Abstract
Xq28 (involving MECP2 ) duplication syndrome is a severe
neurodevelopmental disorder in males, most females are asymptomatic
carriers, but there are phenotypic heterogeneities in the females.
Skewed X-chromosome inactivation (XCI) seems to prevent duplicated
region activation in asymptomatic females, but it remains controversial.
Herein we reported two asymptomatic females (daughter and mother) with
interstitial Xq28 duplication. HUMARA and RP2 assays
showed that both had complete skewed XCI, the Xq28 duplicated chromosome
was inactivated in the daughter, but surprisingly, it was activated in
her mother. Interestingly, by combining RNA sequencing and whole-exome
sequencing, we confirmed that XIST only expressed in the Xq28
duplication chromosomes of the two females, indicating that the Xq28
duplication chromosomes were inactive. Meanwhile, MECP2 and most
XCI genes in the duplicated X-chromosomes were not transcriptionally
expressed or upregulated, precluding major clinical phenotypes in the
two females, especially the mother. We showed that XCI status detected
by RNA sequencing was more relevant for establishing the clinical
phenotype of MECP2 duplication females. It suggested there were
other factors maintaining the XCI status in addition to DNA methylation,
a possible additional inhibition mechanism occured at the
transcriptional level in the unmethylated X-chromosome, counter
balancing the MECP2 duplication’s detrimental phenotype effects.