MECP2 duplications in six patients with complex sex chromosome rearrangements

Abstract

Duplications of the Xq28 chromosome region resulting in functional disomy are associated with a distinct clinical phenotype characterized by infantile hypotonia, severe developmental delay, progressive neurological impairment, absent speech, and proneness to infections. Increased expression of the dosage-sensitive MECP2 gene is considered responsible for the severe neurological impairments observed in affected individuals. Although cytogenetically visible duplications of Xq28 are well documented in the published literature, recent advances using array comparative genomic hybridization (CGH) led to the detection of an increasing number of microduplications spanning MECP2. In rare cases, duplication results from intrachromosomal rearrangement between the X and Y chromosomes. We report six cases with sex chromosome rearrangements involving duplication of MECP2. Cases 1-4 are unbalanced rearrangements between X and Y, resulting in MECP2 duplication. The additional Xq material was translocated to Yp in three cases (cases 1-3), and to the heterochromatic region of Yq12 in one case (case 4). Cases 5 and 6 were identified by array CGH to have a loss in copy number at Xp and a gain in copy number at Xq28 involving the MECP2 gene. In both cases, fluorescent in situ hybridization (FISH) analysis revealed a recombinant X chromosome containing the duplicated material from Xq28 on Xp, resulting from a maternal pericentric inversion. These cases add to a growing number of MECP2 duplications that have been detected by array CGH, while demonstrating the value of confirmatory chromosome and FISH studies for the localization of the duplicated material and the identification of complex rearrangements.

Figure 1

Facial features of case 4 (a), case 5 (b), and case 6 (c). Prominent features include small mouth, round face, short neck, low-set ears, brachycephaly, midface hypoplasia and flat nasal bridge.

Figure 2

Cytogenetic and molecular cytogenetics analyses. Array plots for the distal Xq region (a) and distal Xp region (b) are shown for each case. The bottom horizontal bar indicates coordinates in Mb. Red boxes indicate probes that detected a gain or loss in copy number for each patient. Vertical black line indicates location of the MECP2 gene. A log2 ratio of zero indicates a copy number (CN) of two for males. In the chromosome analysis suite software, the PAR regions of X are CN=2 in normal males (probes on the X and Y contribute to the signal), whereas the rest of the X chromosome is CN=1. Copy number changes involving the PAR regions display a shift in the log2 ratio (pink highlighted regions). In case 4, the shift on Xq PAR is not observed, suggesting that the PAR on Yq was lost in the t(Xq;Yq) translocation. (c) GTG-banded chromosomes X and Y for cases 1, 2, 4, 5 and 6. (d) FISH analyses for cases 1 and 2 show an Xq28 probe in red (RP11-119A22 in case 1, RP11-143H17 in case 2) hybridizing to Yp. FISH analysis for case 6 shows an Xq28 probe (yellow) hybridizing to both distal Xq and distal Xp. (e) GTG-banded X chromosomes from the mother of patient 5. Arrows indicate the approximate breakpoints of the pericentric inversion.