Multiplex ligation‐dependent probe amplification to detect subtelomeric rearrangements in routine diagnostics

Abstract

Subtelomeric rearrangements are believed to be responsible for 5-7% of idiopathic mental retardation cases. Due to the relative complexity and high cost of the screening methods used till now, only preselected patient populations including mostly the more severely affected cases have been screened. Recently, multiplex ligation-dependent probe amplification (MLPA) has been adapted for use in subtelomeric screening, and we have incorporated this technique into routine diagnostics of our laboratory. Since the evaluation of MLPA as a screening method, we tested 275 unselected patients with idiopathic mental retardation and detected 12 possible subtelomeric aberrations: a der(11)t(11;20)(qter;qter), a 19pter duplication, a der(18)t(18;10)(qter; pter), a 15qter deletion, a 8pter deletion, a 6qter deletion, a der(X)t(X;1)(pter;qter), a der(X)t(X;3)(pter;pter), a 5qter duplication, a 3pter deletion, and two 3qter duplications. The patients can be subdivided into two groups: the first containing de novo rearrangements that are likely related to the clinical presentation of the patient and the second including aberrations also present in one of the parents that may or may not be causative of the mental retardation. In our patient cohort, five (1.8%) subtelomeric rearrangements were de novo, three (1.1%) rearrangements were familial and suggestively disease causing, and four (1.5%) were possible polymorphisms. This high frequency of subtelomeric abnormalities detected in an unselected population warrants further investigation about the feasibility of routine screening for subtelomeric aberrations in mentally retarded patients.

Case Report Familial balanced translocation leading to an offspring with phenotypic manifestations of 9p syndrome

“…In contrast, her mother and her grandfather, did not show features of mental retardation or congenital anomalies due to the 1q terminal duplication and had only short stature as clinical presentation (Balikova et al, 2007). Thus, it is probable that duplication of ~2.20 Mb detected in both cousins did not cause pathogenic effects, as in the family described by Rooms et al (2006).…”

“…Our results obtained through the use of P036 and P070 MLPA kits allow us to assume that the region involved in 1q rearrangement has a minimum size of ~2.20 Mb, which cannot be identified by cytogenetic examination with resolution (500 bands) that in theory can only detect changes ~5.0 Mb in size. Rooms et al (2006) described a girl without mental retardation but with facial anomalies, including a broad nasal bridge, epicanthus, long deep philtrum and a normal magnetic resonance imaging of the brain. After the examination with MLPA (P036 kit), they were able to detect a terminal deletion in Xp and a duplication of the terminal region of 1q 2.90 Mb in size (Balikova et al, 2007), which was also shared with her mother and grandfather.…”

Detection of chromosomal imbalances using combined MLPA kits in patients with syndromic intellectual disability

“…Previously reported studies that performed subtelomere analysis showed an overall abnormality rate of 6%, varying between different studies from 2 to 29% (11)(12)(13)(14)(15)(16)(17)(18)(19)(20). The reasons for these differences are the inclusion criteria and the assay used in the study, the size of the cohort and the complete exclusion (or not) of the polymorphisms.…”

“…Subgroup B. Both the manufacturer and the outcomes of previous studies (10)(11)(12) regarding the use of MLPA for subtelomeric rearrangements detection recommend the use of two different probes for the identification of abnormal regions, as an independent confirmation measure. However, establishing the clinical significance of confirmed subtelomeric rearrangements is quite complicated, especially in cases where the DNA samples of the parents are not available.…”

Prenatal detection of cryptic rearrangements by multiplex ligation probe amplification in fetuses with ultrasound abnormalities

“…In the postnatal period, subtelomeric rearrangements are detected in 3-7% of patients with congenital defects and/or mental retardation by FISH, MLPA, quantitative PCR and array-CGH. 4,[11][12][13][14][15] However, there are few reports concerning the detection of such imbalances in the prenatal period. Souter et al 3 reported two prenatal cases of multiple fetal anomalies associated with subtle subtelomeric rearrangements detected by multisubtelomere FISH.…”