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.
Highlights
Cryptic 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
Regarding the proposed predicting power of positive family history, it was assumed that investigation of subtelomeric aberrations could have a higher diagnostic yield in familial rather than sporadic ID
Due to the small family sizes of the previous studies and the limited number of familial ID patients, to the best of our knowledge, no report on a large sample set of familial ID has so far been published to evaluate the contribution of subtelomeric rearrangements in familial ID
Summary
Cryptic 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. The prevalence of subtelomeric aberrations has been reported widely variable among different studies depending on the inclusion criteria selected It is reported from as low as zero in unselected mildly affected cases [11], to 9-15% in highly selected moderate to severe mental retarded patients with dysmorphic features, congenital malformations and the family history of abortions or previous affected cases [6,7,12]. Based on a retrospective evaluation of the mentioned common clinical features in the patients with known subtelomeric aberrations, a checklist for preselecting of cases to improve the rate of informative tests has been developed [13] This checklist and some other investigations suggested prenatal onset growth retardation and positive family history of ID, as important indicators of subtelomeric rearrangements. Due to the small family sizes of the previous studies and the limited number of familial ID patients, to the best of our knowledge, no report on a large sample set of familial ID has so far been published to evaluate the contribution of subtelomeric rearrangements in familial ID
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