Genomic Features of Interstitial Deletions of Chromosome 9q in Acute Myeloid Leukemia.

Interstitial deletion in the long arm of chromosome 9 [del(9q)] is a fairly common cytogenetic finding associated with acute myeloid leukemia (AML), seen in approximately 2-5% of AML patients. However, the genomic features of the deletion remain largely unknown. Using chromosome analysis, single nucleotide polymorphism microarray, and next-generation sequencing, we characterized del(9q)s and other genomic alterations in 9 AML patients. We found several distinct features of the del(9q)s. The proximal breakpoints of the deletions are clustered within a 2.5-Mb region (chr9: 68,513,625-70,984,372; GRCh37) enriched with segmental duplications, which may represent a "hotspot" for genomic rearrangements. However, the distal breakpoints of the deletions vary significantly. In addition, the overall deleted region could be divided into a 14.4-Mb proximal constitutional region (chr9: 70,950,015-85,397,699; 9q21.11q21.32) and a 24.0-Mb distal oncogenic region (chr9: 85,397,700-109,427,261; 9q21.32q31.1). We further identified a 6.8-Mb common overlapped deletion region (CODR) in the distal region (chr9: 90,590,650-97,366,400). This CODR carries multiple genes that are reportedly involved in cancer pathogenesis. The prognostic value of the del(9q) in AML apparently depends on additional genomic alterations in the patients.

Trisomy Xp and partial tetrasomy Xq resulting from gain of a rearranged X chromosome in a female fetus: pathogenic or not?

Cytogenetic analysis of chorionic villous sampling revealed a mosaic karyotype with gain of a rearranged X chromosome. Microarray and additional studies indicated that the rearranged X carried an inverted duplication, a deletion and a satellited Xqter. Gain of this rearranged X was confirmed by follow-up amniocentesis and postnatal cord blood sample. A full-term infant girl was delivered and showed normal physical findings at both birth and 21-month follow-up examinations. Late replication studies demonstrated that the rearranged X was inactivated in all abnormal cells analyzed. Skewed X-inactivation may suppress the potentially deleterious effects of genomic imbalance; however, gain of X chromosomes, particularly rearranged X chromosomes, often presents challenges for prenatal genetic counseling. The gradation of clinical phenotype severity generally correlates with the number of additional X chromosomes. However, the X chromosome regions responsible for the abnormal phenotypes are poorly understood. This case will further elucidate the phenotypic effects of X inactivation and X chromosome abnormalities.

Ring 21 chromosome and a satellited 1p in the same patient: novel origin for an ectopic NOR.

Nucleolus organizer regions (NORs) are present on the satellite stalks located on the short arms of the acrocentric chromosomes. NORs present on non-acrocentric chromosomes (ectopic NORs) are rare and were reported in both phenotypically normal and abnormal individuals. We describe a patient, ascertained prenatally, with an ectopic NOR on 1p and a ring 21 chromosomes. Amniocentesis was performed at 27-weeks gestation on a 19-year-old woman after identification of intrauterine growth retardation (IUGR) by ultrasound. Cytogenetic analysis of amniocytes from the fetus showed a mos 46,XX,1ps,r(21) (p11.2q22.3)[44]/45,XX,1ps,-21[6] karyotype. Parental karyotypes were normal, indicating a de novo origin for these rearrangements in the fetus. Molecular cytogenetic characterization of the 1ps showed no loss of euchromatin and retention of the telomeric repeats. Characterization of the r(21) using array comparative genomic hybridization (CGH) identified that the deletion was approximately 5 Mb encompassing most of chromosome band 21q22.3. The ectopic NOR (1ps) was most likely derived from the acentric 21p fragment generated by the chromosome breakage event that lead to formation of the r(21) chromosome. This represents a novel mechanism for the origin of ectopic NORs. In addition, this study illustrates the importance of FISH analysis with telomeric and subtelomeric probes for characterization of chromosomes with ectopic NORs.