Cryptic telomere imbalance: A 15‐year update

Abstract

It has been 15 years since we proposed that assays of telomere integrity might reveal cryptic translocations and deletions as a significant cause of mental retardation (MR) in patients with normal G-banded karyotypes. Development of unique genomic probes adjacent to the subtelomeric repeats of each chromosome arm allowed multiplex FISH analyses that confirmed such cryptic telomeric imbalances in 3-6% of all unexplained MR. Although such "telomere FISH" analysis quickly became standard of care, limitations of this technology platform included a lack of information on the size and gene content of the deleted/duplicated segments and the failure to detect interstitial deletions not involving the most distal unique clone. The development of "molecular ruler" clone sets for every human telomere provided the foundation for accurate determination of size and gene content of each imbalance, as well as the detection of interstitial deletions within these regions. Array comparative genomic hybridization (aCGH) has emerged as a powerful technology to assess single copy changes (monosomy or trisomy) at targeted loci such as telomeres or across the whole genome. This technology now replaces multiplex FISH for the assessment of telomere integrity in unexplained MR and has the advantage of efficiently determining the size and gene content of the imbalance, as well as detecting interstitial deletions near telomeres or anywhere else in the genome covered by the array design. The application of aCGH in several studies of unexplained MR has confirmed that telomere imbalances are overrepresented compared to "average" chromosomal regions, although this is likely due to random chromosome breakage rather than specific molecular mechanisms associated with the genomic architecture of human telomeres. Telomere imbalances are significantly larger than initially envisioned ( approximately 40% are >5 Mb in size), and indicate the analytic sensitivity of the G-banded karyotype is much lower than previously thought. Finally, experience with smaller benign variants compared to larger pathogenic imbalances at telomeres serves as a model for approaching whole-genome aCGH in a clinical setting.

Identifying Genes Responsible for Intellectual Disability in Consanguineous Families

“…Chromosomal anomalies are a major cause of ID, as 22% of severe ID cases have an underlying chromosomal defect [15] . The most common cause of ID among chromosomal aneuploidies is trisomy 21 (Down syndrome) with a high prevalence rate of 1/1,000 live births [16,17] . CNVs can cause recurrent conditions of ID usually associated with other features, such as in Williams-Beuren syndrome, Prader-Willi syndrome and Smith-Magenis syndrome [18] .…”

Duplication of the Miller-Dieker Critical Region in a Patient with a Subtelomeric Unbalanced Translocation t(10;17)(p15.3;p13.3)

“…Copyright © 2012 S. Karger AG, Basel Subtelomeres are particular chromosome regions made up of a large number of genes and a high amount of different repetitive sequences [Mefford and Trask, 2002;Riethman et al, 2005]. Due to this structural composition, these regions are involved in chromosome rearrangements [Saccone et al, 1992;De Vries, 2003;Linardopoulou et al, 2005;Ledbetter and Martin, 2007]. The development of advanced molecular cytogenetic methods has allowed for the identification of subtelomeric rearrangements as an important cause of mental retardation and/or congenital malformation [Knight and Flint, 2000].…”

Pesquisa dos mecanismos de rearranjos cromossômicos subteloméricos na monossomia 1p36, expansão do espectro da variabilidade fenotípica e comportamental, diagnósticos diferenciais e caracterização de uma região crítica para obesidade

“…Ledbetter (1992) especulou sobre a importância de rearranjos subteloméricos submicroscópicos na etiologia de malformações congênitas múltiplas e retardamento mental (MCA/MR, "Multiple Congenital Anomalies/Mental Retardation"). Esta especulação foi baseada no reconhecimento de uma arquitetura genômica complexa nestas regiões, que associada às altas taxas de recombinação meiótica destes loci e às elevadas taxas de concentração gênica nas bandas cromossômicas distais poderiam intermediar rearranjos patogênicos (Ledbetter 2007).…”

“…The acquisition of a telomere from another chromosome end (telomere capture) can occur through a variety of mechanisms (Ledbetter and Martin 2007). At least two anticipated mechanisms are directly linked to genomic architectural features in the subtelomeric regions: non-allelic homologous recombination (NAHR) and subtelomeric pairing with proximal recombination (SPPR) (Ballif et al 2004a).…”

“…Over the past decade, an increasing number of subtelomeric abnormalities have been reported to cause mental retardation and birth defects (Ledbetter and Martin 2007). Combined data from two of the largest studies of telomere integrity assessments in a diagnostic laboratory established a 2.5% yield of clinically signiWcant cryptic subtelomeric abnormalities Ravnan et al 2006).…”