Investigation of modifier genes within copy number variations in Rett syndrome

Abstract

MECP2 mutations are responsible for two different phenotypes in females, classical Rett syndrome and the milder Zappella variant (Z-RTT). We investigated whether copy number variants (CNVs) may modulate the phenotype by comparison of array-CGH data from two discordant pairs of sisters and four additional discordant pairs of unrelated girls matched by mutation type. We also searched for potential MeCP2 targets within CNVs by chromatin immunopreceipitation microarray (ChIP-chip) analysis. We did not identify one major common gene/region, suggesting that modifiers may be complex and variable between cases. However, we detected CNVs correlating with disease severity that contain candidate modifiers. CROCC (1p36.13) is a potential MeCP2 target, in which a duplication in a Z-RTT and a deletion in a classic patient were observed. CROCC encodes a structural component of ciliary motility that is required for correct brain development. CFHR1 and CFHR3, on 1q31.3, may be involved in the regulation of complement during synapse elimination, and were found to be deleted in a Z-RTT but duplicated in two classic patients. The duplication of 10q11.22, present in two Z-RTT patients, includes GPRIN2, a regulator of neurite outgrowth and PPYR1, involved in energy homeostasis. Functional analyses are necessary to confirm candidates and to define targets for future therapies.

Figure 1

Array-CGH ratio profiles. a) Array-CGH ratio profiles of CNV on 1p36.13 of #402 classic RTT patient. On the left, the chromosome 1 ideogram. On the right, the log 2 ratio of the chromosome 1 probes plotted as a function of chromosomal position. Copy number loss shifts the ratio to the left. b) Array-CGH ratio profiles of CNV on 1q31.3 of #368 Z-RTT patient. On the left, the chromosome 1 ideogram. On the right, the log 2 ratio of the chromosome 1 probes plotted as a function of chromosomal position. Copy number loss shifts the ratio to the left. c) Array-CGH ratio profiles of CNV on 10q11.22 of #139 Z-RTT patient. On the left, the chromosome 10 ideogram. On the right, the log 2 ratio of the chromosome 10 probes plotted as a function of chromosomal position. Copy number gain shifts the ratio to the right.