Subtelomeric chromosome rearrangements in children with idiopathic mental retardation: applicability of three molecular-cytogenetic methods.

AIM: To identify cryptic subtelomeric rearrangement, a possible cause of idiopathic mental retardation by means of multiprobe telomere fluorescent in situ hybridization (T-FISH). METHODS: Hundred patients (median age 3.0 years) with mental retardation and dysmorphic features were screened using specific T-FISH probes. Multiplex ligation-dependent probe amplification and comparative genomic hybridization were used for the confirmation of results. RESULTS: Telomere fluorescent in situ hybridization revealed 11 subtelomeric abnormalities in 10 patients (10%; 95% CI, 5.0-17.5). Four of these had only a deletion of subtelomere 2q, which was apparently a normal variant. Among 6 true aberrations (6%; 95% CI, 2.5-12.5) we found 2 de novo subtelomeric deletions and 4 unbalanced subtelomeric rearrangements (one de novo). All clinically significant subtelomeric rearrangements were confirmed by multiplex ligation-dependent probe amplification. Comparative genomic hybridization was used to investigate the whole genome of patients in whom a subtelomeric anomaly was found, confirming some, but not all subtelomeric rearrangements. CONCLUSION: Telomere fluorescent in situ hybridization and multiplex ligation-dependent probe amplification are both very useful and interchangeable methods for detection of unbalanced chromosome rearrangements, but T-FISH also detects balanced rearrangements. In our experiment the resolution power of comparative genomic hybridization was too low for subtelomeric screening compared with T-FISH and multiplex ligation-dependent probe amplification.

Screening of TERC gene amplification as an additional genetic diagnostic test in detection of cervical preneoplastic lesions.

TERC gene amplification was investigated as a possible diagnostic marker for use in routine cytological screening to improve the accuracy of conventional screening procedures in detection of cervical preneoplastic lesions. Cervical smears were screened and classified as low-grade or high-grade squamous intraepithelial lesions (LSIL or HSIL). A fluorescence in situ hybridization procedure using a TERC-specific DNA probe was performed on the same specimens and TERC gene copy number was evaluated. More than two signals per cell were defined as TERC positive. In cervical smears graded after conization as cervical intraepithelial neoplasia grade 1 (CIN 1), no TERC-positive cases were found in either LSIL or HSIL, and no TERC amplification was found in LSIL cases with histological results CIN 1 and CIN 2. Amplifications of the TERC gene first appeared in HSIL cases with CIN 2 histology. In the CIN 3 group, TERC-positive cases were present in both LSIL and HSIL; in these, there were no statistically significant differences between TERC-positive and TERC-negative cases. Statistically significant differences in TERC-positive cases were found between LSIL and HSIL without regard to the CIN grade. From the results obtained, it can be concluded that TERC gene amplifications inevitably lead to a high risk of CIN 3 in both LSIL and HSIL after cytological smear examination. A high CIN grade is not necessarily correlated with TERC amplification, but a positive TERC result certainly demands a high CIN classification.

Subterminal deletion/duplication event in an affected male due to maternal X chromosome pericentric inversion.

UNLABELLED: We report a 13-month-old male infant with an apparently normal karyotype, severe growth and developmental delay, ichthyosis, hypogonadism, limb shortness, hypoplasia of the corpus callosum and a round, flat face and thin upper lip as a consequence of a subtelomeric del/dup event of the X chromosome. The recombinant X chromosome (rec(X)), derived from crossing-over within the inversion, was identified in a family, in which the mother is a carrier of pericentric inversion of one X chromosome and pericentric inversion of the heterochromatic region of chromosome 9. The inv(X) chromosome was also analysed in her sister and daughter. The rec(X) had a duplication of the segment Xq27.3-->Xqter and deletion of the Xp22.31-->Xpter and was interpreted as Xqter-Xq27.3::Xp22.31-Xqter. The rec (X) was characterised by FISH using a number of BAC probes. There are only three published reports of chromosome rearrangements resulting in a similar subtelomeric duplication of Xq in males. The proband's phenotype corresponds to descriptions of contiguous gene syndromes due to deletion of the STS, SHOX, ARSE and KAL genes. Despite the loss of the ARSE gene there was no evidence of chondrodysplasia punctata. Additional conditions associated with duplication of the Xq28 segment, such as severe growth retardation and developmental delay, a peculiar head shape, atrophy of the cerebral hemispheres and hypoplasia of the cerebellum and corpus callosum, were observed. CONCLUSION: Fluorescent in situ hybridisation techniques using subtelomeric DNA probes are essential tools for detection of such complex submicroscopic chromosomal rearrangements as the dup/del event of the X chromosome described in our patient.