Subtelomeric imbalances in phenotypically normal individuals

Molecular Cytogenetics, 2009

Background Submicroscopic imbalances in the subtelomeric regions of the chromosomes are considered to play an important role in the aetiology of mental retardation (MR). The aim of the study was to evaluate a quantitative PCR (qPCR) protocol established by Boehm et al. (2004) in the clinical routine of subtelomeric testing. Results 296 patients with MR and a normal karyotype (500–550 bands) were screened for subtelomeric imbalances by using qPCR combined with SYBR green detection. In total, 17 patients (5.8%) with 20 subtelomeric imbalances were identified. Six of the aberrations (2%) were classified as causative for the symptoms, because they occurred either de novo in the patients (5 cases) or the aberration were be detected in the patient and an equally affected parent (1 case). The extent of the deletions ranged from 1.8 to approximately 10 Mb, duplications were 1.8 to approximately 5 Mb in size. In 6 patients, the copy number variations (CNVs) were rated as benign polymorphisms...

BMC medical genetics, 2005

Cryptic chromosome imbalances are increasingly acknowledged as a cause for mental retardation and learning disability. New phenotypes associated with specific rearrangements are also being recognized. Techniques for screening for subtelomeric rearrangements are commercially available, allowing the implementation in a diagnostic service laboratory. We report the diagnostic yield in a series of 132 subjects with mental retardation, and the associated clinical phenotypes. We applied commercially available subtelomeric fluorescence in situ hybridization (FISH). All patients referred for subtelomeric screening in a 5-year period were reviewed and abnormal cases were further characterized clinically and if possible molecularly. We identified nine chromosomal rearrangements (two of which were in sisters) corresponding to a diagnostic yield of approx. 7%. All had dysmorphic features. Five had imbalances leading to recognizable phenotypes. Subtelomeric screening is a useful adjunct to conven...

Human Genetics, 2001

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 Zürich, 152 from Liège) 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 Zürich 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 Liège versus the Zürich series (3/102), similar selection criteria in Zürich as in Liège 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 seletion 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.

American Journal of Medical Genetics Part A, 2005

Journal of Medical Genetics, 2004

Introduction: It has been estimated that cytogenetically visible rearrangements are present in ,1% of newborns. These chromosomal changes can cause a wide range of deleterious developmental effects, including mental retardation (MR). It is assumed that many other cases exist where the cause is a submicroscopic deletion or duplication. To facilitate the detection of such cases, different techniques have been developed, which have differing efficiency as to the number of loci and patients that can be tested. Methods: We implemented multiplex amplifiable probe hybridisation (MAPH) to test areas known to be rearranged in MR patients (for example, subtelomeric/pericentromeric regions and those affected in microdeletion syndromes) and to look for new regions that might be related to MR. Results: In this study, over 30 000 screens for duplications and deletions were carried out; 162 different loci tested in each of 188 developmentally delayed patients. The analysis resulted in the detection of 19 rearrangements, of which ,65% would not have been detected by conventional cytogenetic analysis. A significant fraction (46%) of the rearrangements found were interstitial, despite the fact that only a limited number of these loci have so far been tested. Discussion: Our results strengthen the arguments for whole genome screening within this population, as it can be assumed that many more interstitial rearrangements would be detected. The strengths of MAPH for this analysis are the simplicity, the high throughput potential, and the high resolution of analysis. This combination should help in the future identification of the specific genes that are responsible for MR.

American Journal of Medical Genetics, 2004

American Journal of Medical Genetics Part A, 2005

For a number of years we have used high resolution metaphase comparative genomic hybridization (CGH, referred to as HR-CGH in our prior papers) for detection of cryptic chromosomal imbalances in patients with mental retardation and dysmorphic features. Although this technique detects imbalances in as many as 12% of patients, additional diagnoses can be obtained if CGH is combined with subtelomeric FISH analysis . In this study, we set out to test the diagnostic yield of subtelomeric multiplex ligation-dependent probe amplification (MLPA) in patients already investigated by CGH.

Journal of Medical Genetics, 2004

Background: Subtelomeric rearrangements contribute to idiopathic mental retardation and human malformations, sometimes as distinct mental retardation syndromes. However, for most subtelomeric defects a characteristic clinical phenotype remains to be elucidated. Objective: To screen for submicroscopic subtelomeric aberrations using multiplex ligation dependent probe amplification (MLPA). Methods: 210 individuals with unexplained mental retardation were studied. A new set of subtelomeric probes, the SALSA P036 human telomere test kit, was used. Results: A subtelomeric aberration was identified in 14 patients (6.7%) (10 deletions and four duplications). Five deletions were de novo; four were inherited from phenotypically normal parents, suggesting that these were polymorphisms. For one deletion, DNA samples of the parents were not available. Two de novo submicroscopic duplications were detected (dup 5qter, dup 12pter), while the other duplications (dup 18qter and dup 22qter) were inherited from phenotypically similarly affected parents. All clinically relevant aberrations (de novo or inherited from similarly affected parents) occurred in patients with a clinical score of >3 using an established checklist for subtelomeric rearrangements. Testing of patients with a clinical score of >3 increased the diagnostic yield twofold to 12.4%. Abnormalities with clinical relevance occurred in 6.3%, 5.1%, and 1.7% of mildly, moderately, and severely retarded patients, respectively, indicating that testing for subtelomeric aberrations among mildly retarded individuals is necessary. Conclusions: The value of MLPA is confirmed. Subtelomeric screening can be offered to all mentally retarded patients, although clinical preselection increases the percentage of chromosomal aberrations detected. Duplications may be a more common cause of mental retardation than has been appreciated.

Croatian medical journal, 2006

To identify cryptic subtelomeric rearrangement, a possible cause of idiopathic mental retardation by means of multiprobe telomere fluorescent in situ hybridization (T-FISH). Hundred patients (median age 3.0 years) with mental retardation and dysmorphic features were screened using specific T-FISH probes. Multiplex ligation-dependent probe amplification and comparative genomic hybridization were used for the confirmation of results. Telomere fluorescent in situ hybridization revealed 11 subtelomeric abnormalities in 10 patients (10%; 95% CI, 5.0-17.5). Four of these had only a deletion of subtelomere 2q, which was apparently a normal variant. Among 6 true aberrations (6%; 95% CI, 2.5-12.5) we found 2 de novo subtelomeric deletions and 4 unbalanced subtelomeric rearrangements (one de novo). All clinically significant subtelomeric rearrangements were confirmed by multiplex ligation-dependent probe amplification. Comparative genomic hybridization was used to investigate the whole genome...

2004

Cryptic unbalanced rearrangements involving chromosome ends are a significant cause of idiopathic mental retardation. The most frequently used technique to screen for these subtle rearrangements is Multiprobe fluorescence in situ hybridization (FISH). As this is a labor-intensive technique, we used microsatellite genotyping to detect possible subtelomeric rearrangements in a study population. Out of the 70 patients we screened, three chromosomal rearrangements were detected: a deletion of marker D2S2986, a deletion of marker D7S594 and a deletion of marker D19S424. However, none of these aberrations appeared to be disease causing.