Molecular determination of X inactivation pattern correlates with phenotype in women with a structurally abnormal X chromosome.
OBJECTIVE
To correlate the X inactivation pattern, as determined by one or more molecular assays, with phenotype in individuals with structurally abnormal X chromosomes.


METHODS
We utilized methylation analysis of androgen receptor (AR) and Fragile X (FMR1) genes and expression studies of an XIST polymorphism to assess X inactivation patterns of 28 females with structurally abnormal X chromosomes. Individuals were placed in one of three categories: (1) completely nonrandom inactivation of one X chromosome, (2) preferential or skewed inactivation of one X chromosome, or (3) random inactivation of either X chromosome.


RESULTS
In 19 of 21 cases with complete (>97%) skewing of X inactivation, the phenotype was either normal, consistent with a single gene disorder, or consistent with classical Turner syndrome; two cases with completely nonrandom X inactivation had unexplained mental retardation phenotypes. In contrast, six of seven cases that did not exhibit completely nonrandom X inactivation were phenotypically abnormal. Carriers of two balanced translocations, two duplicated Xs, one deleted X, and one 45,X/46,X,r(X) presented with mental retardation and/or multiple congenital anomalies.


CONCLUSIONS
In patients with random or skewed X inactivation, the abnormal phenotype was hypothesized to be due to functional nullisomy or disomy of X-linked genes. Based on these results, we propose that X inactivation studies should be performed on all women with structurally abnormal X chromosomes. This should aid in the understanding of abnormal phenotypes in liveborn individuals with abnormal X chromosomes and may help to predict phenotypes for prenatally detected cases in the future.
Wolff
D J
DJ
Department of Genetics and Center for Human Genetics, Case Western Reserve University School of Medicine and University Hospitals of Cleveland, , Ohio, USA.
Schwartz
S
S
Carrel
L
L
D041321:Chromosomes, Human, X; D019175:DNA Methylation; D004303:Dosage Compensation, Genetic; D005260:Female; D051860:Fragile X Messenger Ribonucleoprotein 1; D006801:Humans; D009419:Nerve Tissue Proteins / Q000378:metabolism; D010641:Phenotype; D016601:RNA-Binding Proteins / Q000378:metabolism; D011944:Receptors, Androgen / Q000378:metabolism
D051860:Fragile X Messenger Ribonucleoprotein 1; D009419:Nerve Tissue Proteins; D016601:RNA-Binding Proteins; D011944:Receptors, Androgen; C497683:FMR1 protein, human