Partial Xp duplication in a girl with dysmorphic features: the change in replication pattern of late‐replicating dupX chromosome

Abstract

In this paper we present the case of a girl at the age of 32 months with dysmorphic features, including general muscular hypotonia, developmental delay and mental retardation. The cytogenetic analysis revealed de novo partial duplication of Xp: 46,X,dup(X)(p11.23-->p22.33: :p11.23-->p22.33). To characterize the duplication, X painting, Kallman (KAL), yeast artificial chromosomes (YACs) and bacterial artificial chromosomes (BACs) covering Xp11.23-->Xp22.33 region were used. Selective inactivation of the abnormal X chromosome using HpaII digestion of the AR gene was evident. After BrdU incorporation the abnormal X was late-replicating in all lymphocytes examined. There was one peculiar exception observed: the break-point region was consistently early replicating. The replicating pattern of this region corresponded to the active X chromosome. Methylation pattern of late replicating X chromosome was studied also using antibodies against 5-methylcytosine. The pattern corresponded to the normally inactive X chromosome, with the exception of the previously observed break-point region which revealed an early replicating pattern with strong fluorescent signal, similar to the pattern of the active X chromosome. The observed phenomenon could lead to the abnormal phenotype of the patient, with some normally inactive genes of the break-point region escaping the inactivation process. The abnormal clinical findings could also be due to tissue-dependent differences in the inactivation pattern.

A de novo duplication of Xp11.22–p11.4 in a girl with intellectual disability, structural brain anomalies, and preferential inactivation of the normal X chromosome

“…As with both males and females who have overlapping duplications of the proximal part of the short arm of the X chromosome our patient has an abnormal EEG [Nielsen and Langkjaer, 1982; Kokalj Vokac et al, 2002; Tzschach et al, 2008]. Mutations in many of the genes in the duplicated Xp segment in our patient have been associated with seizures (Table I).…”

“…X inactivation initially occurs at random, but in females with structural rearrangements of the X chromosome several factors will determine whether there is subsequent cell selection against the abnormal X. Duplications which are restricted to Xp11.2–Xp11.4 are generally associated with random patterns of X inactivation [Matsuo et al, 1999; Portnoi et al, 2000; Monnot et al, 2008], while females with larger overlapping duplications have been reported to have selective inactivation of the abnormal X [Nielsen and Langkjaer, 1982; Kokalj Vokac et al, 2002]. In contrast, X‐inactivation analysis in our patient showed that the normal X chromosome is inactivated in the majority of cells in DNA extracted from whole blood.…”

“…To date, only a handful of individuals with pure duplications of the proximal short arm of the X chromosome encompassing band p11.2 have been reported. Five of these patients have relatively large duplications with the distal breakpoint within or beyond Xp21.2 [Nielsen and Langkjaer, 1982; Tuck‐Muller et al, 1993; Matsuo et al, 1999; Portnoi et al, 2000; Kokalj Vokac et al, 2002]. In other patients, the duplicated segment has been confined to bands p11.22 and p11.23 [Giorda et al, 2009; Hunter et al, 2009].…”

Clinical and molecular characterization of overlapping interstitial Xp21‐p22 duplications in two unrelated individuals

“…Females who do not have skewed X‐inactivation can exhibit severe phenotypic abnormalities, similar to those seen in males with X chromosome duplications [Carrozzo et al, 1997; Matsuo et al, 1999]. Even when selective X‐inactivation does occur, several mechanisms may contribute to abnormal phenotypes in females with X chromosome duplications, including: (1) expression of recessive mutant genes on the active, nonduplicated X chromosome, (2) incomplete inactivation of the duplicated region [Kokalj Vokac et al, 2002], (3) tissue‐dependant X‐inactivation pattern, or (4) coincidental abnormalities independent of X chromosome aberrations [Aughton et al, 1993]. Additionally, since skewing occurs by cell selection after inactivation was established randomly, cells containing the active abnormal X chromosome could have deleterious effects before their elimination by the selection process [Monnot et al, 2008].…”

Functional disomy of proximal Xp causes a distinct phenotype comprising early hypotonia, hypertelorism, small hands and feet, ear abnormalities, myopia and cognitive impairment

“…We identified from the literature 10 patients who have either a karyotype 47,+ESAC(X), or another karyotype resulting in functional disomy of X chromosome genes [Nielsen and Langkjaer, 1982; Koch et al, 1990; Duncan et al, 1993; Silahtaroglu et al, 1995; Manea et al, 1997; Fritz et al, 1998; Tumer et al, 1998; Huang et al, 1999; Portnoi et al, 2000; Kokalj Vokac et al, 2002; Kolomietz et al, 2005; Bonnet et al, 2006; Musio et al, 2006]. The clinical details of these patients are summarized in Table I and the chromosome breakpoints shown in Figure 2.…”