapped to the telomeres of 2q, 7q, 8p, and 14q. Chromosome-specific STSs for 27 telomeres were identified from the 196 TYACs. More than 30,000 nucleotides derived from the TYAC vector-insert junction regions or from regions flanking TYAC microsatellites were compared to reported sequences using BLASTN. In addition to identifying homology with previously reported telomere sequences and human repeat elements, gene sequences and a number of ESTs were found to be highly homologous to the TYAC sequences. These genes include human coagulation factor V (F5), Weel protein tyrosine kinase (WEE1), neurotropic protein tyrosine kinase type 2 (NTRE2), glutathione S-transferase (GST1), and beta tubulin (TUBB). The TYAC/P1 resource, derivative STSs, and polymorphisms constitute an enabling resource to further studies of telomere structure and function and a means for physical and genetic map integration and closure.Close

We describe two patients (first cousins, once removed) with an unusual head shape, high arched palate, flat nasal bridge, abnormal ears, hand and feet abnormalities and other anomalies. The patients were ascertained independently and it was initially unknown that they were related to each other. Cytogenetic and fluorescent in situ hybridization (FISH) analysis identified a der(2)t(2;10)(q37.3;q24.1) unbalanced translocation resulting in loss of 2q37.3-qter and duplication 10q24.1-qter. The clinical features of these two patients are compared with previously described cases of 2q deletion and 10q duplication. These patients also emphasize the difficulty in some families of understanding and sharing genetic information and in the difficulties in obtaining an accurate pedigree in a genetics clinic.Close

We describe 2 karyotypically male infants with terminal deletion of 10q and mental retardation, multiple phenotypic anomalies and abnormal genitalia. One [karyotype 46,XY, del(10)(q26.1)] had female external genitalia; the other [karyotype 46,XY,-10,+der(10)t (10;16)(q26.2;q21)] had an intersex phenotype. Of 8 males previously reported with terminal 10q deletion as the major or only cytogenetic abnormality, 2 had an intersex phenotype, and the others all had combinations of cryptorchidism, micropenis, and hypospadias. Terminal 10q deletions appear to be strongly associated with abnormal male genital development, and should be specifically searched for in the cytogenetic workup of such cases.Close