M.D. Coll

Cytogenetic studies in 112 cases of untreated myelodysplastic syndromes

Cytogenetic studies were performed in 112 untreated cases of myelodysplastic syndrome (MDS) between 1985 and 1990. Among 112 patients who were examined at the time of diagnosis, 54 had an abnormal karyotype (48%). The highest frequency of chromosome abnormalities was observed in refractory anemia with excess of blasts (RAEB) and RAEB in transformation (RAEB-t) and the lowest in refractory anemia with ring sideroblasts (RARS) and chronic myelomonocytic leukemia (CMMoL). Numerical changes were observed in 19 cases and structural in 17; chromosome 8 was most frequently gained (11 cases), whereas chromosome 7 was most frequently lost (6 cases), 5q- in 14 (4 as a sole anomaly); involvement of 7q22 was seen in 3 cases, 11p in 2 patients, 11q in 3 (one patient as a sole anomaly), 12p in 4 (2 patients as a sole anomaly), i(17q) in 4 (3 patients as a sole anomaly), and complex chromosomal defects in 10 patients. If one takes into account the prognosis value, a complex karyotype and the presence of ring chromosomes were correlated with the worst prognosis, followed by -7/7q-; an intermediate prognosis corresponds to i(17q), 12p as a sole anomaly, +8 (as a sole anomaly or plus other anomalies), and involvement of 12p. Patients with a 5q- as a sole anomaly or with a normal karyotype, had the best prognosis.

Cytogenetic studies in acute nonlymphocytic leukemia

Cytogenetic studies were performed in 74 untreated patients with acute nonlymphocytic leukemia (ANLL) between 1985 and 1988. Among 56 patients who were examined successfully at the time of diagnosis, 36 had abnormal karyotypes (64.2%). The distribution of chromosome abnormalities was uneven, according to the categories of the French-American-British (FAB) nomenclature. The highest frequency of chromosome abnormalities was observed in ANLL M4 with bone marrow (BM) eosinophilia (M4Eo). Numerical changes were observed in 11 cases; chromosome 8 was most frequently gained (11 patients), whereas chromosome 7 was most frequently lost (4 patients). Structural rearrangements were detected in 18 patients. Involvement of 16q22 was noted in 7 patients, 5q- was noted in 5, t(8;21) in 3, t(1;7) in 2, del(20) in 2, and involvement of 11q23 was noted in 2. The inversion of chromosome 16 was restricted to the M4Eo subtype. This study identified a novel abnormality [inv(2) (p11.2q11.2)] that had not been reported previously by other investigators.

A common cognitive, psychiatric, and dysmorphic phenotype in carriers of NRXN1 deletion.

Deletions in the 2p16.3 region that includes the neurexin (NRXN1) gene are associated with intellectual disability and various psychiatric disorders, in particular, autism and schizophrenia. We present three unrelated patients, two adults and one child, in whom we identified an intragenic 2p16.3 deletion within the NRXN1 gene using an oligonucleotide comparative genomic hybridization array. The three patients presented dual diagnosis that consisted of mild intellectual disability and autism and bipolar disorder. Also, they all shared a dysmorphic phenotype characterized by a long face, deep set eyes, and prominent premaxilla. Genetic analysis of family members showed two inherited deletions. A comprehensive neuropsychological examination of the 2p16.3 deletion carriers revealed the same phenotype, characterized by anxiety disorder, borderline intelligence, and dysexecutive syndrome. The cognitive pattern of dysexecutive syndrome with poor working memory and reduced attention switching, mental flexibility, and verbal fluency was the same than those of the adult probands. We suggest that in addition to intellectual disability and psychiatric disease, NRXN1 deletion is a risk factor for a characteristic cognitive and dysmorphic profile. The new cognitive phenotype found in the 2p16.3 deletion carriers suggests that 2p16.3 deletions might have a wide variable expressivity instead of incomplete penetrance.

