Analysis of genomic instability using multiple assays in a patient with Rothmund-Thomson syndrome.

We report on a patient with Rothmund-Thomson syndrome (RTS) whose cytogenetic evaluation showed a normal karyotype with no evidence of trisomy mosaicism or chromosomal rearrangements. Cultured lymphocytes from the patient, her mother, and a control exposed to mitomycin C and diepoxybutane did not show increased sensitivity to the dialkylating agents. Unlike some previous reports, we found no evidence of a deficiency in nucleotide excision repair, as measured with the functional unscheduled DNA synthesis assay. Glycophorin A analysis of red blood cells for somatic mutation revealed suspiciously high frequencies of both allele loss and loss-and-duplication variants in the blood of the patient, a pattern consistent with observations in other RecQ-related human diseases, and evidence for clonal expansion of a mutant clone in the mother. Discrepant results in the literature may reflect true heterogeneity in the disease or the fact that a consistent set of tests has not been applied to RTS patients.

Ring chromosome X in a child with manifestations of Kabuki syndrome.

A female patient with the karyotype 45,X/46, X, r(X)(p11.2 q13) and severe developmental delay, prominent fingertip pads, long palpebral fissures, short stature, and history of hypotonia had a phenotype reminiscent of Kabuki syndrome. We hypothesized that overexpression of X chromosome-derived sequences might be associated with the Kabuki-like phenotype observed. The nature and parental origin of this small-ring X were ascertained using a combination of genotyping with microsatellite markers and quantitative Southern blotting. PCR-based genotyping demonstrated heterozygosity at X-linked loci SBMA (Xq11-q12) and DXS227 (Xq13.1). Hemizygosity was observed at several loci: DMD STR-49 (Xp21.2), DXS1003 (Xp11.23), DXS988 (Xp11.21), DXS101 (Xq21.3), FMR-1 (Xq27.3), and DXYS64 (Xq28). This ring X chromosome is paternally derived since only maternal alleles are inherited at three informative microsatellite loci. Results of FISH and RT-PCR experiments indicate that the XIST locus is missing in the ring X chromosome and not expressed. These data indicated a large deletion of the X chromosome consistent with a small-ring X chromosome with approximate breakpoints near p11.2 and q13. These results are comparable to the observation of others where an atypically severe phenotype has been associated with the presence of an r(X), or small mar(X).

Familial cryptic translocation resulting in Angelman syndrome:implications for imprinting or location of the Angelman gene?

Angelman syndrome (AS) is associated with a loss of maternal genetic information, which typically occurs as a result of a deletion at 15q11-q13 or paternal uniparental disomy of chromosome 15. We report a patient with AS as a result of an unbalanced cryptic translocation whose breakpoint, at 15q11.2, falls within this region. The proband was diagnosed clinically as having Angelman syndrome, but without a detectable cytogenetic deletion, by using high-resolution G-banding. FISH detected a deletion of D15S11 (IR4-3R), with an intact GABRB3 locus. Subsequent studies of the proband's mother and sister detected a cryptic reciprocal translocation between chromosomes 14 and 15 with the breakpoint being between SNRPN and D15S10 (3- 21). The proband was found to have inherited an unbalanced form, being monosomic from 15pter through SNRPN and trisomic for 14pter to 14q11.2. DNA methylation studies showed that the proband had a paternal-only DNA methylation pattern at SNRPN, D15S63 (PW71), and ZNF127. The mother and unaffected sister, both having the balanced translocation, demonstrated normal DNA methylation patterns at all three loci. These data suggest that the gene for AS most likely lies proximal to D15S10, in contrast to the previously published position, although a less likely possibility is that the maternally inherited imprinting center acts in trans in the unaffected balanced translocation carrier sister.

Kabuki syndrome: underdiagnosed recognizable pattern in cleft palate patients.

Eight cases of Kabuki syndrome in non-Japanese patients are presented. (Although the name Kabuki Make-up syndrome has been used to identify this condition, the authors recommend that the term "make-up" be deleted from the designation as it has caused problems with some of the families.) Clinical features include a characteristic facies, developmental delay, musculoskeletal abnormalities, and dermatoglyphic differences. The phenotype appears to evolve over time making the diagnosis difficult in infancy. The progressive changes in the facial characteristics as well as the musculoskeletal problems suggest an underlying defect of the connective tissue. Finally, the syndrome appears to be more common in the non-Japanese population than previously appreciated, particularly in the cleft palate population.