Kabuki syndrome-like features associated with a small ring chromosome X andXIST gene expression

Abstract

Although clinical features in Kabuki syndrome (KS; Niikawa-Kuroki syndrome) have been well defined, the underlying genetic mechanism still remains unclear. We report a 9-year-old girl with typical KS-like facial appearance, skeletal and dermatoglyphic abnormalities, severe mental retardation, and growth deficiency. In 60 of 100 GTG-banded metaphases from peripheral blood lymphocytes, a ring chromosome smaller than a G group chromosome was found, which, according to reverse painting, consisted of Xq11.1q13. The proband's karyotype was described as mos45,X/46,X,+r(X). Several loci were analyzed with fluorescence in situ hybridization (FISH) and microsatellite markers revealing that one r(X) breakpoint mapped proximal to DXS422 (Xp11.21) and the second mapped distal to XIST gene, between loci DXS128E and DXS441 (Xq13.2). Uniparental disomy for X and r(X) was excluded and the paternal origin of r(X) was identified. XIST expression was demonstrated by nested reverse transcription polymerase chain reaction (RT-PCR) using primers spanning exons 5, 6i, and 6 in RNA prepared from lymphocytes. The observation of XIST expression is in contrast to two other cases in which the XIST gene was either not present on r(X) or not expressed. To our knowledge, this is the first case of Kabuki-like syndrome manifestations with r(X) and XIST expression.

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

“…However, our series significantly adds to the group of individuals who appear to fall outside this standard pattern of phenotype correlated to the presence/absence of XIST and the X-inactivation status of the r(X) [Dennis et al, 1993El Abd et al, 1999;Kuntsi et al, 2000;Matsuo et al, 2000a;Migeon et al, 2000;Turner et al, 2000;Stankiewicz et al, 2001]. Indeed, a significant number of our subjects with mental retardation had a r(X) that contained XIST and those who were informative showed AR methylation, indicative of inactivation of the r(X).…”

“…Due to the limited amount of sample available, we were not able to determine whether XIST was expressed in all cases; thus some of the rings may contain a silent or non-functional XIST, which could lead to non-inactivation of the r(X), as has been described in some cases [Migeon et al, 1993[Migeon et al, , 1994Jani et al, 1995;Yorifuji et al, 1998;Dennis et al, 2000;Tomkins et al, 2002]. However, even in the presence of XIST expression, cases with abnormal phenotypes have been described [Migeon et al, 2000;Stankiewicz et al, 2001]. In two of these cases, a second ring X chromosome that lacked XIST was found, which could explain the abnormal phenotype [Migeon et al, 2000].…”

“…However, it has been suggested that the phenotype of r(X) individuals cannot be entirely defined in terms of X inactivation patterns. Indeed, recent studies have confirmed exceptions that cannot be explained by the presence or absence of XIST and/or XIST expression and the observed X-inactivation patterns [Dennis et al, 1993El Abd et al, 1999;Kuntsi et al, 2000;Matsuo et al, 2000a;Migeon et al, 2000;Turner et al, 2000;Stankiewicz et al, 2001].…”

“…For this comparison, we reviewed findings for 85 cases reported in the medical literature from 1980-2002 [Dallapiccola et al, 1980;Berkovitz et al, 1983;Kushnick et al, 1987;Koch et al, 1990;Lin et al, 1990;Guttenbach et al, 1991;Johnson et al, 1991;Grompe et al, 1992;Lindgren et al, 1992;Tharapel et al, 1992;Van Dyke et al, 1992;Dennis et al, 1993;Cole et al, 1994;Collins et al, 1994;Wolff et al, 1994;Cantu et al, 1995;Blumenthal and Allanson, 1997;El Abd et al, 1997;McGinniss et al, 1997;Uehara et al, 1997;Yorifuji et al, 1998;El Abd et al, 1999;Dennis et al, 2000;Kuntsi et al, 2000;Migeon et al, 2000;Turner et al, 2000;Stankiewicz et al, 2001;Tomkins et al, 2002]. We have presented separately the data from a large study of 47 cases in Table II because 15 of the cases in this study were reported earlier and included in our literature review Kuntsi et al, 2000].…”

A multiple translocation event in a patient with hexadactyly, facial dysmorphism, mental retardation and behaviour disorder characterised comprehensively by molecular cytogenetics. Case report and review of the literature

“…In patients with congenital abnormalities, FISH techniques have been successfully used to detect submicroscopic deletions [8,32] and to characterise the deleted genes [38,50,57], to clarify the origin of extra marker chromosomes [9,11,52] especially using centromerespecific multicolour FISH [25,31], and to clarify the origin of ring chromosomes [13,27,46,47]. Additionally, FISH techniques allowed the identification of chromosomal duplications [29,40,55] as well as partial trisomy or tetrasomy [9,15,57].…”