Prospective screening for subtelomeric rearrangements in children with mental retardation of unknown aetiology: the Amsterdam experience

Abstract

Objective: The frequency of subtelomeric rearrangements in patients with unexplained mental retardation (MR) is uncertain, as most studies have been retrospective and case retrieval may have been biased towards cases more likely to have a chromosome anomaly. To ascertain the frequency of cytogenetic anomalies, including subtelomeric rearrangements, we prospectively screened a consecutive cohort of cases with unexplained MR in an academic tertiary centre. Methods: Inclusion criteria were: age <18 years at referral, IQ<85, no aetiological diagnosis after complete examination, which included karyotyping with high resolution banding (HRB). Results: In 266 karyotyped children, anomalies were detected in 20 (7.5%, seven numerical, 13 structural); 39 cases were analysed by FISH for specific interstitial microdeletions, and anomalies were found in nine (23%). FISH analyses for subtelomeric microdeletions were performed in 184 children (44% moderate-profound MR, 51% familial MR), and one rearrangement (0.5%) was identified in a non-familial MR female with mild MR (de novo deletion 12q24.33-qter). The number of probable polymorphisms was considerable: 2qter (n=7), Xpter (n=3), and Ypter (n=1). A significantly higher total number of malformations and minor anomalies was present in the cytogenetic anomaly group compared to the group without cytogenetic anomalies. Conclusions: The total frequency of cytogenetic anomalies in this prospective study was high (1:10), but the frequency of subtelomeric rearrangements was low. The most likely explanations are the high quality of HRB cytogenetic studies and the lack of clinical selection bias. Conventional cytogenetic analyses, combined with targeted microdeletion testing, remain the single most effective way of additional investigation in mentally retarded children, also in a tertiary centre.

Diagnostic investigations in individuals with mental retardation: a systematic literature review of their usefulness

“…This was reported in 10 studies. 59,63,65,80,92,99,106,113,114 The median number of families in which relatives with MR were present was 15.0% (range 7.5 -46%). However, it was generally not stated to which extent the family was surveyed for MR nor to which extent it was reported in the publication.…”

“…We found that the frequency of subtelomeric rearrangements in unselected MR patients may be lower than previously reported. As suggested earlier, 65 this investigation should be selectively applied until more efficient, less-expensive techniques become available. There was a marked variation between positive test results of studies.…”

“…A recent study in a group of MR children from our group did provide evidence of the hypothesis frequently brought forward by Dr John Opitz, that individuals with aneuploidy show more and more widespread minor anomalies. 65 As chromosomal aberrations have been found in persons with a very mild phenotype, 14 karyotyping should still be performed in all MR patients without other obvious causes, regardless of the number of abnormal physical findings.…”

Phenotypic variant of Brachydactyly-mental retardation syndrome in a family with an inherited interstitial 2q37.3 microdeletion including HDAC4

“…There is so far only one report on parent to child transmission of an apparently pure terminal 2q37.3 deletion from an unaffected parent which is distally to the HDAC4 gene and does not overlap with the interstitial 2q37.3 deletion reported here. 9 Recently, HDAC4 haploinsufficiency has been identified as the critical genetic mechanism responsible for developmental delay, behavioural abnormalities, and BDE in BDMR patients with 2q37 deletion. 5 This was supported by the detection of intragenic de novo HDAC4 mutations in two patients with core findings of BDMR syndrome.…”

“…The qPCR analysis was performed on ABI Prism 7900HT Sequence Detection System (Applied Biosystems, Foster City, CA, USA) as described previously. 9 Figure 1 Facial features of patients with 2q37.3 deletion including HDAC4. Patient 1 (a, b), a female at age of 2 years and 8 months, shows features like midface hypoplasia, and mild ptosis.…”