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.

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We report on a three-month-old boy with a 46,XY,der(Y)t(Y;7)(p11.32;p15.3) karyotype and growth deficiency, postnatal microcephaly with large fontanels, wide sagittal and metopic sutures, hypertelorism, choanal stenosis, micrognathia, bilateral cryptorchidism, hypospadias, abnormal fingers and toes, and severe developmental delay. FISH studies showed partial trisomy 7p resulting from a de novo unbalanced translocation. The application of molecular probes from the TWIST gene region (7p15.3-p21.1) and probes from the pseudoautosomal region (PAR) demonstrated that the 7p15.3-pter fragment was translocated onto Yp with the breakpoint within approximately 20 kb from the Yp telomere. We discuss the possible role of the TWIST gene in abnormal skull development and suggest that trisomy 7p cases with delayed closure of fontanels can be a result of TWIST gene dosage effect.

Human karyopherin alpha2 (KPNA2), a member of the karyopherin alpha family, plays a key role in the nuclear import of proteins with a classical nuclear localization signal (NLS). KPNA2, as part of a karyopherin alpha-beta heterodimer, directly binds to the NLS of proteins and functions as an adaptor that binds NLS-containing proteins via karyopherin beta to the nuclear pore complex. The NLS protein-receptor complex is translocated through the pore by an energy-dependent mechanism. Recently, we have identified and mapped the gene for KPNA2 in close proximity to a translocation breakpoint within 17q23-q24 associated with Russell-Silver syndrome (RSS). Therefore, we considered KPNA2 as a positional candidate gene for this heterogeneous disorder. RSS is mainly characterized by pre- and postnatal growth retardation, lateral asymmetry, and other dysmorphic features. Here, we present the genomic organization of the human KPNA2 gene with 11 exons spanning approximately 10 kb on chromosome 17q23-q24. Screening for mutations within all exons and adjacent intronic sequences from 31 unrelated RSS patients revealed three single nucleotide polymorphisms (SNPs) in exons 1, 5, and 7, and five SNPs in introns 1, 4 (2 SNPs), 8, and 9, respectively. No disease-related mutation was identified by comparing the sequence data of the RSS patients with their clinically normal parents and controls.

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