"Familial" versus "sporadic" intellectual disability: contribution of subtelomeric rearrangements

Abstract

BackgroundCryptic subtelomeric rearrangements have been proposed as a significant cause of sporadic intellectual disability (ID) but the role of such aberrations in familial ID has not yet been studied. As positive family history of ID had been proposed as an important and significant predicting factor of subtelomeric rearrangements, it was assumed that the contribution of subtelomeric aberrations in familial ID would be much more than the sporadic ones. Three hundred and twenty two patients from 102 unrelated families with more than two ID patients in the first degree relatives have been investigated. Assessment of subtelomeric rearrangements were carried out using Multiplex Ligation-Dependent Probe Amplification (MLPA) technique. Detected aberrations were then confirmed by Fluorescence in Situ Hybridization (FISH) method.ResultsAmong the families studied, 27.4% had 4-12, 36.3% had 3 and 36.3% had 2 affected individuals in the first degree relatives. One unbalanced translocation and 4 polymorphic changes were detected. The prevalence of clinically significant subtelomeric rearrangements was 0.98%.ConclusionThis is the first investigation of subtelomeric aberrations in a large sample set of familial ID patients. Our results show that the contribution of subtelomeric rearrangements to familial ID is not as much as what had been determined for sporadic ones in the literature. Moreover, this study shows that the positive family history by alone, cannot be the most important and determining indicator of subtelomeric aberrations while it would be a good predicting factor when associated with dysmorphism or congenital malformations. These findings propose that other cryptic chromosomal abnormalities or even single gene disorders may be the main cause of familial ID rather than subtelomeric aberrations.

Comparison of two subtelomeric assays for the screening of chromosomal rearrangements: analysis of 383 patients, literature review and further recommendations

“…Our results are close to those published using similar inclusion criteria. The overall diagnostic yield of 8.9 % is in the range calculated by Rafati et al (2012); the gender and age of referred patients, as well as the type and frequency of SR that we reported, are comparable to those found in the largest study with Subt-FISH (Ravnan et al 2006). A similar analysis can be done on whether the percentage of aberration per chromosome is considered (Fig.…”

“…1), although our study showed a proportionally higher compromise of chromosomes 5 and 15 and only one case of deletion 1p, compared with the same work (Ravnan et al 2006). Finally, although few parents were subsequently studied to analyse confidently the inheritance of the SR found, it is presumed that familial ID is scarcely explained by this kind of chromosomal abnormalities (Rafati et al 2012).…”

"Familial" versus "Sporadic" intellectual disability: contribution of common microdeletion and microduplication syndromes

“…The patients studied here had already been investigated for cytogenetically visible chromosomal abnormalities, Fragile-X syndrome and subtelomeric rearrangements with no abnormality detected [ 12 ]. The MLPA probe sets used in this study for detection of CMMSs cover more syndromes than those investigated by Jehee et al Therefore, all CMMSs and at least 76.45% of total chromosomal abnormalities have been ruled out in the families studied.…”

“…2) Normal results of the previous investigations including karyotyping, Fragile-X expansion mutation testing and assessment of subtelomeric rearrangements carried out in at least one of the affected individuals. Subtelomeric aberrations were studied by MLPA technique followed by subsequent confirmation of detected deletions or duplications by FISH method [ 12 ]. 3) No evidence of metabolic, neurodegenerative or other single gene disorders based on the available previous investigations including brain imaging and blood/urinary metabolic screening.…”

“…Here, for the first time, we report the results of the assessment of CMMS in 101 families with familial ID in which cytogenetically visible abnormalities, Fragile-X syndrome and subtelomeric aberrations had already been excluded [ 12 ].…”