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X-chromosome inactivation (XCI) is an essential mechanism in females that compensates for the genome imbalance between females and males. It is known that XCI can spread into an autosome of patients with X;autosome translocations. The subject was a 5-year-old boy with Prader-Willi syndrome (PWS)-like features including hypotonia, hypo-genitalism, hypo-pigmentation, and developmental delay. G-banding, fluorescent in situ hybridization, BrdU-incorporated replication, human androgen receptor gene locus assay, SNP microarrays, ChIP-on-chip assay, bisulfite sequencing, and real-time RT-PCR were performed. Cytogenetic analyses revealed that the karyotype was 46,XY,der(X)t(X;15)(p21.1;q11.2),-15. In the derivative chromosome, the X and half of the chromosome 15 segments showed late replication. The X segment was maternal, and the chromosome 15 region was paternal, indicating its post-zygotic origin. The two chromosome 15s had a biparental origin. The DNA methylation level was relatively high in the region proximal from the breakpoint, and the level decreased toward the middle of the chromosome 15 region; however, scattered areas of hypermethylation were found in the distal region. The promoter regions of the imprinted SNRPN and the non-imprinted OCA2 genes were completely and half methylated, respectively. However, no methylation was found in the adjacent imprinted gene UBE3A, which contained a lower density of LINE1 repeats. Our findings suggest that XCI spread into the paternal chromosome 15 led to the aberrant hypermethylation of SNRPN and OCA2 and their decreased expression, which contributes to the PWS-like features and hypo-pigmentation of the patient. To our knowledge, this is the first chromosome-wide methylation study in which the DNA methylation level is demonstrated in an autosome subject to XCI.

No causative gene has been found for idiopathic central precocious puberty; and FOXP2, located in 7q31, is the only known gene for speech and language disturbances. We report a girl with central precocious puberty, moderate mental retardation, and severe speech impairment; accompanied by a de-novo balanced translocation between 7q31 and 10p14. Physical mapping through molecular cytogenetic investigations demonstrated the breakpoints of 7q31 and 10p14 within a bacterial artificial chromosome (BAC) clone RP11-124G5 and a cosmid clone derived from a BAC clone RP11-1122C18, respectively. FOXP2 was found to be localized approximately 500 kb distant from the centromeric end of the disrupted BAC RP11-124G5 at the 7q31 breakpoint. Speech impairment in the girl might be derived from dysfunction of FOXP2 by a position effect of the 7q31 translocation breakpoint.

We report a 4-year-old boy, a 6-month-old girl, and a 17-week-old fetus all with a chromosomal imbalance derived from a balanced translocation t(13;15)(q34;q26.1) of their father. The boy had a partial trisomy for 15q26.1-qter (46,XY,der(13)t(13;15)(q34;q26.1)) and postnatal overgrowth, as well as craniosynostosis, facial anomalies, and finger joint contractures, while the girl with the same chromosomal aberration did not show overgrowth, although she had similar craniofacial and skeletal abnormalities. The fetus had a partial monosomy for 15q26.1-qter and intrauterine growth retardation (IUGR). Fluorescence in situ hybridization (FISH) analysis with a BAC clone covering the insulin-like growth factor 1 receptor gene (IGF1R) that is located to 15q25-q26 revealed three copies in the boy, one copy in the fetus, and two copies in their phenotypically normal father. Since deletion of IGF1Rhas repeatedly been reported to be associated with IUGR, it is tempting to speculate that the dosage of IGF1R may have determined growth in these children., (Copyright 2002 Wiley-Liss, Inc.)