Does Polysomy of Chromosome 17 Have a Role in ERBB2 and Topoisomerase IIα Expression

Objectives: ERBB2 is an oncogene with prognostic and predictive value. Topoisomerase IIα is an enzyme encoding close to the ERBB2 oncogene, that represents a molecular target for anthracyclines. An indirect mechanism of increasing ERBB2 and topoisomerase IIα gene copy number is chromosome 17 polysomy. The aim of the present study was to clarify the implication of polysomy 17 in ERBB2 and topoisomerase IIα expression. In addition, we assessed the relation of ERBB2 and topoisomerase IIα gene dosage to mRNA and protein levels. Methods: We selected 83 cases diagnosed as invasive breast cancer. We analysed ERBB2 and topoisomerase IIα genes, mRNA and protein by fluorescence in situ hybridisation, real-time reverse-transcription polymerase chain reaction and immunohistochemistry. Results: We observed a progressive increase in mRNA expression from 0+ to 3+ and also a significant difference in the ERBB2 RNA levels between normal and amplified cases. We found that polysomy of chromosome 17 does not affect the ERBB2 expression and that topoisomerase IIα mRNA expression is not related to gene status. Conclusions: Our results demonstrate that polysomy of chromosome 17 is not related to ERBB2 expression. Thereby, it is important to use centromeric probes to clearly discriminate between true ERBB2 gene amplification and polysomy of chromosome 17.

Acute lymphoblastic leukemia with t(4;11) in a patient previously exposed to a carcinogen

A case of early B t(4;11)(q21;q23) acute lymphoblastic leukemia (ALL) with low white blood cell (WBC) count, without splenomegaly, short survival time, in a patient previously exposed to benzol is presented. We discuss the relationship between the t(4;11)(q21;q23) and the exposure to a carcinogen.

Novel UBE3A mutations causing Angelman syndrome: Different parental origin for single nucleotide changes and multiple nucleotide deletions or insertions†

Angelman syndrome (AS) is a genetic disorder caused by a deficiency of UBE3A imprinted gene expression from the maternal chromosome 15. In 10% of AS cases the genetic cause is a mutation affecting the maternal copy of the UBE3A gene. In two large Spanish series of clinically stringently selected and nonstringently selected patients, we have identified 11 pathological mutations—eight of them novel mutations—and 14 sequence changes considered polymorphic variants. Remarkably, single nucleotide substitutions are more likely to be inherited, while multiple nucleotide deletions or insertions are less frequently inherited, thus indicating that single nucleotide substitutions are more likely to originate from the paternal germline. Additionally, there seems to be a different distribution of nucleotide changes and multiple nucleotide deletions or insertions along the UBE3A gene sequence.

Isochromosome 14q in myeloid dysplastic disorder

A case of refractory anemia (RA) with an isochromosome 14q is described. This finding is compared with other hematologic disorders with trisomy 14 as the sole abnormality.

Cytogenetic study of a patient with the Sézary syndrome

A cytogenetic study was performed in a patient with Sézary syndrome, which is a T-helper lymphoproliferative disorder. Metaphases were obtained from a phytohemagglutinin-stimulated lymphocyte culture. Normal, hypodiploid (42 to 45 chromosomes) and hypotetraploid (84 to 88 chromosomes) cells were observed. Both abnormal cell lines showed the same abnormalities involving chromosomes 1, 2, 4, 6, 10, 11, 12, 14, 16, and 20.

Prader-Willi and Angelman syndromes: genetic counseling.

We read with great interest the recent Prader–Willi syndrome (PWS) and Angelman syndrome (AS) review articles by Cassidy and Driscoll (2009)1 and by Van Buggenhout and Fryns (2009),2 respectively. We completely agree with most of the contents. However, we consider it important to point out certain comments appearing in the genetic counseling section of both articles.

Appraisal of fluorescence in situ hybridization (FISH) techniques in prenatal diagnosis

The reliability of FISH was appraised using probes for the X and Y chromosome and for chromosomes 12 and 18 in prenatal and adult interphase nuclei. Detection of a single hybridization spot proved to be quite reliable (80-92% positive nuclei). Detection of two hybridization spots was more difficult; percentages of nuclei showing two signals varied between 62-72%. The percentages of nuclei with the correct number of spots was higher in the metaphases occasionally found. Thus, FISH may complement but not replace cytogenetic analysis. For sex determination and for the detection of mosaicism, we suggest the use of two different probes in separate regions of the same preparation.