Phenotype and X inactivation in 45,X/46,X,r(X) cases

Abstract

We studied a new series of 21 individuals mosaic for a ring X chromosome [r(X)]. Of nine individuals with mental retardation, only one had a r(X) that lacked XIST (X-inactive-specific transcript) and was not subject to X inactivation, which would explain the abnormal phenotype; the remaining eight cases had XIST on their r(X). The majority of cases (five of seven) with mental retardation had an apparently early replicating r(X); but the androgen receptor gene (AR) was methylated on one allele in five of six informative cases, including two cases with an early replicating r(X). These conflicting results on two indicators of X inactivation suggest a potential dissociation between late replication and DNA methylation in these r(X) chromosomes, which may fail to become completely silenced. Of the twelve subjects who were not mentally retarded, all had XIST present on their r(X) and most (8/10) showed a late replicating r(X), together with AR methylation in all five informative cases, indicating r(X) inactivation. Thus, the unusual phenotypic features and mental retardation associated with the presence of a r(X) cannot be explained solely on the basis of presence or absence of XIST. The r(X) in cases with mental retardation were consistently smaller than those in individuals with normal intelligence, perhaps indicating inability for small rings to undergo structural changes associated with complete X inactivation or lethality in cases with a large non-inactivated r(X). Of the Turner syndrome features present in the r(X) cases, only edema was present in a lesser frequency than in 45,X individuals. Our cases generally had a less severe phenotype than those previously reported, suggesting that reported incidences of abnormalities may be influenced by ascertainment bias, with mental retardation potentially unrelated to the presence of the r(X) in some cases.

Clinical practice guidelines for the care of girls and women with Turner syndrome: proceedings from the 2016 Cincinnati International Turner Syndrome Meeting

“…• A ring X chromosome is sometimes associated with variable intellectual disability, and when intellectual disability is present, it does not always correlate to the presence of a small ring X or to the absence of XIST (X-inactive specific transcript) (33).…”

Molecular cytogenetic characterization of two Turner syndrome patients with mosaic ring X chromosome

“…Besides these, individuals with r (X) can also present with mental disorders, learning difficulties, autistic spectrum disorders, craniofacial abnormalities, cardiovascular problems, skeletal system problems and dermatological problems in severe conditions [7,18,19,30,45]. Clinical manifestation in these cases are dependent on origin, size, replication timing of the ring chromosome, genes affected by copy number variations, level of mosaicism and status of X inactivation [17].…”

Kabuki syndrome: new ocular findings but no evidence of 8p22-p23.1 duplications in a clinically defined cohort

“…Recent reports have noted a high incidence of ocular abnormalities in this group of patients. 3,4 Several inconsistent chromosome aberrations have been described in KS patients of which microdeletions of 1q32-41, 5 22q11.2 6 and ring X chromosomes 7 have already been excluded. Recently, high-resolution comparative genomic hybridisation (HR-CGH) was used to detect a duplication of 8p22 to 8p23.1 in 6/6 patients with KS 8 and a circa 3.5 megabase duplication was identified in all patients using locus-specific FISH probes.…”