Deletions of the PRKAR1A locus at 17q24.2-q24.3 in Carney complex: genotype-phenotype correlations and implications for genetic testing.

Background: Carney complex (CNC) is a multiple neoplasia syndrome caused by PRKAR1A-inactivating mutations. One-third of the patients, however, have no detectable PRKAR1A coding sequence defects. Small deletions of the gene were previously reported in few patients, but large deletions of the chromosomal PRKAR1A locus have not been studied systematically in a large cohort of patients with CNC.

Insertion (12;9)(p13;q34q34): a cryptic rearrangement involving ABL1/ETV6 fusion in a patient with Philadelphia-negative chronic myeloid leukemia.

We report a rare cryptic ins(12;9)(p13;q34q34), a chromosomal abnormality involving the ABL1 (9q34) and the ETV6 (alias TEL; 12p13) genes, detectable only by fluorescence in situ hybridization (FISH), in a patient with Philadelphia-negative chronic myeloid leukemia (CML). Using reverse 4',6-diamidino-2-phenylindole banding on metaphase cells, FISH analysis with BCR/ABL dual-fusion and ETV6 break-apart probes showed that a third ABL signal was inserted into 12p, splitting the ETV6 signal into two adjacent signals. CML patients with an ABL1/ETV6 fusion historically have demonstrated a variable and sometimes transient response to treatment with imatinib mesylate, which was also the case in the present patient.

Translocation (2;8)(q35;q13): a recurrent abnormality in congenital embryonal rhabdomyosarcoma.

We report a case of congenital embryonal rhabdomyosarcoma (ERMS), a rare form of rhabdomyosarcoma, featuring a karyotype with a t(2;8)(q35;q13) in a 2-week-old male infant. This is the third reported case of congenital ERMS with cytogenetic findings. The previous cases also showed a similar or possibly identical translocation.

Long-term persistence of nonpathogenic clonal chromosome abnormalities in donor hematopoietic cells after allogeneic stem cell transplantation.

We describe the cases of two unrelated patients who exhibited multiple chromosomal abnormalities in donor cells after allogeneic peripheral blood stem cell transplantation (PBSCT). The patients were diagnosed with chronic myeloid leukemia and chronic lymphocytic leukemia, respectively, and both underwent nonmyeloablative conditioning with cyclophosphamide and fludarabine followed by PBSCT from their HLA-matched opposite-sex siblings. Post-transplant bone marrow cytogenetics showed full engraftment, and the early post-transplant studies demonstrated only normal donor metaphases.

Dicentric (17;20)(p11.2;q11.2): an uncommon cytogenetic abnormality in myeloid malignancies.

We report on two patients with myeloid disorders and complex karyotypes including a dicentric chromosome, dic(17;20)(p11.2;q11.2), resulting in the loss of most of 17p and 20q.

Isolated del(14)(q21) in a case of precursor B-cell acute lymphoblastic leukemia.

We present a case of del(14)(q21) as a sole abnormality in a 4-year-old boy diagnosed with precursor B-cell acute lymphoblastic leukemia (pre-B ALL). To our knowledge, this is the first case of isolated del(14)(q21) in pre-B ALL. Two pretreatment bone marrow samples obtained 5 days apart were analyzed by cytogenetics.

Variant acute promyelocytic leukemia translocation (15;17) originating from two subsequent balanced translocations involving the same chromosomes 15 and 17 while preserving the PML/RARA fusion.

Fluorescence in situ hybridization (FISH) analysis of the bone marrow of a 24-year-old man diagnosed with acute promyelocytic leukemia (APL) revealed a variant pattern with one fusion signal instead of the typical two fusions expected with the probe set used. The combined FISH and conventional chromosome analyses suggested that two subsequent translocations had occurred in this patient involving the same chromosomes 15 and 17. As the prognostic outcome in APL is strictly associated with the presence of a PML/RARA fusion, it is useful and necessary to perform both cytogenetic and FISH analyses of a variant t(15;17) to determine the status of the PML/RARA fusion.

Unexpected retention and concomitant loss of subtelomeric regions in balanced chromosome anomalies by FISH.

Florescence in situ hybridization (FISH) using subtelomeric probes has been useful in detecting cryptic telomeric chromosomal rearrangements. We report, for the first time, that cytogenetically visible chromosome rearrangements can occur between the subtelomeric and telomeric region in clinically normal individuals with balanced chromosome anomalies in which one of the breakpoints involves a terminal band region. Using FISH with subtelomeric probes, we observed in three cases with a balanced reciprocal translocations the retention and subsequent loss of subtelomeric regions.

Rapid interphase analysis for prenatal diagnosis of translocation carriers using subtelomeric probes.

Interphase fluorescence in situ hybridization (FISH) has become an accepted laboratory technique for the rapid and preliminary prenatal assessment of chromosome aneuploidy. The introduction of subtelomeric FISH probes now allows for the molecular-cytogenetic analysis of terminal chromosome rearrangements. In a prospective study, we examined the prenatal use of subtelomeric probes on interphase cells to rapidly detect the carrier status of a fetus when a parent carried a known reciprocal or Robertsonian chromosome translocation.