[Detection of subtelomeric rearrangements in patients with idiopathic mental retardation/developmental delay]

To detect subtelomeric rearrangement in patients with idiopathic mental retardation/developmental delays (MR/DD) and to provide new methods and evidence for the etiologic diagnosis of MR/DD in China.

1.

(1) Moderate to severe MR/DD; (2) no definite perinatal brain injury; (3) no toxication, hypoxia, infection of central nervous system and cranial trauma; (4) routine karyotyping is normal; (5) no evidence of typical inherited metabolic disorder or specific neurodegenerative disorders from cranial neuro-imaging and blood/urinary metabolic diseases screening; (6) no mutation of FMR1 gene in male patients plus one of the following criteria: (1) positive family history of MR; (2) positive family history of miscarriages and perinatal deaths; (3) abnormal growth; (4) facial and non-facial dysmorphism. 2. Multiplex ligation-dependent probe amplification (MLPA) and fluorescence in situ hybridization (FISH) were applied to detect subtelomeric rearrangements in patients and their parents.

Four cases were identified from 39 selected cases with subtelomeric rearrangements (10%), including der (2) t (2; 4) (pter; pter), 11qter del, 8pter del, and 15p11.2 del. The first two abnormalities of chromosome subtelomeric regions have not been reported yet. All these cases had some small dysmorphologies, such as microcephaly, hypertelorism, low nasal bridge, and three of them had hypotonia. One case had recurrent seizure and abnormal behavior (laughter not associated with happiness), and another case with dysgenesis of corpus callosum and septum pellucidum. Family and perinatal histories were normal for all cases. All chromosome rearrangements were de novo which were not from the parents with normal phenotype. It indicated that all these abnormal rearrangements should be responsible for the mental retardation phenotype of these patients. The phenotype of case 4 was similar to Angelman syndrome, his deletion was actually a kind of interstitial rearrangements. It will be confirmed by DNA methylation test to determine whether the deleted allele was of maternal origin.

The subtelomeric rearrangements were found in 10% patients with idiopathic MR. It indicated that subtelomeric rearrangements should be one of major reasons of MR/DD related to genetic factors. Two novel subtelomeric rearrangements were identified. These de novo rearrangements are probably disease related, because they are not inherited from their parents with normal phenotype. The detection should be carried out for all the patients with idiopathic MR/DD with unknown origin, because one cannot figure out the specific signs for subtelomeric rearrangements. Sequentially use of MLPA and FISH is a more efficient and economic method to detect the subtelomeric rearrangements.