Study of 30 patients with unexplained developmental delay and dysmorphic features or congenital abnormalities using conventional cytogenetics and multiplex FISH telomere (M-TEL) integrity assay

Abstract

Cryptic subtelomeric chromosome rearrangements are a major cause of mild to severe mental retardation pointing out the necessity of sensitive screening techniques to detect such aberrations among affected patients. In this prospective study a group of 30 patients with unexplained developmental retardation and dysmorphic features or congenital abnormalities were analysed using the recently published multiplex FISH telomere (M-TEL) integrity assay in combination with conventional G-banding analysis. The patients were selected by one or more of the following criteria defined by de Vries et al.: (a) family history with two or more affected individuals, (b) prenatal onset growth retardation, (c) postnatal growth abnormalities, (d) facial dysmorphic features, (e) non-facial dysmorphism and congenital abnormalities. In addition, we included two patients who met these criteria and revealed questionable chromosome regions requiring further clarification. In four patients (13.3%) cryptic chromosome aberrations were successfully determined by the M-TEL integrity assay and in two patients with abnormal chromosome regions intrachromosomal aberrations were characterized by targetted FISH experiments. Our results accentuate the requirement of strict selection criteria prior to patient testing with the M-TEL integrity assay. Another essential precondition is high-quality banding analysis to identify structural abnormal chromosomes. The detection of familial balanced translocation carriers in 50% of the cases emphasizes the significance of such an integrated approach for genetic counselling and prenatal diagnosis.

Use of Multiplex Ligation-Dependent Probe Amplification (MLPA) in screening of subtelomeric regions in children with idiopathic mental retardation

“…Detection rate of unbalanced chromosomal subtelomeric rearrangements by FISH based studies varies from 1.8% to 13.3% with an average of 4 to 8%. 1,2,9,10 FISH based studies are able to detect translocations, however small segmental duplications may be missed. MLPA is relatively easy to perform, PCR based method, and more cost effective as compared to ultiprobe FISH and array CGH 17,18 , and needs to be incorporated in the evaluation of mental retardation/ developmental delay.…”

Trisomy 8q and partial trisomy 22 in a 43‐year‐old man with moderate intellectual disability, epilepsy and large cell non‐Hodgkin lymphoma

“…Two-color FISH experiments were performed as described [Lichter and Cremer, 1992] using subtelomeric PAC clones for 8qter (PAC-489D14) together with a chromosome 8 specific painting probe (wcp 8), and for 22qter (PAC-99K24) in combination with a partial chromosome painting probe 22q (pcp 22q) (Fig. 2) [Knight and Flint, 2000;Popp et al, 2002]. In addition, a two-color probe set for DiGeorge syndrome (Vysis, Downers Grove, IL) was applied.…”

Cytological indications of the complex subtelomeric structure

“…However, many other clinical pictures of retarded and malformed children remained unexplained being named in general as "idiopathic" syndromes. The present availability of fluorescent probes for the subtelomeric region allowed detection of minute chromosome aberrations located in the subtelomeric region (Fauth et al, 2001;Joyce et al, 2001;Sismani et al, 2001;Popp et al, 2002;Jalal et al, 2003). These aberrations were collectively called "cryptic" because it was not possible to detect them before with the light microscope (de Vries et al, 2001;Fan et al, 2001;Riegel et al, 2001;Anderlid et al, 2002;Baker et al, 2002).…”