Cryptic telomeric rearrangements in subjects with mental retardation associated with dysmorphism and congenital malformations.

EDITOR--Cryptic telomeric rearrangements are a significant cause of idiopathic mental retardation. Knight et al [1] found 7.4% of these rearrangements in children with moderate to severe mental retardation. Clinical selection criteria for testing patients with subtelomeric chromosome specific probes are still not clear cut and the importance of other surveys to define this point has been stressed. [2] With this aim, we examined 200 patients with idiopathic mental retardation, either isolated or associated with dysmorphism and/or congenital anomalies, using FISH analysis with subtelomeric chromosome specific probes.

Material and methods

The sample was collected in four Italian Genetic Centres. Patients were selected on the basis of the following criteria: (1) the presence of mental retardation that was classified as mild, moderate, or severe according to DSM [IV.sup.3]; (2) patients under 1 year of age, too young for psychological assessment, were selected for the presence of developmental delay; (3) exclusion of pre- or perinatal distress through an accurate evaluation of the pre-, peri-, and postnatal patient history; and (4) exclusion of Mendelian syndromes and of genomic disorders [4,5] for which a specific diagnostic test is available.

The essential elements of evaluation also included family history, a complete physical and neurological examination of the patients with particular attention to the presence of mental retardation and multiple congenital anomalies, and assessment of the behavioural phenotype. Electroencephalograms, brain CT scan, and MRI were performed in specific situations.

Abnormal methylation and expansion at FRAXA and FRAXE [6] were excluded in 52 and 50 males and in 37 and 32 females, respectively.

Routine cytogenetic analysis at the 400-550 band level was performed in all the patients. In those patients in whom a cryptic subtelomeric rearrangement was identified by FISH, prometaphase chromosomes were also analysed to determine if the rearrangement could be detected in retrospect by cytogenetic analysis. Chromosome preparations from peripheral blood or from lymphoblastoid cell lines were used for FISH analysis. The Chromoprobe-T kit with telomere specific clones [7] was used according to the supplier's instructions (Cyto-cell, UK) with minor modifications. To establish the origin of each rearrangement, FISH and microsatellite analysis with subtelomeric probes were performed in the parents of the patients. FISH experiments with different YACs from each rearranged chromosomal region were performed to define its size.

Results

Among our 200 patients (table 1), 44 had mild mental retardation (IQ 50-70), 62 were moderately retarded (IQ 50-35), and 55 were severely retarded (IQ 35-20). A total of 39 patients had mental retardation not otherwise specified. Mental retardation was familial in 53 and sporadic in 147 subjects; it was isolated in 23 subjects, associated with dysmorphism and/or congenital anomalies in 160 subjects, and unknown in 17.

We identified 13 rearrangements (table 2). Seven rearrangements were de novo deletions. Six rearrangements were derivative chromosomes inherited by a balanced parent in the five cases where the parents were available. Twelve rearrangements were present in patients with moderate (7/62, 11.2%) or severe (5/55, 9%) mental retardation, whereas one rearrangement was found in a 3 month old patient, too young to assess the degree of his psychomotor retardation. No rearrangements were found among the 44 patients with mild mental retardation.

In all the 13 …